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Sample records for igf-1 receptor igf-1r

  1. Effect Of IGF-1 On Expression Of Gh Receptor, IGF-1, IGF-1 ...

    African Journals Online (AJOL)

    ... and the skin expression of growth hormone receptor (GHR), insulin-like growth factor1 (IGF-1), insulin-like growth factor receptor (IGF- R), KAP3.2 and KAP6-1 mRNA were measured by RT-PCR. The results indicated that IGF-1 could degrade GHR gene expression, have no effect of IGF-1 and IGF-1R gene expression, ...

  2. Compensatory insulin receptor (IR) activation on inhibition of insulin-like growth factor-1 receptor (IGF-1R): rationale for cotargeting IGF-1R and IR in cancer.

    Science.gov (United States)

    Buck, Elizabeth; Gokhale, Prafulla C; Koujak, Susan; Brown, Eric; Eyzaguirre, Alexandra; Tao, Nianjun; Rosenfeld-Franklin, Maryland; Lerner, Lorena; Chiu, M Isabel; Wild, Robert; Epstein, David; Pachter, Jonathan A; Miglarese, Mark R

    2010-10-01

    Insulin-like growth factor-1 receptor (IGF-1R) is a receptor tyrosine kinase (RTK) and critical activator of the phosphatidylinositol 3-kinase-AKT pathway. IGF-1R is required for oncogenic transformation and tumorigenesis. These observations have spurred anticancer drug discovery and development efforts for both biological and small-molecule IGF-1R inhibitors. The ability for one RTK to compensate for another to maintain tumor cell viability is emerging as a common resistance mechanism to antitumor agents targeting individual RTKs. As IGF-1R is structurally and functionally related to the insulin receptor (IR), we asked whether IR is tumorigenic and whether IR-AKT signaling contributes to resistance to IGF-1R inhibition. Both IGF-1R and IR(A) are tumorigenic in a mouse mammary tumor model. In human tumor cells coexpressing IGF-1R and IR, bidirectional cross talk was observed following either knockdown of IR expression or treatment with a selective anti-IGF-1R antibody, MAB391. MAB391 treatment resulted in a compensatory increase in phospho-IR, which was associated with resistance to inhibition of IRS1 and AKT. In contrast, treatment with OSI-906, a small-molecule dual inhibitor of IGF-1R/IR, resulted in enhanced reduction in phospho-IRS1/phospho-AKT relative to MAB391. Insulin or IGF-2 activated the IR-AKT pathway and decreased sensitivity to MAB391 but not to OSI-906. In tumor cells with an autocrine IGF-2 loop, both OSI-906 and an anti-IGF-2 antibody reduced phospho-IR/phospho-AKT, whereas MAB391 was ineffective. Finally, OSI-906 showed superior efficacy compared with MAB391 in human tumor xenograft models in which both IGF-1R and IR were phosphorylated. Collectively, these data indicate that cotargeting IGF-1R and IR may provide superior antitumor efficacy compared with targeting IGF-1R alone.

  3. Gastric cancer: the role of insulin-like growth factor 2 (IGF 2) and its receptors (IGF 1R and M6-P/IGF 2R).

    Science.gov (United States)

    Pavelić, Kresimir; Kolak, Toni; Kapitanović, Sanja; Radosević, Senka; Spaventi, Sime; Kruslin, Bozo; Pavelić, Jasminka

    2003-11-01

    Insulin-like growth factor 2 (IGF 2) appears to be involved in the progression of many tumours. It binds to at least two different types of receptor: IGF type 1 (IGF 1R) and mannose 6-phosphate/IGF type 2 (M6-P/IGF 2R). Ligand binding to IGF 1R provokes mitogenic and anti-apoptotic effects. M6-P/IGF 2R has a tumour suppressor function--it mediates IGF 2 degradation. Mutation of M6-P/IGF 2R causes both diminished growth suppression and augmented growth stimulation. The aim of this study was to investigate the role of IGF 2 and its receptors (IGF 1R and IGF 2R) in human gastric cancer. The expression of IGF 2 and its receptors was measured in order to analyse the possible correlation between the activity of these genes and cell proliferation in two different gastric tumour types: diffuse and intestinal. The effect of IGF 1 receptor blockage on cell proliferation and anchorage-independent cell growth was also examined. Increased expression of IGF 2 and IGF 1R genes (at the mRNA and protein level) was found in gastric cancer when compared with non-tumour tissue. Furthermore, there was a significant difference between IGF 2 expression in the more aggressive diffuse type and that in the intestinal type of gastric cancer. Moreover, the IGF 2 peptide level in the culture media obtained from the diffuse type of cancer cells was significantly higher when compared with the intestinal type. The level of IGF 2 peptide in the conditioned media strongly correlated with [3H]thymidine incorporation and cell proliferation. On the contrary, IGF 2R mRNA expression was much higher in the intestinal type of cancer than in the diffuse type. In addition, IGF 2R protein expression was substantially lower with progression of the diffuse cancer type to a higher stage. The alphaIR3 monoclonal antibody strongly inhibited [3H]thymidine incorporation and decreased the number of colonies in soft agar of cells overexpressing IGF 2. These findings suggest that members of the IGF family are involved

  4. R1507, an Anti-Insulin-Like Growth Factor-1 Receptor (IGF-1R) Antibody, and EWS/FLI-1 siRNA in Ewing's Sarcoma: Convergence at the IGF/IGFR/Akt Axis

    Science.gov (United States)

    Rodon, Jordi; Sun, Michael; Kuenkele, Klaus-Peter; Parsons, Henrique A.; Trent, Jonathan C.; Kurzrock, Razelle

    2011-01-01

    A subset of patients with Ewing's sarcoma responds to anti-insulin-like growth factor-1 receptor (IGF-1R) antibodies. Mechanisms of sensitivity and resistance are unknown. We investigated whether an anti-IGF-1R antibody acts via a pathway that could also be suppressed by small interfering (si) RNA against the EWS/FLI-1 fusion protein, the hallmark of Ewing's sarcoma. The growth of two Ewing's sarcoma cell lines (TC-32 and TC-71) was inhibited by the fully human anti-IGF-1R antibody, R1507 (clonogenic and MTT assays). TC-32 and TC-71 cells express high levels of IGF-2, while RD-ES and A4573 Ewing's cell lines, which were less responsive to R1507 in our assays, express low or undetectable IGF-2, respectively. TC-71 cells also expressed high levels of IGF-1R, and R1507 decreased steady-state levels of this receptor by internalization/degradation, an effect which was associated with a decrease in p-IGF-1R, p-IRS-1, and p-Akt. EWS/FLI-1 siRNA also decreased p-Akt, due to its ability to increase IGF-BP3 levels and subsequently decrease IGF-1 and IGF-2 levels, thus inhibiting signaling through p-IGF-1R. This inhibition correlated with growth suppression and apoptosis. The attenuation of Akt activation was confirmed in TC-71 and HEK-293 (human embryonic kidney) cells by transfecting them with IGF-1R siRNA. We conclude that antibodies and siRNA to IGF-1R, as well as siRNA to EWS/FLI-1, act via intersecting IGF/IGF-1R signals that suppress a common point in this pathway, namely the phosphorylation of Akt. PMID:22022506

  5. R1507, an anti-insulin-like growth factor-1 receptor (IGF-1R antibody, and EWS/FLI-1 siRNA in Ewing's sarcoma: convergence at the IGF/IGFR/Akt axis.

    Directory of Open Access Journals (Sweden)

    Helen J Huang

    Full Text Available A subset of patients with Ewing's sarcoma responds to anti-insulin-like growth factor-1 receptor (IGF-1R antibodies. Mechanisms of sensitivity and resistance are unknown. We investigated whether an anti-IGF-1R antibody acts via a pathway that could also be suppressed by small interfering (si RNA against the EWS/FLI-1 fusion protein, the hallmark of Ewing's sarcoma. The growth of two Ewing's sarcoma cell lines (TC-32 and TC-71 was inhibited by the fully human anti-IGF-1R antibody, R1507 (clonogenic and MTT assays. TC-32 and TC-71 cells express high levels of IGF-2, while RD-ES and A4573 Ewing's cell lines, which were less responsive to R1507 in our assays, express low or undetectable IGF-2, respectively. TC-71 cells also expressed high levels of IGF-1R, and R1507 decreased steady-state levels of this receptor by internalization/degradation, an effect which was associated with a decrease in p-IGF-1R, p-IRS-1, and p-Akt. EWS/FLI-1 siRNA also decreased p-Akt, due to its ability to increase IGF-BP3 levels and subsequently decrease IGF-1 and IGF-2 levels, thus inhibiting signaling through p-IGF-1R. This inhibition correlated with growth suppression and apoptosis. The attenuation of Akt activation was confirmed in TC-71 and HEK-293 (human embryonic kidney cells by transfecting them with IGF-1R siRNA. We conclude that antibodies and siRNA to IGF-1R, as well as siRNA to EWS/FLI-1, act via intersecting IGF/IGF-1R signals that suppress a common point in this pathway, namely the phosphorylation of Akt.

  6. Autocrine IGF-1 Action in Adipocytes Controls Systemic IGF-1 Concentrations and Growth

    OpenAIRE

    Kl?ting, Nora; Koch, Linda; Wunderlich, Thomas; Kern, Matthias; Ruschke, Karen; Krone, Wilhelm; Br?ning, Jens C.; Bl?her, Matthias

    2008-01-01

    OBJECTIVE?IGF-1 and the IGF-1 receptor (IGF-1R) have been implicated in the regulation of adipocyte differentiation and lipid accumulation in vitro. RESEARCH DESIGN AND METHODS?To investigate the role of IGF-1 receptor in vivo, we have inactivated the Igf-1r gene in adipose tissue (IGF-1RaP2Cre mice) using conditional gene targeting strategies. RESULTS?Conditional IGF-1R inactivation resulted in increased adipose tissue mass with a predominantly increased lipid accumulation in epigonadal fat ...

  7. Human GH Receptor-IGF-1 Receptor Interaction: Implications for GH Signaling

    Science.gov (United States)

    Gan, Yujun; Buckels, Ashiya; Liu, Ying; Zhang, Yue; Paterson, Andrew J.; Jiang, Jing; Zinn, Kurt R.

    2014-01-01

    GH signaling yields multiple anabolic and metabolic effects. GH binds the transmembrane GH receptor (GHR) to activate the intracellular GHR-associated tyrosine kinase, Janus kinase 2 (JAK2), and downstream signals, including signal transducer and activator of transcription 5 (STAT5) activation and IGF-1 gene expression. Some GH effects are partly mediated by GH-induced IGF-1 via IGF-1 receptor (IGF-1R), a tyrosine kinase receptor. We previously demonstrated in non-human cells that GH causes formation of a GHR-JAK2-IGF-1R complex and that presence of IGF-1R (even without IGF-1 binding) augments proximal GH signaling. In this study, we use human LNCaP prostate cancer cells as a model system to further study the IGF-1R's role in GH signaling. GH promoted JAK2 and GHR tyrosine phosphorylation and STAT5 activation in LNCaP cells. By coimmunoprecipitation and a new split luciferase complementation assay, we find that GH augments GHR/IGF-1R complex formation, which is inhibited by a Fab of an antagonistic anti-GHR monoclonal antibody. Short hairpin RNA-mediated IGF-1R silencing in LNCaP cells reduced GH-induced GHR, JAK2, and STAT5 phosphorylation. Similarly, a soluble IGF-1R extracellular domain fragment (sol IGF-1R) interacts with GHR in response to GH and blunts GH signaling. Sol IGF-1R also markedly inhibits GH-induced IGF-1 gene expression in both LNCaP cells and mouse primary osteoblast cells. On the basis of these and other findings, we propose a model in which IGF-1R augments GH signaling by allowing a putative IGF-1R-associated molecule that regulates GH signaling to access the activated GHR/JAK2 complex and envision sol IGF-1R as a dominant-negative inhibitor of this IGF-1R-mediated augmentation. Physiological implications of this new model are discussed. PMID:25211187

  8. Impaired IGF1R signaling in cells expressing longevity-associated human IGF1R alleles

    OpenAIRE

    Tazearslan, Cagdas; Huang, Jing; Barzilai, Nir; Suh, Yousin

    2011-01-01

    Dampening of insulin/insulin like growth factor-1 (IGF1) signaling results in extension of lifespan in invertebrate as well as murine models. The impact of this evolutionarily conserved pathway on modulation of human lifespan remains unclear. We previously identified two IGF1R mutations (Ala-37-Thr and Arg-407-His) that are enriched in Ashkenazi Jewish centenarians as compared to younger controls and are associated with reduced activity of the IGF1 receptor as measured in immortalized lymphoc...

  9. Structural analysis of the interaction of IGF I with the IGF types 1 and 2 and insulin receptors

    International Nuclear Information System (INIS)

    Cascieri, M.A.; Chicchi, G.G.; Hayes, N.S.; Green, B.G.; Applebaum, J.A.; Bayne, M.L.

    1987-01-01

    A synthetic gene for human IGF I has been synthesized which directs the synthesis and secretion of fully active human IGF I (rIGF I) from yeast. rIGF I inhibits binding of 125 I-IGF I to type 1 IGF receptors from human placenta (IGF-R1, IC50 = 4 nM), binding of 125 I-insulin to insulin receptors (IR, IC50 = 881 nM), binding of 125 I-MSA to type 2 IGF receptors from rat liver (IGF-R2, IC50 = 80 nM), and binding of 125 I-IGF I to crude human serum binding protein (hBP, IC50 = 0.42 nM). rIGF I is equipotent to human IGF I in stimulating glucose transport in murine BC3H1 cells and in stimulating DNA synthesis in rat A10 cells. Site directed mutagenesis of the synthetic gene is being used to characterize the structural requirements for binding to these receptors. IGF I (FFY) B(23-25) is equipotent to rIGF I at the IGF-R1 (6.9 nM), the IGF-R2 (36 nM), and the IR (841 nM) and is less potent at the hBP (1.7 nM). In contrast, IGF I(SFY) B(23-25) is 20-fold less potent than rIGF I at the IGF-R1 and is 10-fold less potent than rIGF I at hBP. This peptide is greater than 10-fold less active at the IGF-R2 and the IR. This peptide is a full agonist in the cell assays but 20-50 fold less potent than rIGF I. These data are consistent with the hypothesis that the F to S change destabilizes the tertiary structure of IGF I

  10. S-nitrosylation of the IGF-1 receptor disrupts the cell proliferative action of IGF-1.

    Science.gov (United States)

    Okada, Kazushi; Zhu, Bao-Ting

    2017-09-30

    The insulin-like growth factor 1 receptor (IGF-1R) is a disulfide-linked heterotetramer containing two α-subunits and two β-subunits. Earlier studies demonstrate that nitric oxide (NO) can adversely affect IGF-1 action in the central nervous system. It is known that NO can induce S-nitrosylation of the cysteine residues in proteins, thereby partly contributing to the regulation of protein function. In the present study, we sought to determine whether S-nitrosylation of the cysteine residues in IGF-1R is an important post-translational modification that regulates its response to IGF-1. Using cultured SH-SY5Y human neuroblastoma cells as an in vitro model, we found that treatment of cells with S-nitroso-cysteine (SNOC), a NO donor that can nitrosylate the cysteine residues in proteins, induces S-nitrosylation of the β subunit of IGF-1R but not its α-subunit. IGF-1Rβ S-nitrosylation by SNOC is coupled with increased dissociation of the IGF-1R protein complex. In addition, disruption of the IGF-1R function resulting from S-nitrosylation of the IGF-1Rβ subunit is associated with disruption of the phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) signaling pathways. Further, we observed that SNOC-induced IGF-1Rβ S-nitrosylation results in a dose-dependent inhibition of cell proliferation and survival. Together, these results suggest that elevated nitrosative stress may result in dysfunction of cellular IGF-1R signaling through S-nitrosylation of the cysteine residues in the IGF-1Rβ subunit, thereby disrupting the downstream PI3K and MAPK signaling functions and ultimately resulting in inhibition of cell proliferation and survival. Copyright © 2017. Published by Elsevier Inc.

  11. SUMO-modified insulin-like growth factor 1 receptor (IGF-1R) increases cell cycle progression and cell proliferation.

    Science.gov (United States)

    Lin, Yingbo; Liu, Hongyu; Waraky, Ahmed; Haglund, Felix; Agarwal, Prasoon; Jernberg-Wiklund, Helena; Warsito, Dudi; Larsson, Olle

    2017-10-01

    Increasing number of studies have shown nuclear localization of the insulin-like growth factor 1 receptor (nIGF-1R) in tumor cells and its links to adverse clinical outcome in various cancers. Any obvious cell physiological roles of nIGF-1R have, however, still not been disclosed. Previously, we reported that IGF-1R translocates to cell nucleus and modulates gene expression by binding to enhancers, provided that the receptor is SUMOylated. In this study, we constructed stable transfectants of wild type IGF1R (WT) and triple-SUMO-site-mutated IGF1R (TSM) using igf1r knockout mouse fibroblasts (R-). Cell clones (R-WT and R-TSM) expressing equal amounts of IGF-1R were selected for experiments. Phosphorylation of IGF-1R, Akt, and Erk upon IGF-1 stimulation was equal in R-WT and R-TSM. WT was confirmed to enter nuclei. TSM did also undergo nuclear translocation, although to a lesser extent. This may be explained by that TSM heterodimerizes with insulin receptor, which is known to translocate to cell nuclei. R-WT proliferated substantially faster than R-TSM, which did not differ significantly from the empty vector control. Upon IGF-1 stimulation G1-S-phase progression of R-WT increased from 12 to 38%, compared to 13 to 20% of R-TSM. The G1-S progression of R-WT correlated with increased expression of cyclin D1, A, and CDK2, as well as downregulation of p27. This suggests that SUMO-IGF-1R affects upstream mechanisms that control and coordinate expression of cell cycle regulators. Further studies to identify such SUMO-IGF-1R dependent mechanisms seem important. © 2017 The Authors. Journal of Cellular Physiology Published by Wiley Periodicals Inc.

  12. Pancreatic Fibroblasts Stimulate the Motility of Pancreatic Cancer Cells through IGF1/IGF1R Signaling under Hypoxia.

    Directory of Open Access Journals (Sweden)

    Toshiki Hirakawa

    Full Text Available Pancreatic ductal adenocarcinoma (PDAC is characterized by its hypovascularity, with an extremely poor prognosis because of its highly invasive nature. PDAC proliferates with abundant stromal cells, suggesting that its invasive activity might be controlled by intercellular interactions between cancer cells and fibroblasts. Using four PDAC cell lines and two pancreas cancer-associated fibroblasts (CAFs, the expression of insulin-like growth factor-1 (IGF1 and IGF1 receptor (IGF1R was evaluated by RT-PCR, FACScan, western blot, or ELISA. Correlation between IGF1R and the hypoxia marker carbonic anhydrase 9 (CA9 was examined by immunohistochemical staining of 120 pancreatic specimens. The effects of CAFs, IGF1, and IGF1R inhibitors on the motility of cancer cells were examined by wound-healing assay or invasion assay under normoxia (20% O2 and hypoxia (1% O2. IGF1R expression was significantly higher in RWP-1, MiaPaCa-2, and OCUP-AT cells than in Panc-1 cells. Hypoxia increased the expression level of IGF1R in RWP-1, MiaPaCa-2, and OCUP-AT cells. CA9 expression was correlated with IGF1R expression in pancreatic specimens. CAFs produced IGF1 under hypoxia, but PDAC cells did not. A conditioned medium from CAFs, which expressed αSMA, stimulated the migration and invasion ability of MiaPaCa-2, RWP-1, and OCUP-AT cells. The motility of all PDAC cells was greater under hypoxia than under normoxia. The motility-stimulating ability of CAFs was decreased by IGF1R inhibitors. These findings might suggest that pancreas CAFs stimulate the invasion activity of PDAC cells through paracrine IGF1/IGF1R signaling, especially under hypoxia. Therefore the targeting of IGF1R signaling might represent a promising therapeutic approach in IGF1R-dependent PDAC.

  13. IGF-1 receptor inhibition by picropodophyllin in medulloblastoma

    Energy Technology Data Exchange (ETDEWEB)

    Ohshima-Hosoyama, Sachiko; Hosoyama, Tohru; Nelon, Laura D. [Greehey Children' s Cancer Research Institute, University of Texas Health Science Center, San Antonio, TX 78229 (United States); Keller, Charles, E-mail: keller@ohsu.edu [Greehey Children' s Cancer Research Institute, University of Texas Health Science Center, San Antonio, TX 78229 (United States); Department of Pediatrics, University of Texas Health Science Center, San Antonio, TX 78229 (United States); Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, TX 78229 (United States)

    2010-09-03

    Research highlights: {yields} Igf1r is overexpressed and activated in a Sonic Hedgehog driven model of medulloblastoma. {yields} Picropodophyllin targets and abrogates IGF signaling in medulloblastoma. {yields} Picropodophyllin inhibits medulloblastoma tumor cell growth by induction of apoptosis. -- Abstract: The insulin-like growth factor-1 receptor (Igf1r) is a multifunctional membrane-associated tyrosine kinase associated with regulation of transformation, proliferation, differentiation and apoptosis. Increased IGF pathway activity has been reported in human and murine medulloblastoma. Tumors from our genetically-engineered medulloblastoma mouse model over-express Igf1r, and thus this mouse model is a good platform with which to study the role of Igf1r in tumor progression. We hypothesize that inhibition of IGF pathway in medulloblastoma can slow or inhibit tumor growth and metastasis. To test our hypothesis, we tested the role of IGF in tumor growth in vitro by treatment with the tyrosine kinase small molecule inhibitor, picropodophyllin (PPP), which strongly inhibits the IGF pathway. Our results demonstrate that PPP-mediated downregulation of the IGF pathway inhibits mouse tumor cell growth and induces apoptotic cell death in vitro in primary medulloblastoma cultures that are most reflective of tumor cell behavior in vivo.

  14. IGF-1 receptor inhibition by picropodophyllin in medulloblastoma

    International Nuclear Information System (INIS)

    Ohshima-Hosoyama, Sachiko; Hosoyama, Tohru; Nelon, Laura D.; Keller, Charles

    2010-01-01

    Research highlights: → Igf1r is overexpressed and activated in a Sonic Hedgehog driven model of medulloblastoma. → Picropodophyllin targets and abrogates IGF signaling in medulloblastoma. → Picropodophyllin inhibits medulloblastoma tumor cell growth by induction of apoptosis. -- Abstract: The insulin-like growth factor-1 receptor (Igf1r) is a multifunctional membrane-associated tyrosine kinase associated with regulation of transformation, proliferation, differentiation and apoptosis. Increased IGF pathway activity has been reported in human and murine medulloblastoma. Tumors from our genetically-engineered medulloblastoma mouse model over-express Igf1r, and thus this mouse model is a good platform with which to study the role of Igf1r in tumor progression. We hypothesize that inhibition of IGF pathway in medulloblastoma can slow or inhibit tumor growth and metastasis. To test our hypothesis, we tested the role of IGF in tumor growth in vitro by treatment with the tyrosine kinase small molecule inhibitor, picropodophyllin (PPP), which strongly inhibits the IGF pathway. Our results demonstrate that PPP-mediated downregulation of the IGF pathway inhibits mouse tumor cell growth and induces apoptotic cell death in vitro in primary medulloblastoma cultures that are most reflective of tumor cell behavior in vivo.

  15. IGF-1-dependent subunit communication of the IGF-1 holoreceptor: Interactions between αβ heterodimeric receptor halves

    International Nuclear Information System (INIS)

    Wilden, P.A.; Treadway, J.L.; Morrison, B.D.; Pessin, J.E.

    1989-01-01

    Examination of 125 I-IGF-1 affinity cross-linking and β-subunit autophosphorylation has indicated that IGF-1 induces a covalent association of isolated αβ heterodimeric IGF-1 receptors into an α 2 β 2 heterotetrameric state, in a similar manner to that observed for the insulin receptor. The formation of the α 2 β 2 heterotetrameric IGF-1 receptor complex from the partially purified αβ heterodimers was time dependent with half-maximal formation in approximately 30 min at saturating IGF-1 concentrations. The IGF-1-dependent association of the partially purified αβ heterodimers into an α 2 β 2 heterotetrameric state was specific for the IGF-1 receptors since IGF-1 was unable to stimulate the protein kinase activity of the purified αβ heterodimeric insulin receptor complex. Incubation of the α 2 β 2 heterotetrameric IGF-1 holoreceptor with the specific sulfhydryl agent iodoacetamide (IAN) did not alter 125 I-IGF-1 binding or IGF-1 stimulation of protein kinase activity. However, IAN treatment of the αβ heterodimeric IGF-1 receptors inhibited the IGF-1 dependent covalent formation of the disulfide-linked α 2 β 2 heterotetrameric complex. These data indicate that IGF-1 induces the covalent association of isolated αβ heterodimeric IGF-1 receptor complexes into a disulfide-linked α 2 β 2 heterotetrameric state whereas Mn/MgATP induces a noncovalent association. Therefore, unlike the insulin receptor in which noncovalent association is sufficient for kinase activation, only the covalent assembly of the IGF-1 receptor αβ heterodimers into the α 2 β 2 heterotetrameric holoreceptor complex is associated with ligand-stimulated protein kinase activation

  16. Role of Ubiquitination in IGF-1 Receptor Signaling and Degradation

    OpenAIRE

    Sehat, Bita; Andersson, Sandra; Vasilcanu, Radu; Girnita, Leonard; Larsson, Olle

    2007-01-01

    BACKGROUND: The insulin-like growth factor 1 receptor (IGF-1R) plays numerous crucial roles in cancer biology. The majority of knowledge on IGF-1R signaling is concerned with its role in the activation of the canonical phosphatidyl inositol-3 kinase (PI3K)/Akt and MAPK/ERK pathways. However, the role of IGF-1R ubiquitination in modulating IGF-1R function is an area of current research. In light of this we sought to determine the relationship between IGF-1R phosphorylation, ubiquitination, and...

  17. Comparisons of mRNA expression for insulin-like growth factor (IGF) type 2 receptor (IGF2R) and IGF-1 in small ovarian follicles between cattle selected and not selected for twin ovulations

    Science.gov (United States)

    Both IGF-1 and -2 stimulate ovarian follicular cell proliferation and antral follicle development. Actions of IGF-1 and -2 are mediated through the IGF type 1 receptor, whereas binding of IGF-2 to the IGF2R results in its degradation. Information on the role of IGF2R in regulating bovine follicula...

  18. Branchial expression and localization of the insulin-like growth factor 1 (IGF-1) receptor and changes in plasma IGF-1 and IGF-1 binding protein in striped bass during salinity acclimation

    DEFF Research Database (Denmark)

    Tipsmark, Christian Kølbæk; Madsen, Steffen; Borski, Russell

    2006-01-01

    In euryhaline teleosts the insulin-like growth factor 1 (IGF-1)/growth hormone axis is known to affect salinity tolerance and gill Na,K-ATPase activity. However, virtually nothing is known on expression and cellular localization of the IGF-1 receptor (IGF-1R) in the teleost gill during salinity a...

  19. Cross-talk between Integrin α6β4 and Insulin-like Growth Factor-1 Receptor (IGF1R) through Direct α6β4 Binding to IGF1 and Subsequent α6β4-IGF1-IGF1R Ternary Complex Formation in Anchorage-independent Conditions*

    OpenAIRE

    Fujita, Masaaki; Ieguchi, Katsuaki; Davari, Parastoo; Yamaji, Satoshi; Taniguchi, Yukimasa; Sekiguchi, Kiyotoshi; Takada, Yoko K.; Takada, Yoshikazu

    2012-01-01

    Background: Integrin αvβ3-extracellular matrix interaction and/or αvβ3 binding to insulin-like growth factor-1 (IGF1; and integrin-IGF1-IGF1 receptor ternary complex formation) is critical for IGF signaling.

  20. IGF-1 receptor and IGF binding protein-3 might predict prognosis of patients with resectable pancreatic cancer

    International Nuclear Information System (INIS)

    Hirakawa, Toshiki; Yashiro, Masakazu; Murata, Akihiro; Hirata, Keiichiro; Kimura, Kenjiro; Amano, Ryosuke; Yamada, Nobuya; Nakata, Bunzo; Hirakawa, Kosei

    2013-01-01

    The present study aimed to elucidate the clinicopathologic role of insulin-like growth factor-1 receptor (IGF1R) and IGF binding protein-3 (IGFBP3) in patients with pancreatic cancer. The function of IGFBP3 is controversial, because both inhibition and facilitation of the action of IGF as well as IGF-independent effects have been reported. In this study, IGF1R and IGFBP3 expression was examined, and their potential roles as prognostic markers in patients with pancreatic cancer were evaluated. Clinicopathological features of 122 patients with curatively resected pancreatic cancer were retrospectively reviewed, and expression of IGF1R and IGFBP3 was immunohistochemically analyzed. Expression of IGF1R and IGFBP3 was observed in 50 (41.0%) and 37 (30.3%) patients, respectively. IGF1R expression was significantly associated with histological grade (p = 0.037). IGFBP3 expression had a significant association with tumor location (p = 0.023), and a significant inverse association with venous invasion (p = 0.037). Tumors with IGF1R-positive and IGFBP3-negative expression (n = 32) were significantly frequently Stage II and III (p = 0.011). The prognosis for IGF1R positive patients was significantly poorer than that for IGF1R negative patients (p = 0.0181). IGFBP3 protein expression did not correlate significantly with patient survival. The subset of patients with both positive IGF1R and negative IGFBP3 had worse overall survival (8.8 months versus 12.6 months, respectively, p < 0.001). IGF1R signaling might be associated with tumor aggressiveness, and IGFBP3 might show antiproliferative effects in pancreatic cancer. Both high IGF1R expression and low IGFBP3 expression represent useful prognostic markers for patients with curatively resected pancreatic cancer

  1. Prenatal stress affects insulin-like growth factor-1 (IGF-1) level and IGF-1 receptor phosphorylation in the brain of adult rats.

    Science.gov (United States)

    Basta-Kaim, Agnieszka; Szczesny, Ewa; Glombik, Katarzyna; Stachowicz, Katarzyna; Slusarczyk, Joanna; Nalepa, Irena; Zelek-Molik, Agnieszka; Rafa-Zablocka, Katarzyna; Budziszewska, Boguslawa; Kubera, Marta; Leskiewicz, Monika; Lason, Wladyslaw

    2014-09-01

    It has been shown that stressful events occurring in early life have a powerful influence on the development of the central nervous system. Insulin-like growth factor-1 (IGF-1) promotes the growth, differentiation and survival of both neurons and glial cells and is thought to exert antidepressant-like activity. Thus, it is possible that disturbances in the function of the IGF-1 system may be responsible for disturbances observed over the course of depression. Prenatal stress was used as a valid model of depression. Adult male offspring of control and stressed rat dams were subjected to behavioural testing (forced swim test). The level of IGF-1 in the blood and the expression of IGF-1, IGF-1R, and IRS-1/2 in the hippocampus and frontal cortex using RT-PCR, ELISA and western blotting were measured. In addition the effect of intracerebroventricularly administered IGF-1 and/or the IGF-1R receptor antagonist JB1 in the forced swim test was studied. Prenatally stressed rats showed depressive like behaviour, including increased immobility time as well as decreased mobility and climbing. Intracerebroventricular administration of IGF-1 reversed these effects in stressed animals, whereas concomitant administration of the IGF-1R antagonist JB1 completely blocked the effects. Biochemical analysis of homogenates from the hippocampus and frontal cortex revealed decreases in IGF-1 level and IGF-1R phosphorylation along with disturbances in IRS-1 phosphorylation. These findings reveal that prenatal stress alters IGF-1 signalling, which may contribute to the behavioural changes observed in depression. Copyright © 2014 Elsevier B.V. and ECNP. All rights reserved.

  2. Impact of IGF-1, IGF-1R, and IGFBP-3 promoter methylation on the risk and prognosis of esophageal carcinoma.

    Science.gov (United States)

    Ye, Peng; Qu, Chang-Fa; Hu, Xue-Lin

    2016-05-01

    The aim of this study is to investigate IGF-1, IGF-1R, and IGFBP-3 methylations in esophageal carcinoma (EC) patients and their relationship with the development and prognosis of EC. This study population consisted of 264 patients (case group) whom EC radical resection was performed and 283 healthy individuals (control group). Methylation-specific PCR (MSP) detected the methylation status of IGF-1, IGF-1R, and IGFBP-3 in the peripheral blood in both groups. The expressions of IGF-1, IGF-1R, and IGFBP-3 in EC and adjacent normal tissues were detected by immunohistochemistry (IHC). The methylation rates of IGF-1, IGF-1R, IGFBP3, and IGF-1 + IGF1R + IGFBP3 in the case group were higher than those in the control group (all P IGF-1, IGF-1R, IGFBP3, and IGF-1 + IGF1R + IGFBP3 IGF-1 among patients of different clinicopathological features (all P IGF-1 and IGF-1R in EC were significantly higher than those in adjacent normal tissues (both P IGF-1 and IGF1R gene promoter methylation was positively correlated with the positive expressions of IGF-1 (r = 0.139, P = 0.024) and IGF-1R (r = 0.135, P = 0.028), while the IGFBP3 methylation was negatively correlated with the positive expression of IGFBP3 (r = -0.133, P = 0.031). The positive expressions of IGF-1, IGF-1R, and IGFBP-3 were related to different clinicopathological features (all P IGF-1, IGF-1R, and IGF-1 + IGF1R + IGFBP3 ; expressions of IGF-1 and IGF-1R protein; infiltration depth; and lymph node metastasis (LNM) were independent factors of EC prognosis. Our study demonstrated that methylation of IGF-1, IGF1R, IGFBP3, and IGF-1 + IGF1R + IGFBP3 was closely linked with the occurrence of EC and patients' clinicopathological features. Besides, the methylation status of the target genes and the expressions of IGF-1 and IGF-1R protein were independent factors of EC prognosis, which could provide a direction for the prognosis and treatment of EC.

  3. IGF-1 receptor haploinsufficiency leads to age-dependent development of metabolic syndrome.

    Science.gov (United States)

    Thakur, Sachin; Garg, Neha; Zhang, Ning; Hussey, Sophie E; Musi, Nicolas; Adamo, Martin L

    2017-05-13

    Individuals born small for gestational age (SGA) are at a higher risk of developing the metabolic syndrome later in life. IGF-1 resistance has been reported in placentae from SGA births and mutations in the Igf1 receptor gene have been reported in several cohorts of SGA subjects. We have used the Igf1r heterozygous (Igf1r +/- ) male mouse as a model to investigate the mechanisms by which Igf1r haploinsufficiency leads to insulin resistance. Despite exhibiting IGF-1 resistance, insulin signaling is enhanced in young Igf1r +/- mice but is attenuated in the muscle of old Igf1r +/- mice. Although smaller than WT (wild type) mice, old-aged Igf1r +/- had increased adiposity and exhibit increased lipogenesis. We hypothesize that IGF-1 resistance initially causes a transient increase in insulin signaling thereby promoting a lipogenic phenotype, which subsequently leads to insulin resistance. Copyright © 2017. Published by Elsevier Inc.

  4. MiR-223 suppresses cell proliferation by targeting IGF-1R.

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    Cheng You Jia

    Full Text Available To study the roles of microRNA-223 (miR-223 in regulation of cell growth, we established a miR-223 over-expression model in HeLa cells infected with miR-223 by Lentivirus pLL3.7 system. We observed in this model that miR-223 significantly suppressed the proliferation, growth rate, colony formation of HeLa cells in vitro, and in vivo tumorigenicity or tumor formation in nude mice. To investigate the mechanisms involved, we scanned and examined the potential and putative target molecules of miR-223 by informatics, quantitative PCR and Western blot, and found that insulin-like growth factor-1 receptor (IGF-1R was the functional target of miR-223 inhibition of cell proliferation. Targeting IGF-1R by miR-223 was not only seen in HeLa cells, but also in leukemia and hepatoma cells. The downstream pathway, Akt/mTOR/p70S6K, to which the signal was mediated by IGF-1R, was inhibited as well. The relative luciferase activity of the reporter containing wild-type 3'UTR(3'untranslated region of IGF-1R was significantly suppressed, but the mutant not. Silence of IGF-1R expression by vector-based short hairpin RNA resulted in the similar inhibition with miR-223. Contrarily, rescued IGF-1R expression in the cells that over-expressed miR-223, reversed the inhibition caused by miR-223 via introducing IGF-1R cDNA that didn't contain the 3'UTR. Meanwhile, we also noted that miR-223 targeted Rasa1, but the downstream molecules mediated by Rasa1 was neither targeted nor regulated. Therefore we believed that IGF-1R was the functional target for miR-223 suppression of cell proliferation and its downstream PI3K/Akt/mTOR/p70S6K pathway suppressed by miR-223 was by targeting IGF-1R.

  5. Expression of IGF-I, IGF-I receptor and IGF binding proteins-1, -2, -3, -4 and -5 in human atherectomy specimens.

    Science.gov (United States)

    Grant, M B; Wargovich, T J; Ellis, E A; Tarnuzzer, R; Caballero, S; Estes, K; Rossing, M; Spoerri, P E; Pepine, C

    1996-12-17

    The molecular and cellular processes that induce rapid atherosclerotic plaque progression in patients with unstable angina and initiate restenosis following coronary interventional procedures are uncertain. We examined primary (de novo) and restenotic lesions retrieved at the time of directional coronary atherectomy for expression of insulin-like-growth factor-I (IGF-I). IGF-I receptor, and five IGF binding proteins (IGFBPs), IGFBP-1, IGFBP-2, IGFBP-3, IGFBP-4, and IGFBP-5 in smooth muscle cells (SMCs) using colloidal gold immunocytochemistry. IGF-1, its receptor and binding proteins were not detected in SMCs of normal coronary arteries. IGF-I localized primarily in synthetic smooth muscle cells (sSMCs) in both de novo and restenotic plaques. IGF-I receptor localized on sSMCs and their processes and colocalized with IGF-I. Although morphometric analysis of IGF-I and IGF-I receptor immunoreactivity in sSMCs of de novo and restenotic lesions showed comparable levels of IGF-I (3.2 +/- 1.0 and 2.9 +/- 0.9, respectively). IGF-I receptor was significantly higher in de novo lesions as compared to restenotic lesions (10.7 +/- 2.5 and 4.2 +/- 1.3, P system.

  6. IGF-1/IGF-1R/hsa-let-7c axis regulates the committed differentiation of stem cells from apical papilla

    Science.gov (United States)

    Ma, Shu; Liu, Genxia; Jin, Lin; Pang, Xiyao; Wang, Yanqiu; Wang, Zilu; Yu, Yan; Yu, Jinhua

    2016-01-01

    Insulin-like growth factor-1 (IGF-1) and its receptor IGF-1R play a paramount role in tooth/bone formation while hsa-let-7c actively participates in the osteogenic differentiation of mesenchymal stem cells. However, the interaction between IGF-1/IGF-1R and hsa-let-7c on the committed differentiation of stem cells from apical papilla (SCAPs) remains unclear. In this study, human SCAPs were isolated and treated with IGF-1 and hsa-let-7c over/low-expression viruses. The odonto/osteogenic differentiation of these stem cells and the involvement of mitogen-activated protein kinase (MAPK) pathway were subsequently investigated. Alizarin red staining showed that hsa-let-7c low-expression can significantly promote the mineralization of IGF-1 treated SCAPs, while hsa-let-7c over-expression can decrease the calcium deposition of IGF-1 treated SCAPs. Western blot assay and real-time reverse transcription polymerase chain reaction further demonstrated that the expression of odonto/osteogenic markers (ALP, RUNX2/RUNX2, OSX/OSX, OCN/OCN, COL-I/COL-I, DSPP/DSP, and DMP-1/DMP-1) in IGF-1 treated SCAPs were significantly upregulated in Let-7c-low group. On the contrary, hsa-let-7c over-expression could downregulate the expression of these odonto/osteogenic markers. Moreover, western blot assay showed that the JNK and p38 MAPK signaling pathways were activated in Let-7c-low SCAPs but inhibited in Let-7c-over SCAPs. Together, the IGF-1/IGF-1R/hsa-let-7c axis can control the odonto/osteogenic differentiation of IGF-1-treated SCAPs via the regulation of JNK and p38 MAPK signaling pathways. PMID:27833148

  7. Type 1 IGF receptor translocates to the nucleus of human tumor cells

    OpenAIRE

    Aleksic, Tamara; Chitnis, Meenali M.; Perestenko, Olga V.; Gao, Shan; Thomas, Peter H.; Turner, Gareth D.; Protheroe, Andrew S.; Howarth, Mark; Macaulay, Valentine M.

    2010-01-01

    The type 1 insulin-like growth factor receptor (IGF-1R) is a transmembrane glycoprotein comprising two extracellular α subunits and two β subunits with tyrosine kinase activity. The IGF-1R is frequently upregulated in cancers, and signals from the cell surface to promote proliferation and cell survival. Recent attention has focused on the IGF-1R as a target for cancer treatment. Here we report that the nuclei of human tumor cells contain IGF-1R, detectable using multiple antibodies to α- and ...

  8. Role of IGF-1R in ameliorating apoptosis of GNE deficient cells.

    Science.gov (United States)

    Singh, Reema; Chaudhary, Priyanka; Arya, Ranjana

    2018-05-09

    Sialic acids (SAs) are nine carbon acidic amino sugars, found at the outermost termini of glycoconjugates performing various physiological and pathological functions. SA synthesis is regulated by UDP-GlcNAc 2-epimerase/ManNAc kinase (GNE) that catalyzes rate limiting steps. Mutations in GNE result in rare genetic disorders, GNE myopathy and Sialuria. Recent studies indicate an alternate role of GNE in cell apoptosis and adhesion, besides SA biosynthesis. In the present study, using a HEK cell-based model for GNE myopathy, the role of Insulin-like Growth Factor Receptor (IGF-1R) as cell survival receptor protein was studied to counter the apoptotic effect of non-functional GNE. In the absence of functional GNE, IGF-1R was hyposialylated and transduced a downstream signal upon IGF-1 (IGF-1R ligand) treatment. IGF-1 induced activation of IGF-1R led to AKT (Protein Kinase B) phosphorylation that may phosphorylate BAD (BCL2 Associated Death Promoter) and its dissociation from BCL2 to prevent apoptosis. However, reduced ERK (Extracellular signal-regulated kinases) phosphorylation in GNE deficient cells after IGF-1 treatment suggests downregulation of the ERK pathway. A balance between the ERK and AKT pathways may determine the cell fate towards survival or apoptosis. Our study suggests that IGF-1R activation may rescue apoptotic cell death of GNE deficient cell lines and has potential as therapeutic target.

  9. The strength of small: Improved targeting of Insulin-like Growth Factor-1 Receptor (IGF-1R) with F(ab')2-R1507 fragments in Ewing sarcomas

    NARCIS (Netherlands)

    Fleuren, Emmy D. G.; Versleijen-Jonkers, Yvonne M. H.; Heskamp, Sandra; Roeffen, Melissa H. S.; Bouwman, Wilbert H.; Molkenboer-Kuenen, Janneke D. M.; van Laarhoven, Hanneke W. M.; Oyen, Wim J. G.; Boerman, Otto C.; van der Graaf, Winette T. A.

    2013-01-01

    To investigate whether F(ab')2-fragments of the monoclonal Insulin-like Growth Factor-1 Receptor (IGF-1R) antibody R1507 (F(ab')2-R1507) can successfully target IGF-1R in Ewing sarcomas (ES). BALB/c nude mice were subcutaneously implanted with IGF-1R-expressing human ES xenografts (EW-5 and EW-8)

  10. Differential Role of Insulin/IGF-1 Receptor Signaling in Muscle Growth and Glucose Homeostasis

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    Brian T. O’Neill

    2015-05-01

    Full Text Available Insulin and insulin-like growth factor 1 (IGF-1 are major regulators of muscle protein and glucose homeostasis. To determine how these pathways interact, we generated mice with muscle-specific knockout of IGF-1 receptor (IGF1R and insulin receptor (IR. These MIGIRKO mice showed >60% decrease in muscle mass. Despite a complete lack of insulin/IGF-1 signaling in muscle, MIGIRKO mice displayed normal glucose and insulin tolerance. Indeed, MIGIRKO mice showed fasting hypoglycemia and increased basal glucose uptake. This was secondary to decreased TBC1D1 resulting in increased Glut4 and Glut1 membrane localization. Interestingly, overexpression of a dominant-negative IGF1R in muscle induced glucose intolerance in MIGIRKO animals. Thus, loss of insulin/IGF-1 signaling impairs muscle growth, but not whole-body glucose tolerance due to increased membrane localization of glucose transporters. Nonetheless, presence of a dominant-negative receptor, even in the absence of functional IR/IGF1R, induces glucose intolerance, indicating that interactions between these receptors and other proteins in muscle can impair glucose homeostasis.

  11. Essential role of flotillin-1 palmitoylation in the intracellular localization and signaling function of IGF-1 receptor.

    Science.gov (United States)

    Jang, Donghwan; Kwon, Hayeong; Jeong, Kyuho; Lee, Jaewoong; Pak, Yunbae

    2015-06-01

    Here, we explored flotillin-1-mediated regulation of insulin-like growth factor-1 (IGF-1) signaling. Flotillin-1-deficient cells exhibited a reduction in the activation of IGF-1 receptor (IGF-1R), ERK1/2 and Akt pathways, and the transcriptional activation of Elk-1 and the proliferation in response to IGF-1 were reduced in these cells. We found that IGF-1-independent flotillin-1 palmitoylation at Cys34 in the endoplasmic reticulum (ER) was required for the ER exit and the plasma membrane localization of flotillin-1 and IGF-1R. IGF-1-dependent depalmitoylation and repalmitoylation of flotillin-1 sustained tyrosine kinase activation of the plasma-membrane-targeted IGF-1R. Dysfunction and blocking the turnover of flotillin-1 palmitoylation abrogated cancer cell proliferation after IGF-1R signaling activation. Our data show that flotillin-1 palmitoylation is a new mechanism by which the intracellular localization and activation of IGF-1R are controlled. © 2015. Published by The Company of Biologists Ltd.

  12. Role of IGF1R in breast cancer subtypes, stemness, and lineage differentiation

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    Susan M Farabaugh

    2015-04-01

    Full Text Available Insulin-like growth factor (IGF signaling is fundamental for growth and survival. A large body of evidence (laboratory, epidemiological, and clinical implicates the exploitation of this pathway in cancer. Up to 50% of breast tumors express the activated form of the IGF1 receptor (IGF1R. Breast cancers are categorized into subtypes based upon hormone and ERRB2 receptor expression and/or gene expression profiling. Even though IGF1R influences tumorigenic phenotypes and drug resistance across all breast cancer subtypes, it has specific expression and function in each. In some subtypes, IGF1R levels correlate with a favorable prognosis, while in others it is associated with recurrence and poor prognosis, suggesting different actions based upon cellular and molecular contexts. In this review, we examine IGF1R expression and function as it relates to breast cancer subtype and therapy-acquired resistance. Additionally, we discuss the role of IGF1R in stem cell maintenance and lineage differentiation and how these cell fate influences may alter the differentiation potential and cellular composition of breast tumors.

  13. IRS-1 acts as an endocytic regulator of IGF-I receptor to facilitate sustained IGF signaling.

    Science.gov (United States)

    Yoneyama, Yosuke; Lanzerstorfer, Peter; Niwa, Hideaki; Umehara, Takashi; Shibano, Takashi; Yokoyama, Shigeyuki; Chida, Kazuhiro; Weghuber, Julian; Hakuno, Fumihiko; Takahashi, Shin-Ichiro

    2018-04-11

    Insulin-like growth factor-I receptor (IGF-IR) preferentially regulates the long-term IGF activities including growth and metabolism. Kinetics of ligand-dependent IGF-IR endocytosis determines how IGF induces such downstream signaling outputs. Here, we find that the insulin receptor substrate (IRS)-1 modulates how long ligand-activated IGF-IR remains at the cell surface before undergoing endocytosis in mammalian cells. IRS-1 interacts with the clathrin adaptor complex AP2. IRS-1, but not an AP2-binding-deficient mutant, delays AP2-mediated IGF-IR endocytosis after the ligand stimulation. Mechanistically, IRS-1 inhibits the recruitment of IGF-IR into clathrin-coated structures; for this reason, IGF-IR avoids rapid endocytosis and prolongs its activity on the cell surface. Accelerating IGF-IR endocytosis via IRS-1 depletion induces the shift from sustained to transient Akt activation and augments FoxO-mediated transcription. Our study establishes a new role for IRS-1 as an endocytic regulator of IGF-IR that ensures sustained IGF bioactivity, independent of its classic role as an adaptor in IGF-IR signaling. © 2018, Yoneyama et al.

  14. Targeted Morphoproteomic Profiling of Ewing's Sarcoma Treated with Insulin-Like Growth Factor 1 Receptor (IGF1R) Inhibitors: Response/Resistance Signatures

    Science.gov (United States)

    Subbiah, Vivek; Naing, Aung; Brown, Robert E.; Chen, Helen; Doyle, Laurence; LoRusso, Patricia; Benjamin, Robert; Anderson, Pete; Kurzrock, Razelle

    2011-01-01

    Background Insulin-like growth factor 1 receptor (IGF1R) targeted therapies have resulted in responses in a small number of patients with advanced metastatic Ewing's sarcoma. We performed morphoproteomic profiling to better understand response/resistance mechanisms of Ewing's sarcoma to IGF1R inhibitor-based therapy. Methodology/Principal Findings This pilot study assessed two patients with advanced Ewing's sarcoma treated with IGF1R antibody alone followed by combined IGF1R inhibitor plus mammalian target of rapamycin (mTOR) inhibitor treatment once resistance to single-agent IGF1R inhibitor developed. Immunohistochemical probes were applied to detect p-mTOR (Ser2448), p-Akt (Ser473), p-ERK1/2 (Thr202/Tyr204), nestin, and p-STAT3 (Tyr 705) in the original and recurrent tumor. The initial remarkable radiographic responses to IGF1R-antibody therapy was followed by resistance and then response to combined IGF1R plus mTOR inhibitor therapy in both patients, and then resistance to the combination regimen in one patient. In patient 1, upregulation of p-Akt and p-mTOR in the tumor that relapsed after initial response to IGF1R antibody might explain the resistance that developed, and the subsequent response to combined IGF1R plus mTOR inhibitor therapy. In patient 2, upregulation of mTOR was seen in the primary tumor, perhaps explaining the initial response to the IGF1R and mTOR inhibitor combination, while the resistant tumor that emerged showed activation of the ERK pathway as well. Conclusion/Significance Morphoproteomic analysis revealed that the mTOR pathway was activated in these two patients with advanced Ewing's sarcoma who showed response to combined IGF1R and mTOR inhibition, and the ERK pathway in the patient in whom resistance to this combination emerged. Our pilot results suggests that morphoproteomic assessment of signaling pathway activation in Ewing's sarcoma merits further investigation as a guide to understanding response and resistance signatures. PMID

  15. Nuclear targeting of IGF-1 receptor in orbital fibroblasts from Graves' disease: apparent role of ADAM17.

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    Neil Hoa

    Full Text Available Insulin-like growth factor-1 receptor (IGF-1R comprises two subunits, including a ligand binding domain on extra- cellular IGF-1Rα and a tyrosine phosphorylation site located on IGF-1Rβ. IGF-1R is over-expressed by orbital fibroblasts in the autoimmune syndrome, Graves' disease (GD. When activated by IGF-1 or GD-derived IgG (GD-IgG, these fibroblasts produce RANTES and IL-16, while those from healthy donors do not. We now report that IGF-1 and GD-IgG provoke IGF-1R accumulation in the cell nucleus of GD fibroblasts where it co-localizes with chromatin. Nuclear IGF-1R is detected with anti-IGF-1Rα-specific mAb and migrates to approximately 110 kDa, consistent with its identity as an IGF-1R fragment. Nuclear IGF-1R migrating as a 200 kDa protein and consistent with an intact receptor was undetectable when probed with either anti-IGF-1Rα or anti-IGF-1Rβ mAbs. Nuclear redistribution of IGF-1R is absent in control orbital fibroblasts. In GD fibroblasts, it can be abolished by an IGF-1R-blocking mAb, 1H7 and by physiological concentrations of glucocorticoids. When cell-surface IGF-1R is cross-linked with (125I IGF-1, (125I-IGF-1/IGF-1R complexes accumulate in the nuclei of GD fibroblasts. This requires active ADAM17, a membrane associated metalloproteinase, and the phosphorylation of IGF-1R. In contrast, virally encoded IGF-1Rα/GFP fusion protein localizes equivalently in nuclei in both control and GD fibroblasts. This result suggests that generation of IGF-1R fragments may limit the accumulation of nuclear IGF-1R. We thus identify a heretofore-unrecognized behavior of IGF-1R that appears limited to GD-derived fibroblasts. Nuclear IGF-1R may play a role in disease pathogenesis.

  16. IGF-I stimulates ERβ and aromatase expression via IGF1R/PI3K/AKT-mediated transcriptional activation in endometriosis.

    Science.gov (United States)

    Zhou, Yan; Zeng, Cheng; Li, Xin; Wu, Pei-Li; Yin, Ling; Yu, Xiao-Lan; Zhou, Ying-Fang; Xue, Qing

    2016-08-01

    Estrogen receptor beta (ERβ, encoded by ESR2 gene) and cytochrome P450 aromatase (encoded by CYP19A1 gene) play critical roles in endometriosis, and the levels of insulin-like growth factor-I (IGF-I) in the peritoneal fluid are significantly higher in patients with endometriosis compared with those in normal women. However, the effects and mechanisms of IGF-I on ERβ and aromatase expression remain to be fully elucidated. In this study, human endometriotic stromal cells (ESCs) and endometrial cells (EMs) derived from ovarian endometriomas and eutopic endometrial tissues. ESCs were cultured with IGF-I, signal pathway inhibitors, and siRNAs. ERβ and aromatase expression were measured by real-time PCR and Western, respectively. The binding of c-Jun and CREB to the ESR2 and CYP19A1 promoters was assessed by chromatin immunoprecipitation assay. Animal experiments were performed in a xenograft mouse model. Levels of IGF-I mRNA in ESCs were markedly higher than those in EMs. IGF-I upregulated ERβ and aromatase expression in ESCs after stimulation of the IGF1R/PI3K/AKT pathway. Following IGF-I treatment, a marked increase in c-Jun and CREB phosphorylation occurred, enhancing binding to the ESR2 and CYP19A1 promoters. An IGF1R inhibitor in vivo reduced IGF-I-induced endometriosis graft growth and ERβ and aromatase expression. In conclusion, this is the first report to describe a mechanistic analysis of ERβ and aromatase expression regulated by IGF-I in ESCs. Moreover, an IGF1R inhibitor impeded ectopic lesion growth in nude mice. These findings suggest that an inhibitor of IGF1R might have therapeutic potential as an antiendometriotic drug. Level of IGF-I mRNA in ESCs is markedly higher than that in EMs. IGF-I up-regulates ERβ and aromatase expression via IGF1R/PI3K/AKT pathway. C-Jun and CREB are recruited to ESR2 or CYP19A1 promoter by IGF-I stimulation. IGF-1R inhibitors in vivo impede the growth of ectopic lesions in nude mice.

  17. Targeting the IGF-1R: The Tale of The Tortoise and The Hare

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    Caitrin eCrudden

    2015-04-01

    Full Text Available The insulin-like growth factor type 1 receptor (IGF-1R plays a key role in the development and maintenance of cancer. Since the first links between growth factor receptors and oncogenes were noted over three decades ago, targeting the IGF-1R has been of great interest. This review follows the progress from inception through intense pharmaceutical development, disappointing clinical trials and recent updates to the signaling paradigm. In light of major developments in signaling understanding and activation complexities, we examine reasons for failure of first line targeting approaches. Recent findings include the fact that the IGF-1R can signal in the absence of the ligand, in the absence of kinase activity and utilizes components of the GPCR system. With recognition of the unappreciated complexities that this first wave of targeting approaches encountered, we advocate recognition of IGF-1R as a valid target for cancer treatment and look to future directions, where both research and pharmaceutical strengths can lend themselves to finally unearthing anti-IGF-1R potential.

  18. Complement component 1, q subcomponent binding protein (C1QBP) in lipid rafts mediates hepatic metastasis of pancreatic cancer by regulating IGF-1/IGF-1R signaling.

    Science.gov (United States)

    Shi, Haojun; Fang, Winston; Liu, Minda; Fu, Deliang

    2017-10-01

    Pancreatic cancer shows a remarkable predilection for hepatic metastasis. Complement component 1, q subcomponent binding protein (C1QBP) can mediate growth factor-induced cancer cell chemotaxis and distant metastasis by activation of receptor tyrosine kinases. Coincidentally, insulin-like growth factor-1 (IGF-1) derived from the liver and cancer cells itself has been recognized as a critical inducer of hepatic metastasis. However, the mechanism underlying IGF-1-dependent hepatic metastasis of pancreatic cancer, in which C1QBP may be involved, remains unknown. In the study, we demonstrated a significant association between C1QBP expression and hepatic metastasis in patients with pancreatic cancer. IGF-1 induced the translocation of C1QBP from cytoplasm to lipid rafts and further drove the formation of CD44 variant 6 (CD44v6)/C1QBP complex in pancreatic cancer cells. C1QBP interacting with CD44v6 in lipid rafts promoted phosphorylation of IGF-1R and thus activated downstream PI3K and MAPK signaling pathways which mediated metastatic potential of pancreatic cancer cells including proliferation, apoptosis, invasion, adhesion and energy metabolism. Furthermore, C1QBP knockdown suppressed hepatic metastasis of pancreatic cancer cells in nude mice. We therefore conclude that C1QBP in lipid rafts serves a key regulator of IGF-1/IGF-1R-induced hepatic metastasis from pancreatic cancer. Our findings about C1QBP in lipid rafts provide a novel strategy to block IGF-1/IGF-1R signaling in pancreatic cancer and a reliable premise for more efficient combined modality therapies. © 2017 UICC.

  19. Discovery of OSI-906: a selective and orally efficacious dual inhibitor of the IGF-1 receptor and insulin receptor.

    Science.gov (United States)

    Mulvihill, Mark J; Cooke, Andrew; Rosenfeld-Franklin, Maryland; Buck, Elizabeth; Foreman, Ken; Landfair, Darla; O'Connor, Matthew; Pirritt, Caroline; Sun, Yingchaun; Yao, Yan; Arnold, Lee D; Gibson, Neil W; Ji, Qun-Sheng

    2009-09-01

    The IGF-1 receptor (IGF-1R) has been implicated in the promotion of tumorigenesis, metastasis and resistance to cancer therapies. Therefore, this receptor has become a major focus for the development of anticancer agents. Our lead optimization efforts that blended structure-based design and empirical medicinal chemistry led to the discovery of OSI-906, a novel small-molecule dual IGF-1R/insulin receptor (IR) kinase inhibitor. OSI-906 potently and selectively inhibits autophosphorylation of both human IGF-1R and IR, displays in vitro antiproliferative effects in a variety of tumor cell lines and shows robust in vivo anti-tumor efficacy in an IGF-1R-driven xenograft model when administered orally once daily. OSI-906 is a novel, potent, selective and orally bioavailable dual IGF-1R/IR kinase inhibitor with favorable preclinical drug-like properties, which has demonstrated in vivo efficacy in tumor models and is currently in clinical testing.

  20. IGF1R- and ROR1-Specific CAR T Cells as a Potential Therapy for High Risk Sarcomas.

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    Xin Huang

    Full Text Available Patients with metastatic or recurrent and refractory sarcomas have a dismal prognosis. Therefore, new targeted therapies are urgently needed. This study was designed to evaluate chimeric antigen receptor (CAR T cells targeting the type I insulin-like growth factor receptor (IGF1R or tyrosine kinase-like orphan receptor 1 (ROR1 molecules for their therapeutic potential against sarcomas. Here, we report that IGF1R (15/15 and ROR1 (11/15 were highly expressed in sarcoma cell lines including Ewing sarcoma, osteosarcoma, alveolar or embryonal rhabdomyosarcoma, and fibrosarcoma. IGF1R and ROR1 CAR T cells derived from eight healthy donors using the Sleeping Beauty (SB transposon system were cytotoxic against sarcoma cells and produced high levels of IFN-γ, TNF-α and IL-13 in an antigen-specific manner. IGF1R and ROR1 CAR T cells generated from three sarcoma patients released significant amounts of IFN-γ in response to sarcoma stimulation. The adoptive transfer of IGF1R and ROR1 CAR T cells derived from a sarcoma patient significantly reduced tumor growth in pre-established, systemically disseminated and localized osteosarcoma xenograft models in NSG mice. Infusion of IGF1R and ROR1 CAR T cells also prolonged animal survival in a localized sarcoma model using NOD/scid mice. Our data indicate that both IGF1R and ROR1 can be effectively targeted by SB modified CAR T cells and that such CAR T cells may be useful in the treatment of high risk sarcoma patients.

  1. Gene Expression of IGF1, IGF1R, and IGFBP3 in Epiretinal Membranes of Patients with Proliferative Diabetic Retinopathy: Preliminary Study

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    Dorota Romaniuk

    2013-01-01

    Full Text Available The molecular mechanism formation of secondary epiretinal membranes (ERMs after proliferative diabetic retinopathy (PDR or primary idiopathic ERMs is still poorly understood. Therefore, the present study focused on the assessment of IGF1, IGF1R, and IGFBP3 mRNA levels in ERMs and PBMCs from patients with PDR. The examined group comprised 6 patients with secondary ERMs after PDR and the control group consisted of 11 patients with idiopathic ERMs. Quantification of IGF1, IGF1R, and IGFBP3 mRNAs was performed by real-time QRT-PCR technique. In ERMs, IGF1 and IGF1R mRNA levels were significantly higher in patients with diabetes compared to control subjects. In PBMCs, there were no statistically significant differences of IGF1, IGF1R, and IGFBP3 expression between diabetic and nondiabetic patients. In conclusion, our study indicated IGF1 and IGF1R differential expression in ERMs, but not in PBMCs, of diabetic and nondiabetic patients, suggesting that these factors can be involved in the pathogenesis or progression of proliferative vitreoretinal disorders. This trial is registered with NCT00841334.

  2. Evidence That Graves' Ophthalmopathy Immunoglobulins Do Not Directly Activate IGF-1 Receptors.

    Science.gov (United States)

    Marcus-Samuels, Bernice; Krieger, Christine C; Boutin, Alisa; Kahaly, George J; Neumann, Susanne; Gershengorn, Marvin C

    2018-05-01

    Graves' ophthalmopathy (GO) pathogenesis involves thyrotropin (TSH) receptor (TSHR)-stimulating autoantibodies. Whether there are autoantibodies that directly stimulate insulin-like growth factor 1 receptors (IGF-1Rs), stimulating insulin-like growth factor receptor antibodies (IGFRAbs), remains controversial. This study attempted to determine whether there are stimulating IGFRAbs in patients with GO. Immunoglobulins (Igs) were purified from normal volunteers (NV-Igs) and patients with GO (GO-Igs). The effects of TSH, IGF-1, NV-Igs, and GO-Igs on pAKT and pERK1/2, members of pathways used by IGF-1R and TSHR, were compared in orbital fibroblasts from GO patients (GOFs) and U2OS-TSHR cells overexpressing TSHRs, and U2OS cells that express TSHRs at very low endogenous levels. U2OS-TSHR and U2OS cells were used because GOFs are not easily manipulated using molecular techniques such as transfection, and U2OS cells because they express TSHRs at levels that do not measurably stimulate signaling. Thus, comparing U2OS-TSHR and U2OS cells permits specifically distinguishing signaling mediated by the TSHR and IGF-1R. In GOFs, all GO-Igs stimulated pERK1/2 formation and 69% stimulated pAKT. In U2OS-TSHR cells, 15% of NV-IGs and 83% of GO-Igs stimulated increases in pERK1/2, whereas all NV-Igs and GO-Igs stimulated increases in pAKT. In U2OS cells, 70% of GO-Igs stimulated small increases in pAKT. Knockdown of IGF-1R caused a 65 ± 6.3% decrease in IGF-1-stimulated pAKT but had no effect on GO-Igs stimulation of pAKT. Thus, GO-Igs contain factor(s) that stimulate pAKT formation. However, this factor(s) does not directly activate IGF-1R. Based on the findings analyzing these two signaling pathways, it is concluded there is no evidence of stimulating IGFRAbs in GO patients.

  3. Type 1 IGF Receptor Localization in Paediatric Gliomas: Significant Association with WHO Grading and Clinical Outcome.

    Science.gov (United States)

    Clément, Florencia; Martin, Ayelen; Venara, Marcela; de Luján Calcagno, Maria; Mathó, Cecilia; Maglio, Silvana; Lombardi, Mercedes García; Bergadá, Ignacio; Pennisi, Patricia A

    2018-06-01

    Nuclear localization of insulin-like growth factor receptor type 1 (IGF-1R) has been described as adverse prognostic factor in some cancers. We studied the expression and localization of IGF-1R in paediatric patients with gliomas, as well as its association with World Health Organization (WHO) grading and survival. We conducted a single cohort, prospective study of paediatric patients with gliomas. Samples were taken at the time of the initial surgery; IGF-1R expression and localization were characterized by immunohistochemistry (IHC), subcellular fractionation and western blotting. Tumours (47/53) showed positive staining for IGF-1R by IHC. IGF-1R nuclear labelling was observed in 10/47 cases. IGF-1R staining was mostly non-nuclear in low-grade tumours, while IGF-1R nuclear labelling was predominant in high-grade gliomas (p = 0.0001). Survival was significantly longer in patients with gliomas having non-nuclear IGF-1R localization than in patients with nuclear IGF-1R tumours (p = 0.016). In gliomas, IGF-1R nuclear localization was significantly associated with both high-grade tumours and increased risk of death. Based on a prospective design, we provide evidence of a potential usefulness of intracellular localization of IGF-1R as prognostic factor in paediatric patients with gliomas.

  4. Role of IGF-1/IGF-1R in regulation of invasion in DU145 prostate cancer cells

    Directory of Open Access Journals (Sweden)

    Setya Hemani

    2008-07-01

    Full Text Available Abstract Background Prostate cancer progression to androgen independence is the primary cause of mortality by this tumor type. The IGF-1/IGF-1R axis is well known to contribute to prostate cancer initiation, but its contribution to invasiveness and the downstream signalling mechanisms that are involved are unclear at present. Results We examined the invasive response of androgen independent DU145 prostate carcinoma cells to IGF-1 stimulation using Matrigel assays. We then examined the signaling mechanisms and protease activities that are associated with this response. IGF-1 significantly increased the invasive capacity of DU145 cells in vitro, and this increase was inhibited by blocking IGF-1R. We further demonstrated that specific inhibitors of the MAPK and PI3-K pathways decrease IGF-1-mediated invasion. To determine potential molecular mechanisms for this change in invasive capacity, we examined changes in expression and activity of matrix metalloproteinases. We observed that IGF-1 increases the enzymatic activity of MMP-2 and MMP-9 in DU145 cells. These changes in activity are due to differences in expression in the case of MMP-9 but not in the case of MMP-2. This observation is corroborated by the fact that correlated changes of expression in a regulator of MMP-2, TIMP-2, were also seen. Conclusion This work identifies a specific effect of IGF-1 on the invasive capacity of DU145 prostate cancer cells, and furthermore delineates mechanisms that contribute to this effect.

  5. Over-accumulation of nuclear IGF-1 receptor in tumor cells requires elevated expression of the receptor and the SUMO-conjugating enzyme Ubc9

    Energy Technology Data Exchange (ETDEWEB)

    Deng, Hua; Lin, Yingbo; Badin, Margherita; Vasilcanu, Daiana; Stroemberg, Thomas [Department of Oncology and Pathology, The Karolinska Institute, Cancer Center Karolinska, SE-17176 Stockholm (Sweden); Jernberg-Wiklund, Helena [Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala (Sweden); Sehat, Bita [Department of Oncology and Pathology, The Karolinska Institute, Cancer Center Karolinska, SE-17176 Stockholm (Sweden); Larsson, Olle, E-mail: olle.larsson@ki.se [Department of Oncology and Pathology, The Karolinska Institute, Cancer Center Karolinska, SE-17176 Stockholm (Sweden)

    2011-01-14

    Research highlights: {yields} SUMOylation mediates nuclear translocation of IGF-1R which activates transcription. {yields} Here we show that nuclear IGF-1R over-accumulates in tumor cells. {yields} This requires overexpression of the receptor that is a common feature in tumor cells. {yields} An increased expression of the SUMO ligase Ubc9 seems to be an involved mechanism too. -- Abstract: The insulin-like growth factor 1 receptor (IGF-1R) plays crucial roles in tumor cell growth and is overexpressed in many cancers. IGF-1R's trans-membrane kinase signaling pathways have been well characterized. Very recently, we showed that SUMOylation mediates nuclear translocation of the IGF-1R, and that nuclear IGF-1R (nIGF-1R) binds to enhancer regions and activates transcription. We identified three lysine residues in the {beta}-subunit of the receptor and that mutation of these blocks nuclear translocation and gene activation. Furthermore, accumulation of nIGF-1R was proven strongly dependent on the specific SUMO-conjugating enzyme Ubc9. Here we show that nIGF-1R originates solely from the cell membrane and that phosphorylation of the core tyrosine residues of the receptor kinase is crucial for nuclear accumulation. We also compared the levels of nIGF-1R, measured as nuclear/membrane ratios, in tumor and normal cells. We found that the breast cancer cell line MCF-7 has 13-fold higher amounts of nIGF-1R than breast epithelial cells (IME) which showed only a small amount of nIGF-1R. In comparison, the total expression of IGF-1R was only 3.7- higher in MCF-7. Comparison of several other tumor and normal cell lines showed similar tumor cell over-accumulation of nIGF-1R, exceeding the total receptor expression substantially. Ectopic overexpression (>10-fold) of the receptor increased nIGF-1R in IME cells but not to that high level as in wild type MCF-7. The levels of Ubc9 were higher in all tumor cell lines, compared to the normal cells, and this probably contributes to over

  6. Over-accumulation of nuclear IGF-1 receptor in tumor cells requires elevated expression of the receptor and the SUMO-conjugating enzyme Ubc9

    International Nuclear Information System (INIS)

    Deng, Hua; Lin, Yingbo; Badin, Margherita; Vasilcanu, Daiana; Stroemberg, Thomas; Jernberg-Wiklund, Helena; Sehat, Bita; Larsson, Olle

    2011-01-01

    Research highlights: → SUMOylation mediates nuclear translocation of IGF-1R which activates transcription. → Here we show that nuclear IGF-1R over-accumulates in tumor cells. → This requires overexpression of the receptor that is a common feature in tumor cells. → An increased expression of the SUMO ligase Ubc9 seems to be an involved mechanism too. -- Abstract: The insulin-like growth factor 1 receptor (IGF-1R) plays crucial roles in tumor cell growth and is overexpressed in many cancers. IGF-1R's trans-membrane kinase signaling pathways have been well characterized. Very recently, we showed that SUMOylation mediates nuclear translocation of the IGF-1R, and that nuclear IGF-1R (nIGF-1R) binds to enhancer regions and activates transcription. We identified three lysine residues in the β-subunit of the receptor and that mutation of these blocks nuclear translocation and gene activation. Furthermore, accumulation of nIGF-1R was proven strongly dependent on the specific SUMO-conjugating enzyme Ubc9. Here we show that nIGF-1R originates solely from the cell membrane and that phosphorylation of the core tyrosine residues of the receptor kinase is crucial for nuclear accumulation. We also compared the levels of nIGF-1R, measured as nuclear/membrane ratios, in tumor and normal cells. We found that the breast cancer cell line MCF-7 has 13-fold higher amounts of nIGF-1R than breast epithelial cells (IME) which showed only a small amount of nIGF-1R. In comparison, the total expression of IGF-1R was only 3.7- higher in MCF-7. Comparison of several other tumor and normal cell lines showed similar tumor cell over-accumulation of nIGF-1R, exceeding the total receptor expression substantially. Ectopic overexpression (>10-fold) of the receptor increased nIGF-1R in IME cells but not to that high level as in wild type MCF-7. The levels of Ubc9 were higher in all tumor cell lines, compared to the normal cells, and this probably contributes to over-accumulation of nIGF-1R

  7. The fetal programming effect of prenatal smoking on Igf1r and Igf1 methylation is organ- and sex-specific.

    Science.gov (United States)

    Meyer, Karolin F; Verkaik-Schakel, Rikst Nynke; Timens, Wim; Kobzik, Lester; Plösch, Torsten; Hylkema, Machteld N

    2017-01-01

    The impact of prenatal smoke exposure (PSE) on DNA methylation has been demonstrated in blood samples from children of smoking mothers, but evidence for sex-dependent smoke-induced effects is limited. As the identified differentially methylated genes can be associated with developmental processes, and insulin-like growth factors (IGFs) play a critical role in prenatal tissue growth, we hypothesized that PSE induces fetal programming of Igf1r and Igf1. Using a mouse model of smoking during pregnancy, we show that PSE alters promoter methylation of Igf1r and Igf1 and deregulates their gene expression in lung and liver of fetal (E17.5) and neonatal (D3) mouse offspring. By further comparing female versus male, lung versus liver, or fetal versus neonatal time point, our results demonstrate that CpG site-specific aberrant methylation patterns sex-dependently vary per organ and time point. Moreover, PSE reduces gene expression of Igf1r and Igf1, dependent on organ, sex, and offspring's age. Our results indicate that PSE may be a source of organ-specific rather than general systemic fetal programming. This is exemplified here by gene promoter methylation and mRNA levels of Igf1r and Igf1, together with a sex- and organ-specific naturally established correlation of both parameters that is affected by prenatal smoke exposure. Moreover, the comparison of fetuses with neonates suggests a CpG site-dependent reversibility/persistence of PSE-induced differential methylation patterns.

  8. A role for IGF-1R-targeted therapies in small-cell lung cancer?

    LENUS (Irish Health Repository)

    Gately, Kathy

    2012-02-01

    BACKGROUND: Small-cell lung cancer (SCLC) is an aggressive disease with a poor prognosis. The insulin-like growth factor-1 receptor (IGF-1R) is an autocrine growth factor and an attractive therapeutic target in many solid tumors, but particularly in lung cancer. PATIENTS AND METHODS: This study examined tumor samples from 23 patients diagnosed with SCLC, 11 resected specimens and 12 nodal biopsies obtained by mediastinoscopy, for expression of IGF-1R using the monoclonal rabbit anti-IGF-1R (clone G11, Ventana Medical Systems, Tucson, AZ) and standard immunohistochemistry (IHC). RESULTS: All 23 tumor samples expressed IGF-1R with a range of stain intensity from weak (1+) to strong (3+). Ten tumors had a score of 3+, 7 tumors 2+, and 6 tumors 1+. Patient survival data were available for all 23 patients. Two patients died < 30 days post biopsy, therefore, the intensity of anti-IGF-1R immunostaining for 21 patients was correlated to survival. Patients with 3+ immunostaining had a poorer prognosis (P = .003). The overall survival of patients who underwent surgical resection was significantly better (median survival not reached) than patients who were not resected (median survival, 7.4 months) (P = .006). CONCLUSION: IGF-1R targeted therapies may have a role in the treatment of SCLC in combination with chemotherapy or as maintenance therapy. Further studies on the clinical benefit of targeting IGF-1R in SCLC are needed.

  9. IGF-1 Receptor Differentially Regulates Spontaneous and Evoked Transmission via Mitochondria at Hippocampal Synapses

    Science.gov (United States)

    Gazit, Neta; Vertkin, Irena; Shapira, Ilana; Helm, Martin; Slomowitz, Edden; Sheiba, Maayan; Mor, Yael; Rizzoli, Silvio; Slutsky, Inna

    2016-01-01

    Summary The insulin-like growth factor-1 receptor (IGF-1R) signaling is a key regulator of lifespan, growth, and development. While reduced IGF-1R signaling delays aging and Alzheimer’s disease progression, whether and how it regulates information processing at central synapses remains elusive. Here, we show that presynaptic IGF-1Rs are basally active, regulating synaptic vesicle release and short-term plasticity in excitatory hippocampal neurons. Acute IGF-1R blockade or transient knockdown suppresses spike-evoked synaptic transmission and presynaptic cytosolic Ca2+ transients, while promoting spontaneous transmission and resting Ca2+ level. This dual effect on transmitter release is mediated by mitochondria that attenuate Ca2+ buffering in the absence of spikes and decrease ATP production during spiking activity. We conclude that the mitochondria, activated by IGF-1R signaling, constitute a critical regulator of information processing in hippocampal neurons by maintaining evoked-to-spontaneous transmission ratio, while constraining synaptic facilitation at high frequencies. Excessive IGF-1R tone may contribute to hippocampal hyperactivity associated with Alzheimer’s disease. Video Abstract PMID:26804996

  10. The GH-IGF1 axis and longevity. The paradigm of IGF1 deficiency.

    Science.gov (United States)

    Laron, Zvi

    2008-01-01

    Primary or secondary IGF1 deficiency has been implicated in shortening of lifespan. This paper reviews available data on the influence of IGF1 deficiency on lifespan and longevity in animals and man. It has been shown that inactivation of the IGF1 gene or of the GH receptor in both invertebrates (C-elegans, flies-Drosphila) and rodents (mice and rats), leading to IGF1 deficiency, prolong life, particularly in females. In man, evaluation of the 2 largest cohorts of patients with Laron syndrome (inactive GH receptor resulting in IGF1 deficiency) in Israel and Ecuador revealed that despite their dwarfism and marked obesity, patients are alive at the ages of 75-78 years, with some having reached even more advanced ages. It is assumed that a major contributing factor is their protection from cancer, a major cause of death in the general population.

  11. Chromosome 15 structural abnormalities: effect on IGF1R gene expression and function

    Directory of Open Access Journals (Sweden)

    Rossella Cannarella

    2017-09-01

    Full Text Available Insulin-like growth factor 1 receptor (IGF1R, mapping on the 15q26.3 chromosome, is required for normal embryonic and postnatal growth. The aim of the present study was to evaluate the IGF1R gene expression and function in three unrelated patients with chromosome 15 structural abnormalities. We report two male patients with the smallest 15q26.3 chromosome duplication described so far, and a female patient with ring chromosome 15 syndrome. Patient one, with a 568 kb pure duplication, had overgrowth, developmental delay, mental and psychomotor retardation, obesity, cryptorchidism, borderline low testis volume, severe oligoasthenoteratozoospermia and gynecomastia. We found a 1.8-fold increase in the IGF1R mRNA and a 1.3-fold increase in the IGF1R protein expression (P < 0.05. Patient two, with a 650 kb impure duplication, showed overgrowth, developmental delay, mild mental retardation, precocious puberty, low testicular volume and severe oligoasthenoteratozoospermia. The IGF1R mRNA and protein expression was similar to that of the control. Patient three, with a 46,XX r(15 (p10q26.2 karyotype, displayed intrauterine growth retardation, developmental delay, mental and psychomotor retardation. We found a <0.5-fold decrease in the IGF1R mRNA expression and an undetectable IGF1R activity. After reviewing the previously 96 published cases of chromosome 15q duplication, we found that neurological disorders, congenital cardiac defects, typical facial traits and gonadal abnormalities are the prominent features in patients with chromosome 15q duplication. Interestingly, patients with 15q deletion syndrome display similar features. We speculate that both the increased and decreased IGF1R gene expression may play a role in the etiology of neurological and gonadal disorders.

  12. IGF-1 and insulin as growth hormones.

    Science.gov (United States)

    Laron, Zvi

    2004-01-01

    IGF-1 generated in the liver is the anabolic effector and linear growth promoting hormone of the pituitary growth hormone (GH). This is evidenced by dwarfism in states of congenital IGF-1 deficiency, Igf1 gene mutation/deletions or knockouts, and in Laron syndrome (LS), due to GH receptor gene mutations/deletions or IGF-1 receptor blocking. In a positive way, daily IGF-1 administration to stunted patients with LS or hGH gene deletion accelerates linear growth velocity. IGF-1 acts on the proliferative cells of the epiphyseal cartilage. IGF-1 also induces organ and tissue growth; its absence causing organomicria. Insulin shares a common ancestry with IGF-1 and with 45% amino acid homology, as well as very close relationships in the structure of its receptors and post-receptor cascade, also acts as a growth hormone. It has protein anabolic activity and stimulates IGF-1 synthesis. Pancreas agenesis causes short babies, and obese children with hyperinsulinism, with or without pituitary GH, have an accelerated growth rate and skeletal maturation; so do babies with macrosomia. Whether the insulin growth effect is direct, or mediated by IGF-1 or leptin is controversial.

  13. IGF-1R signaling in chondrocytes modulates growth plate development by interacting with the PTHrP/Ihh pathway.

    Science.gov (United States)

    Wang, Yongmei; Cheng, Zhiqiang; Elalieh, Hashem Z; Nakamura, Eiichiro; Nguyen, Minh-Thanh; Mackem, Susan; Clemens, Thomas L; Bikle, Daniel D; Chang, Wenhan

    2011-07-01

    Systemic derangements and perinatal death of generalized insulin-like growth factor 1 (IGF-1) and IGF-1 receptor (IGF-1R) knockout mice preclude definitive assessment of IGF-1R actions in growth-plate (GP) chondrocytes. We generated cartilage-specific Igf1r knockout ((Cart) Igf1r(-/-)) mice to investigate local control of chondrocyte differentiation in the GP by this receptor. These mice died shortly after birth and showed disorganized chondrocyte columns, delayed ossification and vascular invasion, decreased cell proliferation, increased apoptosis, and increased expression of parathyroid hormone-related protein (Pthrp) RNA and protein in their GPs. The increased Pthrp expression in the knockout GPs likely was due to an increase in gene transcription, as determined by the increased activity of a LacZ reporter that was inserted downstream of the endogenous PTHrP promoter and bred into the knockout mice. To circumvent the early death of (Cart) Igf1r(-/-) mice and investigate the role of IGF-1R during postnatal growth, we made tamoxifen (Tam)-inducible, cartilage-specific Igf1r knockout ((TamCart) Igf1r(-/-)) mice. At 2 weeks of age and 7 to 8 days after Tam injection, the (TamCart) Igf1r(-/-) mice showed growth retardation with a disorganized GP, reduced chondrocyte proliferation, decreased type 2 collagen and Indian Hedgehog (Ihh) expression, but increased expression of PTHrP. Consistent with in vivo observations, in vitro knockout of the Igf1r gene by adenoviral expression of Cre recombinase suppressed cell proliferation, promoted apoptosis, and increased Pthrp expression. Our data indicate that the IGF-1R in chondrocytes controls cell growth, survival, and differentiation in embryonic and postnatal GPs in part by suppression of Pthrp expression. Copyright © 2011 American Society for Bone and Mineral Research.

  14. SiRNA-mediated IGF-1R inhibition sensitizes human colon cancer SW480 cells to radiation

    International Nuclear Information System (INIS)

    Yavari, Kamal; Taghikhani, Mohammad; Mesbah-Namin, Seyed A.; Maragheh, Mohammad Ghannadi; Babaei, Mohammad Hosein; Arfaee, Ali Jabbary; Madani, Hossein; Mirzaei, Hamid Reza

    2010-01-01

    Purpose. Insulin like growth factor receptor 1 (IGF-1R) is well-documented to play a key role in radiation response and tumor radiosensitivity, thus offering an attractive clinic drug target to enhance tumor sensitivity to anti-cancer radiotherapy. Material and methods. Human colon carcinoma SW480 cells were transfected with the specific small interference RNA (siRNA) expression vector (pkD-shRNA-IGF-1R-V2) designed to target IGF-1R mRNA. The expression of IGF-1R mRNA and its protein among the transfected and untransfected cells were detected by semi-quantitative RT-PCR and ELISA assay. The changes in cell radiosensitivity were examined by MTT assay. Results. Transfection of mammalian expression vector pkD containing IGF-1R siRNA was shown to reduce IGF-1R mRNA levels by up to 95%. ELISA assay detected a similar inhibition of IGF-1R protein levels in cells transfected with IGF-1R siRNA. SW480 cells transfected with the expression vector for siRNA significantly rendered cells more sensitive to radiation and the highest radiation enhancement ratio was 2.02 ± 0.08. Conclusion. These data provide the first evidence that specific siRNA fragment (pkD-shRNA-IGF-1R-V2) targeting human IGF-1R mRNA is able to enhance colon cancer radiosensitivity. Also results indicated that, combining IGF-1R siRNA and radiation significantly enhances antitumor efficacy compared with either modality alone

  15. Kinase inhibitors of the IGF-1R as a potential therapeutic agent for rheumatoid arthritis.

    Science.gov (United States)

    Tsushima, Hiroshi; Morimoto, Shinji; Fujishiro, Maki; Yoshida, Yuko; Hayakawa, Kunihiro; Hirai, Takuya; Miyashita, Tomoko; Ikeda, Keigo; Yamaji, Ken; Takamori, Kenji; Takasaki, Yoshinari; Sekigawa, Iwao; Tamura, Naoto

    2017-08-01

    We have previously shown that the inhibition of connective tissue growth factor (CTGF) is a potential therapeutic strategy against rheumatoid arthritis (RA). CTGF consists of four distinct modules, including the insulin-like growth factor binding protein (IGFBP). In serum, insulin-like growth factors (IGFs) bind IGFBPs, interact with the IGF-1 receptor (IGF-1R), and regulate anabolic effects and bone metabolism. We investigated the correlation between IGF-1 and the pathogenesis of RA, and the inhibitory effect on osteoclastogenesis and angiogenesis of the small molecular weight kinase inhibitor of the IGF-1R, NVP-AEW541, against pathogenesis of RA in vitro. Cell proliferation was evaluated by cell count and immunoblotting. The expression of IGF-1 and IGF-1R was evaluated by RT-PCR. Osteoclastogenesis was evaluated using tartrate-resistant acid phosphatase staining, a bone resorption assay, and osteoclast-specific enzyme production. Angiogenesis was evaluated by a tube formation assay using human umbilical vein endothelial cells (HUVECs). The proliferation of MH7A cells was found to be inhibited in the presence of NVP-AEW541, and the phosphorylation of extracellular signal-regulated kinase (ERK) and Akt was downregulated in MH7A cells. IGF-1 and IGF-1R mRNA expression levels were upregulated during formation of M-colony stimulating factor (M-CSF) and receptor activator of NF-κB ligand (RANKL)-mediated osteoclast formation. Moreover, osteoclastogenesis was suppressed in the presence of NVP-AEW541. The formation of the tubular network was enhanced by IGF-1, and this effect was neutralized by NVP-ARE541. Our findings suggest that NVP-AEW541 may be utilized as a potential therapeutic agent in the treatment of RA.

  16. IGF-1 signaling mediated cell-specific skeletal mechano-transduction.

    Science.gov (United States)

    Tian, Faming; Wang, Yongmei; Bikle, Daniel D

    2018-02-01

    Mechanical loading preserves bone mass and stimulates bone formation, whereas skeletal unloading leads to bone loss. In addition to osteocytes, which are considered the primary sensor of mechanical load, osteoblasts, and bone specific mesenchymal stem cells also are involved. The skeletal response to mechanical signals is a complex process regulated by multiple signaling pathways including that of insulin-like growth factor-1 (IGF-1). Conditional osteocyte deletion of IGF-1 ablates the osteogenic response to mechanical loading. Similarly, osteocyte IGF-1 receptor (IGF-1R) expression is necessary for reloading-induced periosteal bone formation. Transgenic overexpression of IGF-1 in osteoblasts results in enhanced responsiveness to in vivo mechanical loading in mice, a response which is eliminated by osteoblastic conditional disruption of IGF-1 in vivo. Bone marrow derived stem cells (BMSC) from unloaded bone fail to respond to IGF-1 in vitro. IGF-1R is required for the transduction of a mechanical stimulus to downstream effectors, transduction which is lost when the IGF-1R is deleted. Although the molecular mechanisms are not yet fully elucidated, the IGF signaling pathway and its interactions with potentially interlinked signaling cascades involving integrins, the estrogen receptor, and wnt/β-catenin play an important role in regulating adaptive response of cancer bone cells to mechanical stimuli. In this review, we discuss recent advances investigating how IGF-1 and other interlinked molecules and signaling pathways regulate skeletal mechano-transduction involving different bone cells, providing an overview of the IGF-1 signaling mediated cell-specific response to mechanical stimuli. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:576-583, 2018. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

  17. MicroRNA-214 Reduces Insulin-like Growth Factor-1 (IGF-1) Receptor Expression and Downstream mTORC1 Signaling in Renal Carcinoma Cells*

    Science.gov (United States)

    Das, Falguni; Dey, Nirmalya; Bera, Amit; Kasinath, Balakuntalam S.; Ghosh-Choudhury, Nandini; Choudhury, Goutam Ghosh

    2016-01-01

    Elevated IGF-1/insulin-like growth factor-1 receptor (IGF-1R) autocrine/paracrine signaling in patients with renal cell carcinoma is associated with poor prognosis of the disease independent of their von Hippel-Lindau (VHL) status. Increased expression of IGF-1R in renal cancer cells correlates with their potency of tumor development and progression. The mechanism by which expression of IGF-1R is increased in renal carcinoma is not known. We report that VHL-deficient and VHL-positive renal cancer cells possess significantly decreased levels of mature, pre-, and pri-miR-214 than normal proximal tubular epithelial cells. We identified an miR-214 recognition element in the 3′UTR of IGF-1R mRNA and confirmed its responsiveness to miR-214. Overexpression of miR-214 decreased the IGF-1R protein levels, resulting in the inhibition of Akt kinase activity in both types of renal cancer cells. IGF-1 provoked phosphorylation and inactivation of PRAS40 in an Akt-dependent manner, leading to the activation of mTORC1 signal transduction to increase phosphorylation of S6 kinase and 4EBP-1. Phosphorylation-deficient mutants of PRAS40 and 4EBP-1 significantly inhibited IGF-1R-driven proliferation of renal cancer cells. Expression of miR-214 suppressed IGF-1R-induced phosphorylation of PRAS40, S6 kinase, and 4EBP-1, indicating inhibition of mTORC1 activity. Finally, miR-214 significantly blocked IGF-1R-forced renal cancer cell proliferation, which was reversed by expression of 3′UTR-less IGF-1R and constitutively active mTORC1. Together, our results identify a reciprocal regulation of IGF-1R levels and miR-214 expression in renal cancer cells independent of VHL status. Our data provide evidence for a novel mechanism for IGF-1R-driven renal cancer cell proliferation involving miR-214 and mTORC1. PMID:27226530

  18. The impact of IGF-1R expression on the outcomes of patients with breast cancer: a meta-analysis

    Science.gov (United States)

    Yan, Shunchao; Jiao, Xin; Li, Kai; Li, Wusheng; Zou, Huawei

    2015-01-01

    Purpose The value of insulin-like growth factor 1 receptor (IGF-1R) for predicting survival of patients with breast cancer remains controversial. The purpose of this study was to perform a meta-analysis of the published data to attempt to clarify the impact of IGF-1R. Methods Studies published between January 1, 1990 and October 1, 2014 were identified using an electronic search to aggregate the available survival results. Studies were included if they reported detecting IGF-1R expression in the primary breast cancer and analyzed patient survival data according to IGF-1R status. The principal outcome measures were hazard ratios (HRs) for survival of IGF-1R-positive patients. Combined HRs and 95% confidence intervals (CIs) were estimated using fixed- or random-effects models according to between-study heterogeneity. Results Ten studies, involving 5,406 patients, satisfied our inclusion criteria. Data from five studies provided the impact of IGF-1R on overall survival (OS), three studies the impact on breast cancer-specific survival (BCSS), and seven studies the impact on disease-free survival (DFS). The results of meta-analysis showed that for DFS, membranous IGF-1R positivity was not a significant predictor. The combined HR for OS/BCSS was 0.63 (95% CI: 0.42–0.95, P=0.03), indicating that membranous IGF-1R positivity was a significant predictor of better survival. IGF-1R cytoplasmic positivity was significantly associated with longer DFS and OS/BCSS (combined HR: 0.56, 95% CI: 0.35–0.89, P=0.01; combined HR: 0.55, 95% CI: 0.35–0.85, P=0.008, respectively). The results of subgroup analysis suggested that membranous IGF-1R positivity in hormone-receptor-positive breast cancer was correlated with favorable DFS (combined HR: 0.61, 95% CI: 0.41–0.92, P=0.02) and OS/BCSS (combined HR: 0.73, 95% CI: 0.57–0.93, P=0.01). Membranous IGF-1R positivity in triple-negative breast cancer predicted worse DFS (combined HR: 1.86, 95% CI: 1.03–3.34, P=0.04). Membranous

  19. IGF1 Receptor Targeted Theranostic Nanoparticles for Targeted and Image-Guided Therapy of Pancreatic Cancer.

    Science.gov (United States)

    Zhou, Hongyu; Qian, Weiping; Uckun, Fatih M; Wang, Liya; Wang, Y Andrew; Chen, Hongyu; Kooby, David; Yu, Qian; Lipowska, Malgorzata; Staley, Charles A; Mao, Hui; Yang, Lily

    2015-08-25

    Overcoming resistance to chemotherapy is a major and unmet medical challenge in the treatment of pancreatic cancer. Poor drug delivery due to stromal barriers in the tumor microenvironment and aggressive tumor biology are additional impediments toward a more successful treatment of pancreatic cancer. In attempts to address these challenges, we developed IGF1 receptor (IGF1R)-directed, multifunctional theranostic nanoparticles for targeted delivery of therapeutic agents into IGF1R-expressing drug-resistant tumor cells and tumor-associated stromal cells. These nanoparticles were prepared by conjugating recombinant human IGF1 to magnetic iron oxide nanoparticles (IONPs) carrying the anthracycline doxorubicin (Dox) as the chemotherapeutic payload. Intravenously administered IGF1-IONPs exhibited excellent tumor targeting and penetration in an orthotopic patient-derived xenograft (PDX) model of pancreatic cancer featuring enriched tumor stroma and heterogeneous cancer cells. IGF1R-targeted therapy using the theranostic IGF1-IONP-Dox significantly inhibited the growth of pancreatic PDX tumors. The effects of the intratumoral nanoparticle delivery and therapeutic responses in the orthotopic pancreatic PDX tumors could be detected by magnetic resonance imaging (MRI) with IONP-induced contrasts. Histological analysis showed that IGF1R-targeted delivery of Dox significantly inhibited cell proliferation and induced apoptotic cell death of pancreatic cancer cells. Therefore, further development of IGF1R-targeted theranostic IONPs and MRI-guided cancer therapy as a precision nanomedicine may provide the basis for more effective treatment of pancreatic cancer.

  20. miR-342-3p suppresses hepatocellular carcinoma proliferation through inhibition of IGF-1R-mediated Warburg effect.

    Science.gov (United States)

    Liu, Wenpeng; Kang, Lei; Han, Juqiang; Wang, Yadong; Shen, Chuan; Yan, Zhifeng; Tai, Yanhong; Zhao, Caiyan

    2018-01-01

    Insulin-like growth factor-1 receptor (IGF-1R) is a well-studied oncogenic factor that promotes cell proliferation and energy metabolism and is overexpressed in numerous cancers including hepatocellular carcinoma (HCC). Aerobic glycolysis is a hallmark of cancer, and drugs targeting its regulators, including IGF-1R, are being developed. However, the mechanisms of IGF-1R inhibition and the physiological significance of the IGF-1R inhibitors in cancer cells are unclear. Cell proliferation was evaluated by cell counting Kit-8 and colony formation assay. Western blot and real-time PCR were accordingly used to detect the relevant proteins, miRNA and gene expression. Luciferase reporter assays were used to illustrate the interaction between miR-342-3p and IGF-1R. The effect of miR-342-3p on glycolysis was determined by glucose uptake, ATP concentration, lactate generation, extracellular acidification rate and oxygen consumption rate assays. In vivo, subcutaneous tumor formation assay and PET were performed in nude mice. In this study, we demonstrate that by directly targeting the 3'-UTR (3'-untranslated regions) of IGF-1R, microRNA-342-3p (miR-342-3p) suppresses IGF-1R-mediated PI3K/AKT/GLUT1 signaling pathway both in vitro and in vivo. Through suppression of IGF-1R, miR-342-3p dampens glycolysis by decreasing glucose uptake, lactate generation, ATP production, and extracellular acidification rate (ECAR), and increasing oxygen consumption rate (OCR) in hepatoma cells. Importantly, glycolysis regulated by miR-342-3p is critical for its regulating HCC growth both in vitro and in vivo. Our findings provide clues regarding the role of miR-342-3p as a tumor suppressor in liver cancer mainly through the inhibition of IGF-1R. Targeting IGF-1R by miR-342-3p could be a potential therapeutic strategy in liver cancer.

  1. No preclinical rationale for IGF1R directed therapy in chondrosarcoma of bone.

    Science.gov (United States)

    Peterse, Elisabeth F P; Cleven, Arjen H G; De Jong, Yvonne; Briaire-de Bruijn, Inge; Fletcher, Jonathan A; Danen, Erik H J; Cleton-Jansen, Anne-Marie; Bovée, Judith V M G

    2016-07-14

    Chondrosarcoma is a malignant cartilage forming bone tumour for which no effective systemic treatment is available. Previous studies illustrate the need for a better understanding of the role of the IGF pathway in chondrosarcoma to determine if it can be a target for therapy, which was therefore explored in this study. Expression of mediators of IGF1R signalling and phosphorylation status of IRS1 was determined in chondrosarcoma cell lines by qRT-PCR and western blot. The effect of activation and inhibition of IGF1R signalling on downstream targets was assessed by western blot. Ten chondrosarcoma cell lines were treated with OSI-906 (IGF1R and IR dual inhibitor) after which cell proliferation and migration were determined by a viability assay and the xCELLigence system, respectively. In addition, four chondrosarcoma cell lines were treated with a combination of doxorubicin and OSI-906. By immunohistochemistry, IGF1R expression levels were determined in tissue microarrays of 187 cartilage tumours and ten paraffin embedded cell lines. Mediators of IGF1R signalling are heterogeneously expressed and phosphorylated IRS1 was detected in 67 % of the tested chondrosarcoma cell lines, suggesting that IGF1R signalling is active in a subset of chondrosarcoma cell lines. In the cell lines with phosphorylated IRS1, inhibition of IGF1R signalling decreased phosphorylated Akt levels and increased IGF1R expression, but it did not influence MAPK or S6 activity. In line with these findings, treatment with IGF1R/IR inhibitors did not impact proliferation or migration in any of the chondrosarcoma cell lines, even upon stimulation with IGF1. Although synergistic effects of IGF1R/IR inhibition with doxorubicin are described for other cancers, our results demonstrate that this was not the case for chondrosarcoma. In addition, we found minimal IGF1R expression in primary tumours in contrast to the high expression detected in chondrosarcoma cell lines, even if both were derived from the

  2. Brain IGF-1 receptors control mammalian growth and lifespan through a neuroendocrine mechanism.

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    Laurent Kappeler

    2008-10-01

    Full Text Available Mutations that decrease insulin-like growth factor (IGF and growth hormone signaling limit body size and prolong lifespan in mice. In vertebrates, these somatotropic hormones are controlled by the neuroendocrine brain. Hormone-like regulations discovered in nematodes and flies suggest that IGF signals in the nervous system can determine lifespan, but it is unknown whether this applies to higher organisms. Using conditional mutagenesis in the mouse, we show that brain IGF receptors (IGF-1R efficiently regulate somatotropic development. Partial inactivation of IGF-1R in the embryonic brain selectively inhibited GH and IGF-I pathways after birth. This caused growth retardation, smaller adult size, and metabolic alterations, and led to delayed mortality and longer mean lifespan. Thus, early changes in neuroendocrine development can durably modify the life trajectory in mammals. The underlying mechanism appears to be an adaptive plasticity of somatotropic functions allowing individuals to decelerate growth and preserve resources, and thereby improve fitness in challenging environments. Our results also suggest that tonic somatotropic signaling entails the risk of shortened lifespan.

  3. No preclinical rationale for IGF1R directed therapy in chondrosarcoma of bone

    International Nuclear Information System (INIS)

    Peterse, Elisabeth F. P.; Cleven, Arjen H. G.; De Jong, Yvonne; Briaire-de Bruijn, Inge; Fletcher, Jonathan A.; Danen, Erik H. J.; Cleton-Jansen, Anne-Marie; Bovée, Judith V. M. G.

    2016-01-01

    Chondrosarcoma is a malignant cartilage forming bone tumour for which no effective systemic treatment is available. Previous studies illustrate the need for a better understanding of the role of the IGF pathway in chondrosarcoma to determine if it can be a target for therapy, which was therefore explored in this study. Expression of mediators of IGF1R signalling and phosphorylation status of IRS1 was determined in chondrosarcoma cell lines by qRT-PCR and western blot. The effect of activation and inhibition of IGF1R signalling on downstream targets was assessed by western blot. Ten chondrosarcoma cell lines were treated with OSI-906 (IGF1R and IR dual inhibitor) after which cell proliferation and migration were determined by a viability assay and the xCELLigence system, respectively. In addition, four chondrosarcoma cell lines were treated with a combination of doxorubicin and OSI-906. By immunohistochemistry, IGF1R expression levels were determined in tissue microarrays of 187 cartilage tumours and ten paraffin embedded cell lines. Mediators of IGF1R signalling are heterogeneously expressed and phosphorylated IRS1 was detected in 67 % of the tested chondrosarcoma cell lines, suggesting that IGF1R signalling is active in a subset of chondrosarcoma cell lines. In the cell lines with phosphorylated IRS1, inhibition of IGF1R signalling decreased phosphorylated Akt levels and increased IGF1R expression, but it did not influence MAPK or S6 activity. In line with these findings, treatment with IGF1R/IR inhibitors did not impact proliferation or migration in any of the chondrosarcoma cell lines, even upon stimulation with IGF1. Although synergistic effects of IGF1R/IR inhibition with doxorubicin are described for other cancers, our results demonstrate that this was not the case for chondrosarcoma. In addition, we found minimal IGF1R expression in primary tumours in contrast to the high expression detected in chondrosarcoma cell lines, even if both were derived from the

  4. Optimization of IGF-1R SPECT/CT Imaging Using In-111-Labeled F(ab ')(2) and Fab Fragments of Article the Monoclonal Antibody R1507

    NARCIS (Netherlands)

    Heskamp, Sandra; van Laarhoven, Hanneke W. M.; Molkenboer-Kuenen, Janneke D. M.; Bouwman, Wilbert H.; van der Graaf, Winette T. A.; Oyen, Wim J. G.; Boerman, Otto C.

    2012-01-01

    The insulin-like growth factor 1 receptor (IGF-1R) is a potential new target for the treatment of breast cancer. Patients with breast cancer lesions that express IGF-1R may benefit from treatment with anti-IGF-IR antibodies. IGF-1R expression can be visualized using radiolabeled R1507, a monoclonal

  5. Effect of insulin analogues on insulin/IGF1 hybrid receptors: increased activation by glargine but not by its metabolites M1 and M2.

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    Cécile Pierre-Eugene

    Full Text Available BACKGROUND: In diabetic patients, the pharmacokinetics of injected human insulin does not permit optimal control of glycemia. Fast and slow acting insulin analogues have been developed, but they may have adverse properties, such as increased mitogenic or anti-apoptotic signaling. Insulin/IGF1 hybrid receptors (IR/IGF1R, present in most tissues, have been proposed to transmit biological effects close to those of IGF1R. However, the study of hybrid receptors is difficult because of the presence of IR and IGF1R homodimers. Our objective was to perform the first study on the pharmacological properties of the five marketed insulin analogues towards IR/IGF1R hybrids. METHODOLOGY: To study the effect of insulin analogues on IR/IGF1R hybrids, we used our previously developed Bioluminescence Resonance Energy Transfer (BRET assay that permits specific analysis of the pharmacological properties of hybrid receptors. Moreover, we have developed a new, highly sensitive BRET-based assay to monitor phophatidylinositol-3 phosphate (PIP(3 production in living cells. Using this assay, we performed a detailed pharmacological analysis of PIP(3 production induced by IGF1, insulin and insulin analogues in living breast cancer-derived MCF-7 and MDA-MB231 cells. RESULTS: Among the five insulin analogues tested, only glargine stimulated IR/IGF1R hybrids with an EC50 that was significantly lower than insulin and close to that of IGF1. Glargine more efficiently stimulated PIP(3 production in MCF-7 cells but not in MDA-MB231 cells as compared to insulin. In contrast, glargine metabolites M1 and M2 showed lower potency for hybrid receptors stimulation, PIP(3 production, Akt and Erk1/2 phosphorylation and DNA synthesis in MCF-7 cells, compared to insulin. CONCLUSION: Glargine, possibly acting through IR/IGF1R hybrids, displays higher potency, whereas its metabolites M1 and M2 display lower potency than insulin for the stimulation of proliferative/anti-apoptotic pathways in

  6. Nuclear translocation of IGF1R by intracellular amphiregulin contributes to the resistance of lung tumour cells to EGFR-TKI.

    Science.gov (United States)

    Guerard, Marie; Robin, Thomas; Perron, Pascal; Hatat, Anne-Sophie; David-Boudet, Laurence; Vanwonterghem, Laetitia; Busser, Benoit; Coll, Jean-Luc; Lantuejoul, Sylvie; Eymin, Beatrice; Hurbin, Amandine; Gazzeri, Sylvie

    2018-04-28

    Many Receptor Tyrosine Kinases translocate from the cell surface to the nucleus in normal and pathological conditions, including cancer. Here we report the nuclear expression of insulin-like growth factor-1 receptor (IGF1R) in primary human lung tumours. Using lung cancer cell lines and lung tumour xenografts, we demonstrate that the epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) gefitinib induces the nuclear accumulation of IGF1R in mucinous lung adenocarcinoma by a mechanism involving the intracellular re-localization of the growth factor amphiregulin. Amphiregulin allows the binding of IGF1R to importin-β1 and promotes its nuclear transport. The nuclear accumulation of IGF1R by amphiregulin induces cell cycle arrest through p21 WAF1/CIP1 upregulation, and prevents the induction of apoptosis in response to gefitinib. These results identify amphiregulin as the first nuclear localization signal-containing protein that interacts with IGF1R and allows its nuclear translocation. Furthermore they indicate that nuclear expression of IGF1R contributes to EGFR-TKI resistance in lung cancer. Copyright © 2018 Elsevier B.V. All rights reserved.

  7. The impact of IGF-1R expression on the outcomes of patients with breast cancer: a meta-analysis

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    Yan S

    2015-01-01

    Full Text Available Shunchao Yan,1 Xin Jiao,2 Kai Li,1 Wusheng Li,1 Huawei Zou11Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, People’s Republic of China; 2Department of Respiratory Medicine, Shenyang Chest Hospital, Shenyang, People’s Republic of ChinaPurpose: The value of insulin-like growth factor 1 receptor (IGF-1R for predicting survival of patients with breast cancer remains controversial. The purpose of this study was to perform a meta-analysis of the published data to attempt to clarify the impact of IGF-1R.Methods: Studies published between January 1, 1990 and October 1, 2014 were identified using an electronic search to aggregate the available survival results. Studies were included if they reported detecting IGF-1R expression in the primary breast cancer and analyzed patient survival data according to IGF-1R status. The principal outcome measures were hazard ratios (HRs for survival of IGF-1R-positive patients. Combined HRs and 95% confidence intervals (CIs were estimated using fixed- or random-effects models according to between-study heterogeneity.Results: Ten studies, involving 5,406 patients, satisfied our inclusion criteria. Data from five studies provided the impact of IGF-1R on overall survival (OS, three studies the impact on breast cancer-specific survival (BCSS, and seven studies the impact on disease-free survival (DFS. The results of meta-analysis showed that for DFS, membranous IGF-1R positivity was not a significant predictor. The combined HR for OS/BCSS was 0.63 (95% CI: 0.42–0.95, P=0.03, indicating that membranous IGF-1R positivity was a significant predictor of better survival. IGF-1R cytoplasmic positivity was significantly associated with longer DFS and OS/BCSS (combined HR: 0.56, 95% CI: 0.35–0.89, P=0.01; combined HR: 0.55, 95% CI: 0.35–0.85, P=0.008, respectively. The results of subgroup analysis suggested that membranous IGF-1R positivity in hormone-receptor-positive breast cancer was

  8. Determination of LongR3-IGF-I, R3-IGF-I, Des1-3 IGF-I and their metabolites in human plasma samples by means of LC-MS.

    Science.gov (United States)

    Thomas, Andreas; Walpurgis, Katja; Delahaut, Philippe; Fichant, Eric; Schänzer, Wilhelm; Thevis, Mario

    2017-08-01

    According to the regulations of the World Anti-Doping Agency (WADA), growth promoting peptides such as the insulin-like growth factor-I (IGF-I) and its synthetic analogues belong to the class of prohibited compounds. While several assays to quantify endogenous IGF-I have been established, the potential misuse of synthetic analogues such as LongR 3 -IGF-I, R 3 -IGF-I and Des1-3-IGF-I remains a challenge and superior pharmacokinetic properties have been described for these analogues. Within the present study, it was demonstrated that the target peptides can be successfully detected in plasma samples by means of magnetic beads-based immunoaffinity purification and subsequent nanoscale liquid chromatographic separation with high resolution mass spectrometric detection. Noteworthy, the usage of a specific antibody for LongR 3 -IGF-I enables the determination in low ng/mL levels despite the presence of an enormous excess of endogenous human IGF-I. In addition, different metabolism studies (in-vitro and in-vivo) were performed using sophisticated strategies such as incubation with skin tissue microsomes, degradation in biological fluids (for all analogues), and administration to rats (for LongR 3 -IGF-I). Herewith, several C-and N-terminally truncated metabolites were identified and their relevancy was additionally confirmed by in-vivo experiments with rodents. Especially for LongR 3 -IGF-I, a metabolite ((Des1-11)-LongR 3 -IGF-I) was identified that prolonged the detectability in-vivo by a factor of approximately 2. The method was validated for qualitative interpretation considering the parameters specificity, identification capability, recovery (26-60%), limit of detection (0.5ng/mL), imprecision (IGF-I was used as internal standard to control all sample preparation steps. Copyright © 2017 Elsevier Ltd. All rights reserved.

  9. Relationship between serum IGF-1 and skeletal muscle IGF-1 mRNA expression to phosphocreatine recovery after exercise in obese men with reduced GH.

    Science.gov (United States)

    Hamarneh, Sulaiman R; Murphy, Caitlin A; Shih, Cynthia W; Frontera, Walter; Torriani, Martin; Irazoqui, Javier E; Makimura, Hideo

    2015-02-01

    GH and IGF-1 are believed to be physiological regulators of skeletal muscle mitochondria. The objective of this study was to examine the relationship between GH/IGF-1 and skeletal muscle mitochondria in obese subjects with reduced GH secretion in more detail. Fifteen abdominally obese men with reduced GH secretion were treated for 12 weeks with recombinant human GH. Subjects underwent (31)P-magnetic resonance spectroscopy to assess phosphocreatine (PCr) recovery as an in vivo measure of skeletal muscle mitochondrial function and percutaneous muscle biopsies to assess mRNA expression of IGF-1 and mitochondrial-related genes at baseline and 12 weeks. At baseline, skeletal muscle IGF-1 mRNA expression was significantly associated with PCr recovery (r = 0.79; P = .01) and nuclear respiratory factor-1 (r = 0.87; P = .001), mitochondrial transcription factor A (r = 0.86; P = .001), peroxisome proliferator-activated receptor (PPAR)γ (r = 0.72; P = .02), and PPARα (r = 0.75; P = .01) mRNA expression, and trended to an association with PPARγ coactivator 1-α (r = 0.59; P = .07) mRNA expression. However, serum IGF-1 concentration was not associated with PCr recovery or any mitochondrial gene expression (all P > .10). Administration of recombinant human GH increased both serum IGF-1 (change, 218 ± 29 μg/L; P IGF-1 mRNA in muscle (fold change, 2.1 ± 0.3; P = .002). Increases in serum IGF-1 were associated with improvements in total body fat (r = -0.53; P = .04), trunk fat (r = -0.55; P = .03), and lean mass (r = 0.58; P = .02), but not with PCr recovery (P > .10). Conversely, increase in muscle IGF-1 mRNA was associated with improvements in PCr recovery (r = 0.74; P = .02), but not with body composition parameters (P > .10). These data demonstrate a novel association of skeletal muscle mitochondria with muscle IGF-1 mRNA expression, but independent of serum IGF-1 concentrations.

  10. miR-342-3p suppresses hepatocellular carcinoma proliferation through inhibition of IGF-1R-mediated Warburg effect

    Directory of Open Access Journals (Sweden)

    Liu W

    2018-03-01

    Full Text Available Wenpeng Liu,1,* Lei Kang,2,* Juqiang Han,3 Yadong Wang,1 Chuan Shen,1 Zhifeng Yan,4 Yanhong Tai,5 Caiyan Zhao1 1Department of Infectious Diseases, Third Affiliated Hospital of Hebei Medical University, Shijiazhuang, China; 2Department of Nuclear Medicine, Peking University First Hospital, Beijing, China; 3Institute of Liver Disease, Beijing Military General Hospital, Beijing, China; 4Department of Gynecology and Obstetrics, PLA General Hospital, Beijing, China; 5Department of Pathology, Hospital of PLA, Beijing, China *These authors contributed equally to this work Background: Insulin-like growth factor-1 receptor (IGF-1R is a well-studied oncogenic factor that promotes cell proliferation and energy metabolism and is overexpressed in numerous cancers including hepatocellular carcinoma (HCC. Aerobic glycolysis is a hallmark of cancer, and drugs targeting its regulators, including IGF-1R, are being developed. However, the mechanisms of IGF-1R inhibition and the physiological significance of the IGF-1R inhibitors in cancer cells are unclear. Materials and methods: Cell proliferation was evaluated by cell counting Kit-8 and colony formation assay. Western blot and real-time PCR were accordingly used to detect the relevant proteins, miRNA and gene expression. Luciferase reporter assays were used to illustrate the interaction between miR-342-3p and IGF-1R. The effect of miR-342-3p on glycolysis was determined by glucose uptake, ATP concentration, lactate generation, extracellular acidification rate and oxygen consumption rate assays. In vivo, subcutaneous tumor formation assay and PET were performed in nude mice. Results: In this study, we demonstrate that by directly targeting the 3’-UTR (3’-untranslated regions of IGF-1R, microRNA-342-3p (miR-342-3p suppresses IGF-1R-mediated PI3K/AKT/GLUT1 signaling pathway both in vitro and in vivo. Through suppression of IGF-1R, miR-342-3p dampens glycolysis by decreasing glucose uptake, lactate generation

  11. Involvement of Igf1r in Bronchiolar Epithelial Regeneration: Role during Repair Kinetics after Selective Club Cell Ablation.

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    Icíar P López

    Full Text Available Regeneration of lung epithelium is vital for maintaining airway function and integrity. An imbalance between epithelial damage and repair is at the basis of numerous chronic lung diseases such as asthma, COPD, pulmonary fibrosis and lung cancer. IGF (Insulin-like Growth Factors signaling has been associated with most of these respiratory pathologies, although their mechanisms of action in this tissue remain poorly understood. Expression profiles analyses of IGF system genes performed in mouse lung support their functional implication in pulmonary ontogeny. Immuno-localization revealed high expression levels of Igf1r (Insulin-like Growth Factor 1 Receptor in lung epithelial cells, alveolar macrophages and smooth muscle. To further understand the role of Igf1r in pulmonary homeostasis, two distinct lung epithelial-specific Igf1r mutant mice were generated and studied. The lack of Igf1r disturbed airway epithelial differentiation in adult mice, and revealed enhanced proliferation and altered morphology in distal airway club cells. During recovery after naphthalene-induced club cell injury, the kinetics of terminal bronchiolar epithelium regeneration was hindered in Igf1r mutants, revealing increased proliferation and delayed differentiation of club and ciliated cells. Amid airway restoration, lungs of Igf1r deficient mice showed increased levels of Igf1, Insr, Igfbp3 and epithelial precursor markers, reduced amounts of Scgb1a1 protein, and alterations in IGF signaling mediators. These results support the role of Igf1r in controlling the kinetics of cell proliferation and differentiation during pulmonary airway epithelial regeneration after injury.

  12. Igf1r signaling is indispensable for preimplantation development and is activated via a novel function of E-cadherin.

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    Ivan Bedzhov

    Full Text Available Insulin-like growth factor I receptor (Igf1r signaling controls proliferation, differentiation, growth, and cell survival in many tissues; and its deregulated activity is involved in tumorigenesis. Although important during fetal growth and postnatal life, a function for the Igf pathway during preimplantation development has not been described. We show that abrogating Igf1r signaling with specific inhibitors blocks trophectoderm formation and compromises embryo survival during murine blastocyst formation. In normal embryos total Igf1r is present throughout the membrane, whereas the activated form is found exclusively at cell contact sites, colocalizing with E-cadherin. Using genetic domain switching, we show a requirement for E-cadherin to maintain proper activation of Igf1r. Embryos expressing exclusively a cadherin chimera with N-cadherin extracellular and E-cadherin intracellular domains (NcEc fail to form a trophectoderm and cells die by apoptosis. In contrast, homozygous mutant embryos expressing a reverse-structured chimera (EcNc show trophectoderm survival and blastocoel cavitation, indicating a crucial and non-substitutable role of the E-cadherin ectodomain for these processes. Strikingly, blastocyst formation can be rescued in homozygous NcEc embryos by restoring Igf1r signaling, which enhances cell survival. Hence, perturbation of E-cadherin extracellular integrity, independent of its cell-adhesion function, blocked Igf1r signaling and induced cell death in the trophectoderm. Our results reveal an important and yet undiscovered function of Igf1r during preimplantation development mediated by a unique physical interaction between Igf1r and E-cadherin indispensable for proper receptor activation and anti-apoptotic signaling. We provide novel insights into how ligand-dependent Igf1r activity is additionally gated to sense developmental potential in utero and into a bifunctional role of adhesion molecules in contact formation and signaling.

  13. Shifting the IGF-axis: An age-related decline in human tear IGF-1 correlates with clinical signs of dry eye.

    Science.gov (United States)

    Patel, Roshni; Zhu, Meifang; Robertson, Danielle M

    2018-02-06

    The human corneal epithelium expresses both the insulin-like growth factor type 1 receptor (IGF-1R) and the IGF-1R/insulin receptor (INSR) hybrid. Despite the previous identification of IGF-1 in human tear fluid, little is known regarding the regulation of IGF-1 in tear fluid and its role in corneal epithelial homeostasis. In the present study, we investigated the impact of biological parameters on the concentration of human tear levels of IGF-1. Tear levels of IGF-1 were measured in 41 healthy, human volunteers without any reported symptoms of dry eye. All volunteers underwent standard biomicroscopic examination of the cornea and tear film. In a subgroup of volunteers, corneal staining with sodium fluorescein, tear film break up time and tear production using a Schirmer's test strip were measured to assess clinical signs of dry eye. Tears were collected from the inferior tear meniscus using glass microcapillary tubes and IGF-1 levels were measured using a solid phase sandwich ELISA. Tear levels of IGF-1 were highest in young adults and significantly decreased in older adults (P = 0.003). There were no differences in tear IGF-1 between males and females (P = 0.628). Tear IGF-1 levels were correlated with tear film break up time (R = 0.738) and tear production (R = 0.826). These data indicate that there is a progressive decline in tear IGF-1 due to aging that is associated with clinical signs of dry eye. This effect is likely due to age-related changes in the lacrimal gland. Copyright © 2018 Elsevier Ltd. All rights reserved.

  14. IGF-1 receptor targeted nanoparticles for image-guided therapy of stroma-rich and drug resistant human cancer.

    Science.gov (United States)

    Zhou, Hongyu; Qian, Weiping; Uckun, Fatih M; Zhou, Zhiyang; Wang, Liya; Wang, Andrew; Mao, Hui; Yang, Lily

    2016-04-17

    Low drug delivery efficiency and drug resistance from highly heterogeneous cancer cells and tumor microenvironment represent major challenges in clinical oncology. Growth factor receptor, IGF-1R, is overexpressed in both human tumor cells and tumor associated stromal cells. The level of IGF-1R expression is further up-regulated in drug resistant tumor cells. We have developed IGF-1R targeted magnetic iron oxide nanoparticles (IONPs) carrying multiple anticancer drugs into human tumors. This IGF-1R targeted theranostic nanoparticle delivery system has an iron core for non-invasive MR imaging, amphiphilic polymer coating to ensure the biocompatibility as well as for drug loading and conjugation of recombinant human IGF-1 as targeting molecules. Chemotherapy drugs, Doxorubicin (Dox), was encapsulated into the polymer coating and/or conjugated to the IONP surface by coupling with the carboxyl groups. The ability of IGF1R targeted theranostic nanoparticles to penetrate tumor stromal barrier and enhance tumor cell killing has been demonstrated in human pancreatic cancer patient tissue derived xenograft (PDX) models. Repeated systemic administrations of those IGF-1R targeted theranostic IONP carrying Dox led to breaking the tumor stromal barrier and improved therapeutic effect. Near infrared (NIR) optical and MR imaging enabled noninvasive monitoring of nanoparticle-drug delivery and therapeutic responses. Our results demonstrated that IGF-1R targeted nanoparticles carrying multiple drugs are promising combination therapy approaches for image-guided therapy of stroma-rich and drug resistant human cancer, such as pancreatic cancer.

  15. IGF-1 receptor targeted nanoparticles for image-guided therapy of stroma-rich and drug resistant human cancer

    Science.gov (United States)

    Zhou, Hongyu; Qian, Weiping; Uckun, Fatih M.; Zhou, Zhiyang; Wang, Liya; Wang, Andrew; Mao, Hui; Yang, Lily

    2016-05-01

    Low drug delivery efficiency and drug resistance from highly heterogeneous cancer cells and tumor microenvironment represent major challenges in clinical oncology. Growth factor receptor, IGF-1R, is overexpressed in both human tumor cells and tumor associated stromal cells. The level of IGF-1R expression is further up-regulated in drug resistant tumor cells. We have developed IGF-1R targeted magnetic iron oxide nanoparticles (IONPs) carrying multiple anticancer drugs into human tumors. This IGF-1R targeted theranostic nanoparticle delivery system has an iron core for non-invasive MR imaging, amphiphilic polymer coating to ensure the biocompatibility as well as for drug loading and conjugation of recombinant human IGF-1 as targeting molecules. Chemotherapy drugs, Doxorubicin (Dox), was encapsulated into the polymer coating and/or conjugated to the IONP surface by coupling with the carboxyl groups. The ability of IGF1R targeted theranostic nanoparticles to penetrate tumor stromal barrier and enhance tumor cell killing has been demonstrated in human pancreatic cancer patient tissue derived xenograft (PDX) models. Repeated systemic administrations of those IGF-1R targeted theranostic IONP carrying Dox led to breaking the tumor stromal barrier and improved therapeutic effect. Near infrared (NIR) optical and MR imaging enabled noninvasive monitoring of nanoparticle-drug delivery and therapeutic responses. Our results demonstrated that IGF-1R targeted nanoparticles carrying multiple drugs are promising combination therapy approaches for image-guided therapy of stroma-rich and drug resistant human cancer, such as pancreatic cancer.

  16. Novel cross-talk between IGF-IR and DDR1 regulates IGF-IR trafficking, signaling and biological responses

    Science.gov (United States)

    Sacco, Antonella; Morcavallo, Alaide; Vella, Veronica; Voci, Concetta; Spatuzza, Michela; Xu, Shi-Qiong; Iozzo, Renato V.; Vigneri, Riccardo; Morrione, Andrea; Belfiore, Antonino

    2015-01-01

    The insulin-like growth factor-I receptor (IGF-IR), plays a key role in regulating mammalian development and growth, and is frequently deregulated in cancer contributing to tumor initiation and progression. Discoidin domain receptor 1 (DDR1), a collagen receptor tyrosine-kinase, is as well frequently overexpressed in cancer and implicated in cancer progression. Thus, we investigated whether a functional cross-talk between the IGF-IR and DDR1 exists and plays any role in cancer progression. Using human breast cancer cells we found that DDR1 constitutively associated with the IGF-IR. However, this interaction was enhanced by IGF-I stimulation, which promoted rapid DDR1 tyrosine-phosphorylation and co-internalization with the IGF-IR. Significantly, DDR1 was critical for IGF-IR endocytosis and trafficking into early endosomes, IGF-IR protein expression and IGF-I intracellular signaling and biological effects, including cell proliferation, migration and colony formation. These biological responses were inhibited by DDR1 silencing and enhanced by DDR1 overexpression. Experiments in mouse fibroblasts co-transfected with the human IGF-IR and DDR1 gave similar results and indicated that, in the absence of IGF-IR, collagen-dependent phosphorylation of DDR1 is impaired. These results demonstrate a critical role of DDR1 in the regulation of IGF-IR action, and identify DDR1 as a novel important target for breast cancers that overexpress IGF-IR. PMID:25840417

  17. Resveratrol suppresses IGF-1 induced human colon cancer cell proliferation and elevates apoptosis via suppression of IGF-1R/Wnt and activation of p53 signaling pathways

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    Radhakrishnan Sridhar

    2010-05-01

    Full Text Available Abstract Background Obesity is a global phenomenon and is associated with various types of cancer, including colon cancer. There is a growing interest for safe and effective bioactive compounds that suppress the risk for obesity-promoted colon cancer. Resveratrol (trans-3, 4', 5,-trihydroxystilbene, a stilbenoid found in the skin of red grapes and peanuts suppresses many types of cancers by regulating cell proliferation and apoptosis through a variety of mechanisms, however, resveratrol effects on obesity-promoted colon cancer are not clearly established. Methods We investigated the anti-proliferative effects of resveratrol on HT-29 and SW480 human colon cancer cells in the presence and absence of insulin like growth factor-1 (IGF-1; elevated during obesity and elucidated the mechanisms of action using IGF-1R siRNA in HT-29 cells which represents advanced colon carcinogenesis. Results Resveratrol (100-150 μM exhibited anti-proliferative properties in HT-29 cells even after IGF-1 exposure by arresting G0/G1-S phase cell cycle progression through p27 stimulation and cyclin D1 suppression. Treatment with resveratrol suppressed IGF-1R protein levels and concurrently attenuated the downstream Akt/Wnt signaling pathways that play a critical role in cell proliferation. Targeted suppression of IGF-1R using IGF-1R siRNA also affected these signaling pathways in a similar manner. Resveratrol treatment induced apoptosis by activating tumor suppressor p53 protein, whereas IGF-1R siRNA treatment did not affect apoptosis. Our data suggests that resveratrol not only suppresses cell proliferation by inhibiting IGF-1R and its downstream signaling pathways similar to that of IGF-1R siRNA but also enhances apoptosis via activation of the p53 pathway. Conclusions For the first time, we report that resveratrol suppresses colon cancer cell proliferation and elevates apoptosis even in the presence of IGF-1 via suppression of IGF-1R/Akt/Wnt signaling pathways and

  18. Resveratrol suppresses IGF-1 induced human colon cancer cell proliferation and elevates apoptosis via suppression of IGF-1R/Wnt and activation of p53 signaling pathways

    International Nuclear Information System (INIS)

    Vanamala, Jairam; Reddivari, Lavanya; Radhakrishnan, Sridhar; Tarver, Chris

    2010-01-01

    Obesity is a global phenomenon and is associated with various types of cancer, including colon cancer. There is a growing interest for safe and effective bioactive compounds that suppress the risk for obesity-promoted colon cancer. Resveratrol (trans-3, 4', 5,-trihydroxystilbene), a stilbenoid found in the skin of red grapes and peanuts suppresses many types of cancers by regulating cell proliferation and apoptosis through a variety of mechanisms, however, resveratrol effects on obesity-promoted colon cancer are not clearly established. We investigated the anti-proliferative effects of resveratrol on HT-29 and SW480 human colon cancer cells in the presence and absence of insulin like growth factor-1 (IGF-1; elevated during obesity) and elucidated the mechanisms of action using IGF-1R siRNA in HT-29 cells which represents advanced colon carcinogenesis. Resveratrol (100-150 μM) exhibited anti-proliferative properties in HT-29 cells even after IGF-1 exposure by arresting G 0 /G 1 -S phase cell cycle progression through p27 stimulation and cyclin D1 suppression. Treatment with resveratrol suppressed IGF-1R protein levels and concurrently attenuated the downstream Akt/Wnt signaling pathways that play a critical role in cell proliferation. Targeted suppression of IGF-1R using IGF-1R siRNA also affected these signaling pathways in a similar manner. Resveratrol treatment induced apoptosis by activating tumor suppressor p53 protein, whereas IGF-1R siRNA treatment did not affect apoptosis. Our data suggests that resveratrol not only suppresses cell proliferation by inhibiting IGF-1R and its downstream signaling pathways similar to that of IGF-1R siRNA but also enhances apoptosis via activation of the p53 pathway. For the first time, we report that resveratrol suppresses colon cancer cell proliferation and elevates apoptosis even in the presence of IGF-1 via suppression of IGF-1R/Akt/Wnt signaling pathways and activation of p53, suggesting its potential role as a

  19. miR-598 acts as a tumor suppressor in human gastric cancer by targeting IGF-1R.

    Science.gov (United States)

    Liu, Na; Yang, Hua; Wang, Hong

    2018-01-01

    In recent years, the aberrant expression of miR-598 in tumorigenesis has been demonstrated, as well as the fact that the IGF-1R pathway is also involved in the development of human gastric cancer (GC). The present study aimed to investigate the molecular mechanisms underlying miR-598-regulated IGF-1R expression in human GC. We analyzed the expression of miR-598 and IGF-1R in GC samples and cells, and evaluated the clinical significance of miR-598 and IGF-1R in GC patients. Furthermore, in vitro and in vivo assays were used to investigate the molecular mechanisms of miR-598 and IGF-1R. miR-598 expression was frequently downregulated in GC tissues and cells, and significantly correlated with poor prognosis, vascular invasion, TNM stage, and lymph node metastases as well as IGF-1R expression. The overexpression of miR-598 obviously inhibited cell proliferation, migration, invasion, and induced cell cycle arrest in the G1/S phase, and increased the apoptosis of GC cells. The overexpression of miR-598 also significantly inhibited ERK1/2 and Akt phosphorylation level. In vivo assay validated the inhibitory effect of miR-598 on tumor growth. Further studies showed that miR-598 inhibited IGF-1R protein expression by directly targeting its 3'-UTR. Besides, over-expression of IGF-1R reversed the inhibitory effects of miR-598, while suppression of IGF-1R expression showed inverse effects. miR-598 suppresses GC cell proliferation, migration and invasion by directly targeting IGF-1R expression. Thus, miR-598 may be a useful target for GC patients.

  20. ERK phosphorylation is predictive of resistance to IGF-1R inhibition in small cell lung cancer.

    Science.gov (United States)

    Zinn, Rebekah L; Gardner, Eric E; Marchionni, Luigi; Murphy, Sara C; Dobromilskaya, Irina; Hann, Christine L; Rudin, Charles M

    2013-06-01

    New therapies are critically needed to improve the outcome for patients with small cell lung cancer (SCLC). Insulin-like growth factor 1 receptor (IGF-1R) inhibition is a potential treatment strategy for SCLC: the IGF-1R pathway is commonly upregulated in SCLC and has been associated with inhibition of apoptosis and stimulation of proliferation through downstream signaling pathways, including phosphatidylinositol-3-kinase-Akt and mitogen-activated protein kinase. To evaluate potential determinants of response to IGF-1R inhibition, we assessed the relative sensitivity of 19 SCLC cell lines to OSI-906, a small molecule inhibitor of IGF-1R, and the closely related insulin receptor. Approximately one third of these cell lines were sensitive to OSI-906, with an IC50 OSI-906. Interestingly, OSI-906 sensitive lines expressed significantly lower levels of baseline phospho-ERK relative to resistant lines (P = 0.006). OSI-906 treatment resulted in dose-dependent inhibition of phospho-IGF-1R and phospho-Akt in both sensitive and resistant cell lines, but induced apoptosis and cell-cycle arrest only in sensitive lines. We tested the in vivo efficacy of OSI-906 using an NCI-H187 xenograft model and two SCLC patient xenografts in mice. OSI-906 treatment resulted in 50% tumor growth inhibition in NCI-H187 and 30% inhibition in the primary patient xenograft models compared with mock-treated animals. Taken together our data support IGF-1R inhibition as a viable treatment strategy for a defined subset of SCLC and suggest that low pretreatment levels of phospho-ERK may be indicative of sensitivity to this therapeutic approach. ©2013 AACR

  1. IGF-II receptors and IGF-II-stimulated glucose transport in human fat cells

    International Nuclear Information System (INIS)

    Sinha, M.K.; Buchanan, C.; Raineri-Maldonado, C.; Khazanie, P.; Atkinson, S.; DiMarchi, R.; Caro, J.F.

    1990-01-01

    Insulin-like growth factor II (IGF-II) receptors have been described in rat but not in human adipocytes. In both species, IGF-II has been reported to stimulate glucose transport by interacting with the insulin receptor. In this study, we have unequivocally demonstrated the presence of IGF-II receptors in human adipocytes. 125I-labeled IGF-II specifically binds to intact adipocytes, membranes, and lectin-purified detergent solubilized extracts. Through the use of 0.5 mM disuccinimidyl suberate, 125I-IGF-II is cross-linked to a 260-kDa protein that is identified as the IGF-II receptor by displacement experiments with unlabeled IGF-II, IGF-I, and insulin and either by immunoprecipitation or by Western blot analysis with mannose 6-phosphate receptor antibodies. The concentrations of IGF-II required for half-maximal and maximal stimulation of glucose transport in human adipocytes are 35 and 100 times more than that of insulin. The possibility of IGF-II stimulating glucose transport by interacting predominantly with the insulin receptor is suggested by the following: (1) the concentration of IGF-II that inhibits half of insulin binding is only 20 times more than that of insulin; (2) the lack of an additive effect of IGF-II and insulin for maximal stimulation of glucose transport; (3) the ability of monoclonal insulin receptor antibodies to decrease glucose transport stimulated by submaximal concentrations of both IGF-II and insulin; and (4) the ability of IGF-II to stimulate insulin receptor autophosphorylation albeit at a reduced potency when compared with insulin

  2. IGF-1R mRNA expression is increased in obese children.

    Science.gov (United States)

    Ricco, Rafaela Cristina; Ricco, Rubens Garcia; Queluz, Mariangela Carletti; de Paula, Mariana Teresa Sarti; Atique, Patricia Volpon; Custódio, Rodrigo José; Tourinho Filho, Hugo; Del Roio Liberatori, Raphael; Martinelli, Carlos Eduardo

    2018-04-01

    Obese children are often taller than age-matched subjects. Reports on GH and IGF-I levels in obese individuals are controversial, with normal and reduced GH-IGF-I levels having been reported in this group of patients. Thus, the aim of this study was to analyse insulin-like growth factor type 1 receptor (IGF-IR) mRNA expression in obese children. Forty-seven pre-pubertal children were included in this study: 29 were obese and taller than their target height, and 18 were normal eutrophic controls. Fasting blood samples were collected for IGF-IR mRNA expression in isolated lymphocytes and serum IGF-I, ALS, IGFBP-3, and IGFBP-1 concentration analysis. Relative IGF-IR gene expression (2 -ΔΔCT ) was significantly (P=0.025) higher in obese children (median 1.87) than in controls (1.15). Fourteen of the 29 obese subjects showed 2 -ΔΔCT values greater than or equal to 2, while only 2 individuals in the control group showed values above 2 (P=0.01). Obese children showed significantly (P=0.01) higher IGF-I concentrations than the control group (237ng/ml and 144ng/ml, respectively). Among obese patients, 65.5% had IGF-I values above the 75 percentile of the control group (P=0.02). ALS concentration was significantly (P=0.04) higher in the obese group, while IGFBP-3 levels were similar in obese and control children. IGFBP-1 concentration was lower in obese children, while insulin levels and HOMA-IR index were higher than in controls. The higher IGF-IR mRNA expression observed in obese children, associated with the higher IGF-I and ALS and the lower IGFBP-1 levels, suggest that the higher stature observed in these children may be due to increased IGF-I bioactivity. Copyright © 2017 Elsevier Ltd. All rights reserved.

  3. Serial analysis of resected prostate cancer suggests up-regulation of type 1 IGF receptor with disease progression.

    Science.gov (United States)

    Turney, Benjamin W; Turner, Gareth D H; Brewster, Simon F; Macaulay, Valentine M

    2011-05-01

    • To compare immunostaining protocols using different antibodies for the type 1 insulin-like growth factor receptor (IGF-1R) in channel transurethal resection of the prostate (chTURP) chips, and to investigate how IGF-1R expression varies with time in serial prostate cancer specimens from individual patients. • We studied IGF-1R expression in 44 prostate cancer specimens from 18 patients who had undergone serial chTURP at least 3 months apart. • Retrospective analysis of the hospital notes was undertaken to obtain clinical information, including age, Gleason score, prostate-specific antigen (PSA) level, hormone treatment and metastatic disease status at the time of each operation. • After an optimization process using three commercially-available IGF-1R antibodies, we used two antibodies for semiquantititve immunostaining of serial chTURP chips. • Santa Cruz antibody sc713 gave positive staining in IGF-1R null R- cells, and was not used further. Antibodies from Cell Signaling Technology (Beverly, MA, USA) (CS) and NeoMarkers Inc. (Fremont, CA, USA) (NM) did not stain R- cells and, in prostate tissue, showed staining of the glandular epithelium, with negligible stromal staining. All 44 chTURP samples contained identifiable malignant tissue and, of these, 73% and 64% scored moderately or strongly (score 3 or 4) with the CS and NM antibodies respectively. • There was significant correlation of IGF-1R scores of malignant tissue between the two antibodies (P < 0.001). By contrast, staining of benign glands showed poor correlation between antibodies: CS gave significantly weaker staining than malignant epithelium in the same sections (P < 0.001), whereas NM showed poor discrimination between malignant and benign glands. IGF-1R staining scores generated by the CS antibody were used to analyze the clinical data. • Most patients (six of seven) with falling IGF-1R staining scores were responding to androgen deprivation therapy (confirmed by PSA response

  4. H2O2 attenuates IGF-1R tyrosine phosphorylation and its survival signaling properties in neuronal cells via NR2B containing NMDA receptor.

    Science.gov (United States)

    Zeng, Zhiwen; Wang, Dejun; Gaur, Uma; Rifang, Liao; Wang, Haitao; Zheng, Wenhua

    2017-09-12

    Impairment of insulin-like growth factor I (IGF-I) signaling plays an important role in the development of neurodegeneration. In the present study, we investigated the effect of H 2 O 2 on the survival signaling of IGF-1 and its underlying mechanisms in human neuronal cells SH-SY5Y. Our results showed that IGF-1 promoted cell survival and stimulated phosphorylation of IGF-1R as well as its downstream targets like AKT and ERK1/2 in these cells. Meanwhile, these effects of IGF-1 were abolished by H 2 O 2 at 200μM concentration which did not cause any significant toxicity to cells itself in our experiments. Moreover, studies using various glutamate receptor subtype antagonists displayed that N-methyl-D -aspartate (NMDA) receptor antagonist dizocilpine maleate (MK-801) blocked the effects of H 2 O 2 , whereas other glutamate receptor subtype antagonists, such as non-NMDA receptor antagonist 6,7-dinitroquinoxaline-2,3-dione (DNQX), metabolic glutamate receptor antagonists LY341495 and CPCCOEt, had no effect. Further studies revealed that NR2B-containing NMDARs are responsible for these effects as its effects were blocked by pharmacological inhibitor Ro25-698 or specific siRNA for NR2B, but not NR2A. Finally, our data also showed that Ca 2+ influx contributes to the effects of H 2 O 2 . Similar results were obtained in primary cultured cortical neurons. Taken together, the results from the present study suggested that H 2 O 2 attenuated IGF-1R tyrosine phosphorylation and its survival signaling properties via NR2B containing NMDA receptors and Ca 2+ influx in SH-SY5Y cells. Therefore, NMDAR antagonists, especially NR2B-selective ones, combined with IGF-1 may serve as an alternative therapeutic agent for oxidative stress related neurodegenerative disease.

  5. Insulin-like growth factor 1 (IGF1) and its active peptide (1-3)IGF1 enhance the expression of synaptic markers in neuronal circuits through different cellular mechanisms.

    LENUS (Irish Health Repository)

    Corvin, Aiden P

    2012-06-27

    Insulin-like growth factor-1 (IGF1) and its active peptide (1-3)IGF1 modulate brain growth and plasticity and are candidate molecules for treatment of brain disorders. IGF1 N-terminal portion is naturally cleaved to generate the tri-peptide (1-3)IGF1 (glycine-praline-glutamate). IGF1 and (1-3)IGF have been proposed as treatment for neuropathologies, yet their effect on nerve cells has not been directly compared. In this study we examine the effects of IGF1 and (1-3)IGF1 in primary cortical cultures and measure the expression levels of markers for intracellular pathways and synaptic function. We find that both treatments activate the IGF1 receptor and enhance the expression of synaptic markers, however, they activate different intracellular pathways. Furthermore, (1-3)IGF1 administration increases the expression of endogenous IGF1, suggesting a direct interaction between the two molecules. The results show that the two molecules increase the expression of synaptic proteins through activating different cellular mechanisms.

  6. IGF-1 facilitates thrombopoiesis primarily through Akt activation.

    Science.gov (United States)

    Chen, Shilei; Hu, Mengjia; Shen, Mingqiang; Wang, Song; Wang, Cheng; Chen, Fang; Tang, Yong; Wang, Xinmiao; Zeng, Hao; Chen, Mo; Gao, Jining; Wang, Fengchao; Su, Yongping; Xu, Yang; Wang, Junping

    2018-05-25

    It is known that insulin-like growth factor-1 (IGF-1) also functions as a hematopoietic factor, while its direct effect on thrombopoiesis remains unclear. In this study, we show that IGF-1 is able to promote CD34+ cell differentiation toward megakaryocytes (MKs), as well as the facilitation of proplatelet formation (PPF) and platelet production from cultured MKs. The in vivo study demonstrates that IGF-1 administration accelerates platelet recovery in mice after 6.0Gy of irradiation and in mice that received bone marrow transplantation (BMT) following 10.0Gy of lethal irradiation. Subsequent investigations reveal that ERK1/2 and Akt activation mediate the effect of IGF-1 on thrombopoiesis. Notably, Akt activation induced by IGF-1 is more apparent than that of ERK1/2, compared with that of thrombopoietin (TPO) treatment. Moreover, the effect of IGF-1 on thrombopoiesis is independent of TPO signaling, because IGF-1 treatment can also lead to a significant increase of platelet counts in homozygous TPO receptor mutant mice. Further analysis indicates that the activation of Akt triggered by IGF-1 requires the assistance of steroid receptor coactivator-3 (SRC-3). Therefore, our data reveal a distinct role of IGF-1 in regulating thrombopoiesis, providing new insights into TPO-independent regulation of platelet generation. Copyright © 2018 American Society of Hematology.

  7. IGF-I, IGF-II, and Insulin Stimulate Different Gene Expression Responses through Binding to the IGF-I Receptor

    DEFF Research Database (Denmark)

    Versteyhe, Soetkin; Klaproth, Birgit; Borup, Rehannah

    2013-01-01

    Insulin and the insulin-like growth factors (IGF)-I and -II are closely related peptides important for regulation of metabolism, growth, differentiation, and development. The IGFs exert their main effects through the IGF-I receptor. Although the insulin receptor is the main physiological receptor...... for insulin, this peptide hormone can also bind at higher concentrations to the IGF-I receptor and exert effects through it. We used microarray gene expression profiling to investigate the gene expression regulated by IGF-I, IGF-II, and insulin after stimulation of the IGF-I receptor. Fibroblasts from mice......, knockout for IGF-II and the IGF-II/cation-independent mannose-6-phosphate receptor, and expressing functional IGF-I but no insulin receptors, were stimulated for 4 h with equipotent saturating concentrations of insulin, IGF-I, and IGF-II. Each ligand specifically regulated a group of transcripts...

  8. (igf1/igf1r) with milk production tr

    African Journals Online (AJOL)

    Gosia

    2016-06-15

    Jun 15, 2016 ... fragment length polymorphism (PCR-RFLP) (TaiI and MspI restriction enzymes) and amplification-created restriction site (ACRS) (SnaBI ... is the first association study based on polymorphisms of the primary genes encoding the IGF-1 system in a small herd of .... However, protein content was highest in milk ...

  9. Interference of silibinin with IGF-1R signalling pathways protects human epidermoid carcinoma A431 cells from UVB-induced apoptosis

    International Nuclear Information System (INIS)

    Liu, Weiwei; Otkur, Wuxiyar; Li, Lingzhi; Wang, Qiong; He, Hao; Zang, Linghe; Hayashi, Toshihiko; Tashiro, Shin-ichi; Onodera, Satoshi; Xia, Mingyu; Ikejima, Takashi

    2013-01-01

    Highlights: ► Silibinin protects A431 cells from UVB irradiation-induced apoptosis. ► Up-regulation of the IGF-1R-JNK/ERK pathways by UVB induces cell apoptosis. ► Silibinin inhibits IGF-1R pathways to repress caspase-8-mediated apoptosis. -- Abstract: Ultraviolet B (UVB) from sunlight is a major cause of cutaneous lesion. Silibinin, a traditional hepatic protectant, elicits protective effects against UVB-induced cellular damage. In A431 cells, the insulin-like growth factor-1 receptor (IGF-1R) was markedly up-regulated by UVB irradiation. The activation of the IGF-1R signalling pathways contributed to apoptosis of the cells rather than rescuing the cells from death. Up-regulated IGF-1R stimulated downstream mitogen-activated protein kinases (MAPKs), such as c-Jun N-terminal kinases (JNK) and extracellular signal-regulated protein kinases 1/2 (ERK1/2). The subsequent activation of caspase-8 and caspase-3 led to apoptosis. The activation of IGF-1R signalling pathways is the cause of A431 cell death. The pharmacological inhibitors and the small interfering RNA (siRNA) targeting IGF-1R suppressed the downstream activation of JNK/ERK-caspases to help the survival of the UVB-irradiated A431 cells. Indeed, silibinin treatment suppressed the IGF-1R-JNK/ERK pathways and thus protected the cells from UVB-induced apoptosis

  10. Rufinamide, an antiepileptic drug, improves cognition and increases neurogenesis in the aged gerbil hippocampal dentate gyrus via increasing expressions of IGF-1, IGF-1R and p-CREB.

    Science.gov (United States)

    Chen, Bai Hui; Ahn, Ji Hyeon; Park, Joon Ha; Song, Minah; Kim, Hyunjung; Lee, Tae-Kyeong; Lee, Jae Chul; Kim, Young-Myeong; Hwang, In Koo; Kim, Dae Won; Lee, Choong-Hyun; Yan, Bing Chun; Kang, Il Jun; Won, Moo-Ho

    2018-04-25

    Rufinamide is a novel antiepileptic drug and commonly used in the treatment of Lennox-Gastaut syndrome. In the present study, we investigated effects of rufinamide on cognitive function using passive avoidance test and neurogenesis in the hippocampal dentate gyrus using Ki-67 (a marker for cell proliferation), doublecortin (DCX, a marker for neuroblast) and BrdU/NeuN (markers for newly generated mature neurons) immunohistochemistry in aged gerbils. Aged gerbils (24-month old) were treated with 1 mg/kg and 3 mg/kg rufinamide for 4 weeks. Treatment with 3 mg/kg rufinamide, not 1 mg/kg rufinamide, significantly improved cognitive function and increased neurogenesis, showing that proliferating cells (Ki-67-immunoreactive cells), differentiating neuroblasts (DCX-immunoreactive neuroblasts) and mature neurons (BrdU/NeuN-immunoreactive cells) in the aged dentate gyrus compared with those in the control group. When we examined its mechanisms, rufinamide significantly increased immunoreactivities of insulin-like growth factor-1 (IGF-1), its receptor (IGF-1R), and phosphorylated cAMP response element binding protein (p-CREB). However, rufinamide did not show any increase in immunoreactivities of brain-derived neurotrophic factor and its receptor. Therefore, our results indicate that rufinamide can improve cognitive function and increase neurogenesis in the hippocampus of the aged gerbil via increasing expressions of IGF-1, IGF-1R and p-CREB. Copyright © 2018 Elsevier B.V. All rights reserved.

  11. Insulin and IGF1 Receptors Are Essential for XX and XY Gonadal Differentiation and Adrenal Development in Mice

    Science.gov (United States)

    Romero, Yannick; Conne, Béatrice; Truong, Vy; Papaioannou, Marilena D.; Schaad, Olivier; Docquier, Mylène; Herrera, Pedro Luis; Wilhelm, Dagmar; Nef, Serge

    2013-01-01

    Mouse sex determination provides an attractive model to study how regulatory genetic networks and signaling pathways control cell specification and cell fate decisions. This study characterizes in detail the essential role played by the insulin receptor (INSR) and the IGF type I receptor (IGF1R) in adrenogenital development and primary sex determination. Constitutive ablation of insulin/IGF signaling pathway led to reduced proliferation rate of somatic progenitor cells in both XX and XY gonads prior to sex determination together with the downregulation of hundreds of genes associated with the adrenal, testicular, and ovarian genetic programs. These findings indicate that prior to sex determination somatic progenitors in Insr;Igf1r mutant gonads are not lineage primed and thus incapable of upregulating/repressing the male and female genetic programs required for cell fate restriction. In consequence, embryos lacking functional insulin/IGF signaling exhibit (i) complete agenesis of the adrenal cortex, (ii) embryonic XY gonadal sex reversal, with a delay of Sry upregulation and the subsequent failure of the testicular genetic program, and (iii) a delay in ovarian differentiation so that Insr;Igf1r mutant gonads, irrespective of genetic sex, remained in an extended undifferentiated state, before the ovarian differentiation program ultimately is initiated at around E16.5. PMID:23300479

  12. Stress-altered synaptic plasticity and DAMP signaling in the hippocampus-PFC axis; elucidating the significance of IGF-1/IGF-1R/CaMKIIα expression in neural changes associated with a prolonged exposure therapy.

    Science.gov (United States)

    Ogundele, Olalekan M; Ebenezer, Philip J; Lee, Charles C; Francis, Joseph

    2017-06-14

    Traumatic stress patients showed significant improvement in behavior after a prolonged exposure to an unrelated stimulus. This treatment method attempts to promote extinction of the fear memory associated with the initial traumatic experience. However, the subsequent prolonged exposure to such stimulus creates an additional layer of neural stress. Although the mechanism remains unclear, prolonged exposure therapy (PET) likely involves changes in synaptic plasticity, neurotransmitter function and inflammation; especially in parts of the brain concerned with the formation and retrieval of fear memory (Hippocampus and Prefrontal Cortex: PFC). Since certain synaptic proteins are also involved in danger-associated molecular pattern signaling (DAMP), we identified the significance of IGF-1/IGF-1R/CaMKIIα expression as a potential link between the concurrent progression of synaptic and inflammatory changes in stress. Thus, a comparison between IGF-1/IGF-1R/CaMKIIα, synaptic and DAMP proteins in stress and PET may highlight the significance of PET on synaptic morphology and neuronal inflammatory response. In behaviorally characterized Sprague-Dawley rats, there was a significant decline in neural IGF-1 (pIGF-1R expression. These animals showed a significant loss of presynaptic markers (synaptophysin; pIGF-1 (pIGF-1R was recorded in the Stress-PET group (pIGF-1/IGF-1R, an increase in activated hippocampal and cortical microglia was seen in stress (pIGF1/IGF-1R/CaMKIIα. Firstly, we showed a direct relationship between IGF-1/IGF-1R expression, presynaptic function (synaptophysin) and neurotransmitter activity in stress and PET. Secondly, we identified the possible role of CaMKIIα in post-synaptic function and regulation of small ion conductance channels. Lastly, we highlighted some of the possible links between IGF1/IGF-1R/CaMKIIα, the expression of DAMP proteins, Microglia activation, and its implication on synaptic plasticity during stress and PET. Copyright © 2017

  13. Inhibition of IGF1-R overcomes IGFBP7-induced chemotherapy resistance in T-ALL

    International Nuclear Information System (INIS)

    Bartram, Isabelle; Erben, Ulrike; Ortiz-Tanchez, Jutta; Blunert, Katja; Schlee, Cornelia; Neumann, Martin; Heesch, Sandra; Baldus, Claudia D.

    2015-01-01

    T-cell acute lymphoblastic leukemia (T-ALL) is a genetically heterogeneous disease with the need for treatment optimization. Previously, high expression of Insulin-like growth factor binding protein 7 (IGFBP7), a member of the IGF system, was identified as negative prognostic factor in adult T-ALL patients. Since aberrant IGFBP7 expression was observed in a variety of neoplasia and was relevant for prognosis in T-ALL, we investigated the functional role of IGFBP7 in Jurkat and Molt-4 cells as in vitro models for T-ALL. Jurkat and Molt-4 cells were stably transfected with an IGFBP7 over-expression vector or the empty vector as control. Proliferation of the cells was assessed by WST-1 assays and cell cycle status was measured by flow-cytometry after BrDU/7-AAD staining. The effect of IGFBP7 over-expression on sensitivity to cytostatic drugs was determined in AnnexinV/7-AAD assays. IGF1-R protein expression was measured by Western Blot and flow-cytometric analysis. IGF1-R associated gene expression profiles were generated from microarray gene expression data of 86 T-ALL patients from the Microarrays Innovations in Leukemia (MILE) multicenter study. IGFBP7-transfected Jurkat cells proliferated less, leading to a longer survival in a nutrient–limited environment. Both IGFBP7-transfected Jurkat and Molt-4 cells showed an arrest in the G0/G1 cell cycle phase. Furthermore, Jurkat IGFBP7-transfected cells were resistant to vincristine and asparaginase treatment. Surface expression and whole protein measurement of IGF1-R protein expression showed a reduced abundance of the receptor after IGFBP7 transfection in Jurkat cells. Interestingly, combination of the IGF1-R inhibitor NPV-AEW541 restored sensitivity to vincristine in IGFBP7-transfected cells. Additionally, IGF1-R associated GEP revealed an up-regulation of important drivers of T-ALL pathogenesis and regulators of chemo-resistance and apoptosis such as NOTCH1, BCL-2, PRKCI, and TP53. This study revealed a

  14. Unbound (bioavailable IGF1 enhances somatic growth

    Directory of Open Access Journals (Sweden)

    Sebastien Elis

    2011-09-01

    Understanding insulin-like growth factor-1 (IGF1 biology is of particular importance because, apart from its role in mediating growth, it plays key roles in cellular transformation, organ regeneration, immune function, development of the musculoskeletal system and aging. IGF1 bioactivity is modulated by its binding to IGF-binding proteins (IGFBPs and the acid labile subunit (ALS, which are present in serum and tissues. To determine whether IGF1 binding to IGFBPs is necessary to facilitate normal growth and development, we used a gene-targeting approach and generated two novel knock-in mouse models of mutated IGF1, in which the native Igf1 gene was replaced by Des-Igf1 (KID mice or R3-Igf1 (KIR mice. The KID and KIR mutant proteins have reduced affinity for the IGFBPs, and therefore present as unbound IGF1, or ‘free IGF1’. We found that both KID and KIR mice have reduced serum IGF1 levels and a concomitant increase in serum growth hormone levels. Ternary complex formation of IGF1 with the IGFBPs and the ALS was markedly reduced in sera from KID and KIR mice compared with wild type. Both mutant mice showed increased body weight, body and bone lengths, and relative lean mass. We found selective organomegaly of the spleen, kidneys and uterus, enhanced mammary gland complexity, and increased skeletal acquisition. The KID and KIR models show unequivocally that IGF1-complex formation with the IGFBPs is fundamental for establishing normal body and organ size, and that uncontrolled IGF bioactivity could lead to pathological conditions.

  15. Targeting both IGF-1R and mTOR synergistically inhibits growth of renal cell carcinoma in vitro

    International Nuclear Information System (INIS)

    Cardillo, Thomas M; Trisal, Preeti; Arrojo, Roberto; Goldenberg, David M; Chang, Chien-Hsing

    2013-01-01

    Advanced or metastatic renal cell carcinoma (RCC) has a poor prognosis, because it is relatively resistant to conventional chemotherapy or radiotherapy. Treatments with human interferon-α2b alone or in combination with mammalian target of rapamycin (mTOR) inhibitors have led to only a modest improvement in clinical outcome. One observation made with mTOR inhibitors is that carcinomas can overcome these inhibitory effects by activating the insulin-like growth factor-I (IGF-I) signaling pathway. Clinically, there is an association of IGF-I receptor (IGF-IR) expression in RCC and poor long-term patient survival. We have developed a humanized anti-IGF-IR monoclonal antibody, hR1, which binds to RCC, resulting in effective down-regulation of IGF-IR and moderate inhibition of cell proliferation in vitro. In this work, we evaluate the anti-tumor activity of two novel IGF-1R-targeting agents against renal cell carcinoma given alone or in combination with an mTOR inhibitor. hR1 was linked by the DOCK-AND-LOCK™ (DNL™) method to four Fabs of hR1, generating Hex-hR1, or to four molecules of interferon-α2b, generating 1R-2b. Eight human RCC cell lines were screened for IGF-1R expression and sensitivity to treatment with hR1 in vitro. Synergy with an mTOR inhibitor, temsirolimus, was tested in a cell line (ACHN) with low sensitivity to hR1. Hex-hR1 induced the down-regulation of IGF-IR at 10-fold lower concentrations compared to the parental hR1. Sensitivity to growth inhibition mediated by hR1 and Hex-hR1 treatments correlated with IGF-1R expression (higher expression was more sensitive). The potency of 1R-2b to inhibit the in vitro growth of RCC was also demonstrated in two human cell lines, ACHN and 786-O, with EC 50 –values of 63 and 48 pM, respectively. When combined with temsirolimus, a synergistic growth-inhibition with hR1, Hex-hR1, and 1R-2b was observed in ACHN cells at concentrations as low as 10 nM for hR1, 1 nM for Hex-hR1, and 2.6 nM for 1R-2b. Both Hex-hR1

  16. Depletion of the type 1 IGF receptor delays repair of radiation-induced DNA double strand breaks

    International Nuclear Information System (INIS)

    Turney, Benjamin W.; Kerr, Martin; Chitnis, Meenali M.; Lodhia, Kunal; Wang, Yong; Riedemann, Johann; Rochester, Mark; Protheroe, Andrew S.; Brewster, Simon F.; Macaulay, Valentine M.

    2012-01-01

    Background and purpose: IGF-1R depletion sensitizes prostate cancer cells to ionizing radiation and DNA-damaging cytotoxic drugs. This study investigated the hypothesis that IGF-1R regulates DNA double strand break (DSB) repair. Methods: We tested effects of IGF-1R siRNA transfection on the repair of radiation-induced DSBs by immunoblotting and immunofluorescence for γH2AX, and pulsed-field gel electrophoresis. Homologous recombination (HR) was quantified by reporter assays, and cell cycle distribution by flow cytometry. Results: We confirmed that IGF-1R depletion sensitized DU145 and PC3 prostate cancer cells to ionizing radiation. DU145 control transfectants resolved radiation-induced DSBs within 24 h, while IGF-1R depleted cells contained 30–40% unrepaired breaks at 24 h. IGF-1R depletion induced significant reduction in DSB repair by HR, although the magnitude of the repair defect suggests additional contributory factors. Radiation-induced G2-M arrest was attenuated by IGF-1R depletion, potentially suppressing cell cycle-dependent processes required for HR. In contrast, IGF-1R depletion induced only minor radiosensitization in LNCaP cells, and did not influence repair. Cell cycle profiles were similar to DU145, so were unlikely to account for differences in repair responses. Conclusions: These data indicate a role for IGF-1R in DSB repair, at least in part via HR, and support use of IGF-1R inhibitors with DNA damaging cancer treatments.

  17. Depletion of the type 1 IGF receptor delays repair of radiation-induced DNA double strand breaks.

    Science.gov (United States)

    Turney, Benjamin W; Kerr, Martin; Chitnis, Meenali M; Lodhia, Kunal; Wang, Yong; Riedemann, Johann; Rochester, Mark; Protheroe, Andrew S; Brewster, Simon F; Macaulay, Valentine M

    2012-06-01

    IGF-1R depletion sensitizes prostate cancer cells to ionizing radiation and DNA-damaging cytotoxic drugs. This study investigated the hypothesis that IGF-1R regulates DNA double strand break (DSB) repair. We tested effects of IGF-1R siRNA transfection on the repair of radiation-induced DSBs by immunoblotting and immunofluorescence for γH2AX, and pulsed-field gel electrophoresis. Homologous recombination (HR) was quantified by reporter assays, and cell cycle distribution by flow cytometry. We confirmed that IGF-1R depletion sensitized DU145 and PC3 prostate cancer cells to ionizing radiation. DU145 control transfectants resolved radiation-induced DSBs within 24 h, while IGF-1R depleted cells contained 30-40% unrepaired breaks at 24 h. IGF-1R depletion induced significant reduction in DSB repair by HR, although the magnitude of the repair defect suggests additional contributory factors. Radiation-induced G2-M arrest was attenuated by IGF-1R depletion, potentially suppressing cell cycle-dependent processes required for HR. In contrast, IGF-1R depletion induced only minor radiosensitization in LNCaP cells, and did not influence repair. Cell cycle profiles were similar to DU145, so were unlikely to account for differences in repair responses. These data indicate a role for IGF-1R in DSB repair, at least in part via HR, and support use of IGF-1R inhibitors with DNA damaging cancer treatments. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  18. CD99 triggering induces methuosis of Ewing sarcoma cells through IGF-1R/RAS/Rac1 signaling.

    Science.gov (United States)

    Manara, Maria Cristina; Terracciano, Mario; Mancarella, Caterina; Sciandra, Marika; Guerzoni, Clara; Pasello, Michela; Grilli, Andrea; Zini, Nicoletta; Picci, Piero; Colombo, Mario P; Morrione, Andrea; Scotlandi, Katia

    2016-11-29

    CD99 is a cell surface molecule that has emerged as a novel target for Ewing sarcoma (EWS), an aggressive pediatric bone cancer. This report provides the first evidence of methuosis in EWS, a non-apoptotic form of cell death induced by an antibody directed against the CD99 molecule. Upon mAb triggering, CD99 induces an IGF-1R/RAS/Rac1 complex, which is internalized into RAB5-positive endocytic vacuoles. This complex is then dissociated, with the IGF-1R recycling to the cell membrane while CD99 and RAS/Rac1 are sorted into immature LAMP-1-positive vacuoles, whose excessive accumulation provokes methuosis. This process, which is not detected in CD99-expressing normal mesenchymal cells, is inhibited by disruption of the IGF-1R signaling, whereas enhanced by IGF-1 stimulation. Induction of IGF-1R/RAS/Rac1 was also observed in the EWS xenografts that respond to anti-CD99 mAb, further supporting the role of the IGF/RAS/Rac1 axis in the hyperstimulation of macropinocytosis and selective death of EWS cells. Thus, we describe a vulnerability of EWS cells, including those resistant to standard chemotherapy, to a treatment with anti-CD99 mAb, which requires IGF-1R/RAS signaling but bypasses the need for their direct targeting. Overall, we propose CD99 targeting as new opportunity to treat EWS patients resistant to canonical apoptosis-inducing agents.

  19. Integrated molecular targeting of IGF1R and HER2 surface receptors and destruction of breast cancer cells using single wall carbon nanotubes

    International Nuclear Information System (INIS)

    Shao Ning; Lu Shaoxin; Wickstrom, Eric; Panchapakesan, Balaji

    2007-01-01

    Molecular targeting and photodynamic therapy have shown great potential for selective cancer therapy. We hypothesized that monoclonal antibodies that are specific to the IGF1 receptor and HER2 cell surface antigens could be bound to single wall carbon nanotubes (SWCNT) in order to concentrate SWCNT on breast cancer cells for specific near-infrared phototherapy. SWCNT functionalized with HER2 and IGF1R specific antibodies showed selective attachment to breast cancer cells compared to SWCNT functionalized with non-specific antibodies. After the complexes were attached to specific cancer cells, SWCNT were excited by ∼808 nm infrared photons at ∼800 mW cm -2 for 3 min. Viability after phototherapy was determined by Trypan blue exclusion. Cells incubated with SWCNT/non-specific antibody hybrids were still alive after photo-thermal treatment due to the lack of SWNT binding to the cell membrane. All cancerous cells treated with IGF1R and HER2 specific antibody/SWCNT hybrids and receiving infrared photons showed cell death after the laser excitation. Quantitative analysis demonstrated that all the cells treated with SWCNT/IGF1R and HER2 specific antibody complex were completely destroyed, while more than 80% of the cells with SWCNT/non-specific antibody hybrids remained alive. Following multi-component targeting of IGF1R and HER2 surface receptors, integrated photo-thermal therapy in breast cancer cells led to the complete destruction of cancer cells. Functionalizing SWCNT with antibodies in combination with their intrinsic optical properties can therefore lead to a new class of molecular delivery and cancer therapeutic systems

  20. IGF-II Promotes Stemness of Neural Restricted Precursors

    Science.gov (United States)

    Ziegler, Amber N.; Schneider, Joel S.; Qin, Mei; Tyler, William A.; Pintar, John E.; Fraidenraich, Diego; Wood, Teresa L.; Levison, Steven W.

    2016-01-01

    Insulin-like growth factor (IGF)-I and IGF-II regulate brain development and growth through the IGF type 1 receptor (IGF-1R). Less appreciated is that IGF-II, but not IGF-I, activates a splice variant of the insulin receptor (IR) known as IR-A. We hypothesized that IGF-II exerts distinct effects from IGF-I on neural stem/progenitor cells (NSPs) via its interaction with IR-A. Immunofluorescence revealed high IGF-II in the medial region of the subventricular zone (SVZ) comprising the neural stem cell niche, with IGF-II mRNA predominant in the adjacent choroid plexus. The IGF-1R and the IR isoforms were differentially expressed with IR-A predominant in the medial SVZ, whereas the IGF-1R was more abundant laterally. Similarly, IR-A was more highly expressed by NSPs, whereas the IGF-1R was more highly expressed by lineage restricted cells. In vitro, IGF-II was more potent in promoting NSP expansion than either IGF-I or standard growth medium. Limiting dilution and differentiation assays revealed that IGF-II was superior to IGF-I in promoting stemness. In vivo, NSPs propagated in IGF-II migrated to and took up residence in periventricular niches while IGF-I-treated NSPs predominantly colonized white matter. Knockdown of IR or IGF-1R using shRNAs supported the conclusion that the IGF-1R promotes progenitor proliferation, whereas the IR is important for self-renewal. Q-PCR revealed that IGF-II increased Oct4, Sox1, and FABP7 mRNA levels in NSPs. Our data support the conclusion that IGF-II promotes the self-renewal of neural stem/progenitors via the IR. By contrast, IGF-1R functions as a mitogenic receptor to increase precursor abundance. PMID:22593020

  1. IGF1 regulates RUNX1 expression via IRS1/2: Implications for antler chondrocyte differentiation

    OpenAIRE

    Yang, Zhan-Qing; Zhang, Hong-Liang; Duan, Cui-Cui; Geng, Shuang; Wang, Kai; Yu, Hai-Fan; Yue, Zhan-Peng; Guo, Bin

    2017-01-01

    Although IGF1 is important for the proliferation and differentiation of chondrocytes, its underlying molecular mechanism is still unknown. Here we addressed the physiologic function of IGF1 in antler cartilage and explored the interplay of IGF1, IRS1/2 and RUNX1 in chondrocyte differentiation. The results showed that IGF1 was highly expressed in antler chondrocytes. Exogenous rIGF1 could increase the proliferation of chondrocytes and cell proportion in the S phase, whereas IGF1R inhibitor PQ4...

  2. IGF system targeted therapy: Therapeutic opportunities for ovarian cancer.

    Science.gov (United States)

    Liefers-Visser, J A L; Meijering, R A M; Reyners, A K L; van der Zee, A G J; de Jong, S

    2017-11-01

    The insulin-like growth factor (IGF) system comprises multiple growth factor receptors, including insulin-like growth factor 1 receptor (IGF-1R), insulin receptor (IR) -A and -B. These receptors are activated upon binding to their respective growth factor ligands, IGF-I, IGF-II and insulin, and play an important role in development, maintenance, progression, survival and chemotherapeutic response of ovarian cancer. In many pre-clinical studies anti-IGF-1R/IR targeted strategies proved effective in reducing growth of ovarian cancer models. In addition, anti-IGF-1R targeted strategies potentiated the efficacy of platinum based chemotherapy. Despite the vast amount of encouraging and promising pre-clinical data, anti-IGF-1R/IR targeted strategies lacked efficacy in the clinic. The question is whether targeting the IGF-1R/IR signaling pathway still holds therapeutic potential. In this review we address the complexity of the IGF-1R/IR signaling pathway, including receptor heterodimerization within and outside the IGF system and downstream signaling. Further, we discuss the implications of this complexity on current targeted strategies and indicate therapeutic opportunities for successful targeting of the IGF-1R/IR signaling pathway in ovarian cancer. Multiple-targeted approaches circumventing bidirectional receptor tyrosine kinase (RTK) compensation and prevention of system rewiring are expected to have more therapeutic potential. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

  3. 1.42 A crystal structure of mini-IGF-1(2): an analysis of the disulfide isomerization property and receptor binding property of IGF-1 based on the three-dimensional structure

    International Nuclear Information System (INIS)

    Yun Caihong; Tang Yuehua; Feng Youmin; An Xiaomin; Chang Wenrui; Liang Dongcai

    2004-01-01

    Insulin and insulin-like growth factor 1 (IGF-1) share a homologous sequence, a similar three-dimensional structure and weakly overlapping biological activity, but IGF-1 folds into two thermodynamically stable disulfide isomers, while insulin folds into one unique stable tertiary structure. This is a very interesting phenomenon in which one amino acid sequence encodes two three-dimensional structures, and its molecular mechanism has remained unclear for a long time. In this study, the crystal structure of mini-IGF-1(2), a disulfide isomer of an artificial analog of IGF-1, was solved by the SAD/SIRAS method using our in-house X-ray source. Evidence was found in the structure showing that the intra-A-chain/domain disulfide bond of some molecules was broken; thus, it was proposed that disulfide isomerization begins with the breakdown of this disulfide bond. Furthermore, based on the structural comparison of IGF-1 and insulin, a new assumption was made that in insulin the several hydrogen bonds formed between the N-terminal region of the B-chain and the intra-A-chain disulfide region of the A-chain are the main reason for the stability of the intra-A-chain disulfide bond and for the prevention of disulfide isomerization, while Phe B1 and His B5 are very important for the formation of these hydrogen bonds. Moreover, the receptor binding property of IGF-1 was analyzed in detail based on the structural comparison of mini-IGF-1(2), native IGF-1, and small mini-IGF-1

  4. Metabolic Fingerprints of Circulating IGF-1 and the IGF-1/IGFBP-3 Ratio

    DEFF Research Database (Denmark)

    Knacke, Henrike; Pietzner, Maik; Do, Kieu Trinh

    2016-01-01

    OBJECTIVE: IGF-1 is known for its various physiological and severe pathophysiological effects on human metabolism; however, underlying molecular mechanisms still remain unsolved. To reveal possible molecular mechanisms mediating these effects, for the first time, we associated serum IGF-1 levels...... with multifluid untargeted metabolomics data. METHODS: Plasma/urine samples of 995 nondiabetic participants of the Study of Health in Pomerania were characterized by mass spectrometry. Sex-specific linear regression analyses were performed to assess the association of IGF-1 and IGF-1/IGF binding protein 3 ratio...... with metabolites. Additionally, the predictive ability of the plasma and urine metabolome for IGF-1 was assessed by orthogonal partial least squares analyses. RESULTS AND CONCLUSIONS: We revealed a multifaceted image of associated metabolites with large sex differences. Confirming previous reports, we detected...

  5. A chimeric receptor of the insulin-like growth factor receptor type 1 (IGFR1) and a single chain antibody specific to myelin oligodendrocyte glycoprotein activates the IGF1R signalling cascade in CG4 oligodendrocyte progenitors.

    Science.gov (United States)

    Annenkov, Alexander; Rigby, Anne; Amor, Sandra; Zhou, Dun; Yousaf, Nasim; Hemmer, Bernhard; Chernajovsky, Yuti

    2011-08-01

    In order to generate neural stem cells with increased ability to survive after transplantation in brain parenchyma we developed a chimeric receptor (ChR) that binds to myelin oligodendrocyte glycoprotein (MOG) via its ectodomain and activates the insulin-like growth factor receptor type 1 ‎‎(IGF1R) signalling cascade. Activation of this pro-survival pathway in response to ligand broadly available in the brain might increase neuroregenerative potential of transplanted precursors. The ChR was produced by fusing a MOG-specific single ‎chain antibody with the extracellular boundary of the IGF1R transmembrane segment. The ChR is expressed on the cellular surface, predominantly as a monomer, and is not N-glycosylated. To show MOG-dependent functionality of the ChR, neuroblastoma cells B104 expressing this ChR were stimulated with monolayers of cells expressing recombinant MOG. The ChR undergoes MOG-dependent tyrosine phosphorylation and homodimerisation. It promotes insulin and IGF-independent growth of the oligodendrocyte progenitor cell line CG4. The proposed mode of the ChR activation is by MOG-induced dimerisation which promotes kinase domain transphosphorylation, by-passing the requirement of conformation changes known to be important for IGF1R activation. Another ChR, which contains a segment of the β-chain ectodomain, was produced in an attempt to recapitulate some of these conformational changes, but proved non-functional. 2011 Elsevier B.V. All rights reserved.

  6. Inhibition of p70S6K1 activation by Pdcd4 overcomes the resistance to an IGF-1R/IR inhibitor in colon carcinoma cells

    OpenAIRE

    Zhang, Yan; Wang, Qing; Chen, Li; Yang, Hsin-Sheng

    2015-01-01

    Agents targeting insulin-like growth factor 1 receptor (IGF-1R) are being actively examined in clinical trials. Although there has been some initial success of single agent targeting IGF-1R, attempts in later studies failed due to resistance. This study aimed to understand the effects of programmed cell death 4 (Pdcd4) on the chemosensitivity of the IGF-1R inhibitor, OSI-906, in colorectal cancer (CRC) cells and the mechanism underlying this impact. Using OSI-906 resistant and sensitive CRC c...

  7. IGF-I Stimulates Cooperative Interaction between the IGF-I Receptor and CSK Homologous Kinase that Regulates SHPS-1 Phosphorylation in Vascular Smooth Muscle Cells

    Science.gov (United States)

    Radhakrishnan, Yashwanth; Shen, Xinchun; Maile, Laura A.; Xi, Gang

    2011-01-01

    IGF-I plays an important role in smooth muscle cell proliferation and migration. In vascular smooth muscle cells cultured in 25 mm glucose, IGF-I stimulated a significant increase in Src homology 2 domain containing protein tyrosine phosphatase substrate-1 (SHPS-1) phosphorylation compared with 5 mm glucose and this increase was required for smooth muscle cell proliferation. A proteome-wide screen revealed that carboxyl-terminal SRC kinase homologous kinase (CTK) bound directly to phosphotyrosines in the SHPS-1 cytoplasmic domain. Because the kinase(s) that phosphorylates these tyrosines in response to IGF-I is unknown, we determined the roles of IGF-I receptor (IGF-IR) and CTK in mediating SHPS-1 phosphorylation. After IGF-I stimulation, CTK was recruited to IGF-IR and subsequently to phospho-SHPS-1. Expression of an IGF-IR mutant that eliminated CTK binding reduced CTK transfer to SHPS-1, SHPS-1 phosphorylation, and cell proliferation. IGF-IR phosphorylated SHPS-1, which provided a binding site for CTK. CTK recruitment to SHPS-1 resulted in a further enhancement of SHPS-1 phosphorylation. CTK knockdown also impaired IGF-I-stimulated SHPS-1 phosphorylation and downstream signaling. Analysis of specific tyrosines showed that mutation of tyrosines 428/452 in SHPS-1 to phenylalanine reduced SHPS-1 phosphorylation but allowed CTK binding. In contrast, the mutation of tyrosines 469/495 inhibited IGF-IR-mediated the phosphorylation of SHPS-1 and CTK binding, suggesting that IGF-IR phosphorylated Y469/495, allowing CTK binding, and that CTK subsequently phosphorylated Y428/452. Based on the above findings, we conclude that after IGF-I stimulation, CTK is recruited to IGF-IR and its recruitment facilitates CTK's subsequent association with phospho-SHPS-1. This results in the enhanced CTK transfer to SHPS-1, and the two kinases then fully phosphorylate SHPS-1, which is necessary for IGF-I stimulated cellular proliferation. PMID:21799000

  8. The insulin and IGF1 receptor kinase domains are functional dimers in the activated state

    Science.gov (United States)

    Cabail, M. Zulema; Li, Shiqing; Lemmon, Eric; Bowen, Mark E.; Hubbard, Stevan R.; Miller, W. Todd

    2015-03-01

    The insulin receptor (IR) and insulin-like growth factor-1 receptor (IGF1R) are highly related receptor tyrosine kinases with a disulfide-linked homodimeric architecture. Ligand binding to the receptor ectodomain triggers tyrosine autophosphorylation of the cytoplasmic domains, which stimulates catalytic activity and creates recruitment sites for downstream signalling proteins. Whether the two phosphorylated tyrosine kinase domains within the receptor dimer function independently or cooperatively to phosphorylate protein substrates is not known. Here we provide crystallographic, biophysical and biochemical evidence demonstrating that the phosphorylated kinase domains of IR and IGF1R form a specific dimeric arrangement involving an exchange of the juxtamembrane region proximal to the kinase domain. In this dimer, the active position of α-helix C in the kinase N lobe is stabilized, which promotes downstream substrate phosphorylation. These studies afford a novel strategy for the design of small-molecule IR agonists as potential therapeutic agents for type 2 diabetes.

  9. IGF-IR internalizes with Caveolin-1 and PTRF/Cavin in HaCat cells.

    Directory of Open Access Journals (Sweden)

    Barbara Salani

    Full Text Available BACKGROUND: Insulin-like growth factor-I receptor (IGF-IR is a tyrosine kinase receptor (RTK associated with caveolae, invaginations of the plasma membrane that regulate vesicular transport, endocytosis and intracellular signaling. IGF-IR internalization represents a key mechanism of down-modulation of receptors number on plasma membrane. IGF-IR interacts directly with Caveolin-1 (Cav-1, the most relevant protein of caveolae. Recently it has been demonstrated that the Polymerase I and Transcript Release Factor I (PTRF/Cavin is required for caveolae biogenesis and function. The role of Cav-1 and PTRF/Cavin in IGF-IR internalization is still to be clarified. METHODOLOGY/PRINCIPAL FINDINGS: We have investigated the interaction of IGF-IR with Cav-1 and PTRF/Cavin in the presence of IGF1in human Hacat cells. We show that IGF-IR internalization triggers Cav-1 and PTRF/Cavin translocation from plasma membrane to cytosol and increases IGF-IR interaction with these proteins. In fact, Cav-1 and PTRF/Cavin co-immunoprecipitate with IGF-IR during receptor internalization. We found a different time course of co-immunoprecipitation between IGF-IR and Cav-1 compared to IGF-IR and PTRF/Cavin. Cav-1 and PTRF/Cavin silencing by siRNA differently affect surface IGF-IR levels following IGF1 treatment: Cav-1 and PTRF/Cavin silencing significantly affect IGF-IR rate of internalization, while PTRF/Cavin silencing also decreases IGF-IR plasma membrane recovery. Since Cav-1 phosphorylation could have a role in IGF-IR internalization, the mutant Cav-1Y14F lacking Tyr14 was transfected. Cav-1Y14F transfected cells showed a reduced internalization of IGF-IR compared with cells expressing wild type Cav-1. Receptor internalization was not impaired by Clathrin silencing. These findings support a critical role of caveolae in IGF-IR intracellular traveling. CONCLUSIONS/SIGNIFICANCE: These data indicate that Caveolae play a role in IGF-IR internalization. Based on these findings

  10. TSH-Mediated TNFα Production in Human Fibrocytes Is Inhibited by Teprotumumab, an IGF-1R Antagonist.

    Directory of Open Access Journals (Sweden)

    Hong Chen

    Full Text Available Fibrocytes (FC are bone marrow-derived progenitor cells that are more abundant and infiltrate the thyroid and orbit in Graves orbitopathy (GO. FCs express high levels of thyrotropin receptor (TSHR and insulin-like growth factor-1 receptor (IGF-1R. These receptors are physically and functionally associated, but their role in GO pathogenesis is not fully delineated. Treatment of FCs with thyroid stimulating hormone (TSH or M22 (activating antibody to TSHR induces the production of numerous cytokines, including tumor necrosis factor α (TNFα. Teprotumumab (TMB is a human monoclonal IGF-1R blocking antibody currently in clinical trial for GO and inhibits TSHR-mediated actions in FCs.To characterize the molecular mechanisms underlying TSH-induced TNFα production by FCs, and the role of IGF-1R blockade by TMB.FCs from healthy and GD patients were treated with combinations of TSH, M22, MG132 and AKTi (inhibitors of NF-κB and Akt, respectively, and TMB. TNFα protein production was measured by Luminex and flow cytometry. Messenger RNA expression was quantified by real time PCR.Treatment with TSH/M22 induced TNFα protein and mRNA production by FCs, both of which were reduced when FCs were pretreated with MG132 and AKTi (p<0.0001. TMB decreased TSH-induced TNFα protein production in circulating FCs from mean fluorescent index (MFI value of 2.92 to 1.91, and mRNA expression in cultured FCs from 141- to 52-fold expression (p<0.0001. TMB also decreased M22-induced TNFα protein production from MFI of 1.67 to 1.12, and mRNA expression from 6- to 3-fold expression (p<0.0001.TSH/M22 stimulates FC production of TNFα mRNA and protein. This process involves the transcription factor NF-κB and its regulator Akt. Blocking IGF-1R attenuates TSH/M22-induced TNFα production. This further delineates the interaction of TSHR and IGF1-R signaling pathways. By modulating the proinflammatory properties of FCs such as TNFα production, TMB may be a promising

  11. Anabolic effects of IGF-1 signaling on the skeleton

    Science.gov (United States)

    Tahimic, Candice G. T.; Wang, Yongmei; Bikle, Daniel D.

    2013-01-01

    This review focuses on the anabolic effects of IGF-1 signaling on the skeleton, emphasizing the requirement for IGF-1 signaling in normal bone formation and remodeling. We first discuss the genomic context, splicing variants, and species conservation of the IGF-1 locus. The modulation of IGF-1 action by growth hormone (GH) is then reviewed while also discussing the current model which takes into account the GH-independent actions of IGF-1. Next, the skeletal phenotypes of IGF-1-deficient animals are described in both embryonic and postnatal stages of development, which include severe dwarfism and an undermineralized skeleton. We then highlight two mechanisms by which IGF-1 exerts its anabolic action on the skeleton. Firstly, the role of IGF-1 signaling in the modulation of anabolic effects of parathyroid hormone (PTH) on bone will be discussed, presenting in vitro and in vivo studies that establish this concept and the proposed underlying molecular mechanisms involving Indian hedgehog (Ihh) and the ephrins. Secondly, the crosstalk of IGF-1 signaling with mechanosensing pathways will be discussed, beginning with the observation that animals subjected to skeletal unloading by hindlimb elevation are unable to mitigate cessation of bone growth despite infusion with IGF-1 and the failure of IGF-1 to activate its receptor in bone marrow stromal cell cultures from unloaded bone. Disrupted crosstalk between IGF-1 signaling and the integrin mechanotransduction pathways is discussed as one of the potential mechanisms for this IGF-1 resistance. Next, emerging paradigms on bone-muscle crosstalk are examined, focusing on the potential role of IGF-1 signaling in modulating such interactions. Finally, we present a future outlook on IGF research. PMID:23382729

  12. Antibody-based therapeutics against components of the IGF system

    OpenAIRE

    Feng, Yang; Dimitrov, Dimiter S.

    2012-01-01

    The insulin-like growth factor I (IGF-I) receptor (IGF-1R) is overexpressed in most human neoplasms tested so far. Many tumors in young patients produce high levels of the IGF-1R ligands, IGF-I and IGF-II. Given the complexity of the IGF signaling pathway, its complete inhibition may require combination therapies with antibodies targeting both IGF-1R and IGF-II.

  13. Distinct signalling properties of insulin receptor substrate (IRS)-1 and IRS-2 in mediating insulin/IGF-1 action

    DEFF Research Database (Denmark)

    Rabiee, Atefeh; Krüger, Marcus; Ardenkjær-Larsen, Jacob

    2018-01-01

    Insulin/IGF-1 action is driven by a complex and highly integrated signalling network. Loss-of-function studies indicate that the major insulin/IGF-1 receptor substrate (IRS) proteins, IRS-1 and IRS-2, mediate different biological functions in vitro and in vivo, suggesting specific signalling...... properties despite their high degree of homology. To identify mechanisms contributing to the differential signalling properties of IRS-1 and IRS-2 in the mediation of insulin/IGF-1 action, we performed comprehensive mass spectrometry (MS)-based phosphoproteomic profiling of brown preadipocytes from wild type......, IRS-1-/-and IRS-2-/-mice in the basal and IGF-1-stimulated states. We applied stable isotope labeling by amino acids in cell culture (SILAC) for the accurate quantitation of changes in protein phosphorylation. We found ~10% of the 6262 unique phosphorylation sites detected to be regulated by IGF-1...

  14. Reversal of oncogene transformation and suppression of tumor growth by the novel IGF1R kinase inhibitor A-928605

    International Nuclear Information System (INIS)

    Pappano, William N; Sheppard, George S; Donawho, Cherrie; Buchanan, Fritz G; Davidsen, Steven K; Bell, Randy L; Wang, Jieyi; Jung, Paul M; Meulbroek, Jonathan A; Wang, Yi-Chun; Hubbard, Robert D; Zhang, Qian; Grudzien, Meagan M; Soni, Niru B; Johnson, Eric F

    2009-01-01

    The insulin-like growth factor (IGF) axis is an important signaling pathway in the growth and survival of many cell and tissue types. This pathway has also been implicated in many aspects of cancer progression from tumorigenesis to metastasis. The multiple roles of IGF signaling in cancer suggest that inhibition of the pathway might yield clinically effective therapeutics. We describe A-928605, a novel pyrazolo [3,4-d]pyrimidine small molecule inhibitor of the receptor tyrosine kinases (IGF1R and IR) responsible for IGF signal transduction. This compound was first tested for its activity and selectivity via conventional in vitro kinome profiling and cellular IGF1R autophosphorylation. Additionally, cellular selectivity and efficacy of A-928605 were analyzed in an IGF1R oncogene-addicted cell line by proliferation, signaling and microarray studies. Finally, in vivo efficacy of A-928605 was assessed in the oncogene-addicted cell line and in a neuroblastoma model as a single agent as well as in combination with clinically approved therapeutics targeting EGFR in models of pancreatic and non-small cell lung cancers. A-928605 is a selective IGF1R inhibitor that is able to abrogate activation of the pathway both in vitro and in vivo. This novel compound dosed as a single agent is able to produce significant growth inhibition of neuroblastoma xenografts in vivo. A-928605 is also able to provide additive effects when used in combination with clinically approved agents directed against EGFR in non-small cell lung and human pancreatic tumor models. These results suggest that a selective IGF1R inhibitor such as A-928605 may provide a useful clinical therapeutic for IGF pathway affected tumors and warrants further investigation

  15. Cyclic glycine-proline regulates IGF-1 homeostasis by altering the binding of IGFBP-3 to IGF-1

    Science.gov (United States)

    Guan, Jian; Gluckman, Peter; Yang, Panzao; Krissansen, Geoff; Sun, Xueying; Zhou, Yongzhi; Wen, Jingyuan; Phillips, Gemma; Shorten, Paul R.; McMahon, Chris D.; Wake, Graeme C.; Chan, Wendy H. K.; Thomas, Mark F.; Ren, April; Moon, Steve; Liu, Dong-Xu

    2014-03-01

    The homeostasis of insulin-like growth factor-1 (IGF-1) is essential for metabolism, development and survival. Insufficient IGF-1 is associated with poor recovery from wounds whereas excessive IGF-1 contributes to growth of tumours. We have shown that cyclic glycine-proline (cGP), a metabolite of IGF-1, can normalise IGF-1 function by showing its efficacy in improving the recovery from ischemic brain injury in rats and inhibiting the growth of lymphomic tumours in mice. Further investigation in cell culture suggested that cGP promoted the activity of IGF-1 when it was insufficient, but inhibited the activity of IGF-1 when it was excessive. Mathematical modelling revealed that the efficacy of cGP was a modulated IGF-1 effect via changing the binding of IGF-1 to its binding proteins, which dynamically regulates the balance between bioavailable and non-bioavailable IGF-1. Our data reveal a novel mechanism of auto-regulation of IGF-1, which has physiological and pathophysiological consequences and potential pharmacological utility.

  16. Insulin growth factor-1 receptor (IGF-1R) expression as a prognostic indicator of local recurrence in conservatively treated breast cancer: a case-control study

    International Nuclear Information System (INIS)

    Turner, B.C.; Haffty, B.G.; Carter, D.; Gumbs, A.A.; Naryanan, L.; Baserga, R.; Glazer, P.M.

    1996-01-01

    Purpose: The IGF-1R is a glycoprotein receptor that consists of a heterodimer of two alpha and two beta subunits which are processed from a single precursor transmembrane polypeptide and has been found to be overexpressed in a variety of tumors. IGF-1R has been shown to play a critical role in malignant transformation and to influence apoptosis. We have recently shown in gene transfer studies that overexpression of the IGF-1R confers relative radioresistance on mouse fibroblasts in culture. To test the significance of this finding in a clinical setting, we have sought to determine the prognostic significance of overexpression of IGF-1R with respect to ipsilateral breast tumor recurrence (IBTR) in the conservatively treated breast cancer patient. Materials and Methods: Over 1,000 breast cancer patients treated with conservative surgery followed by radiation therapy to the intact breast served as the patient population for this study. Twenty-five patients with a diagnosis of invasive ductal carcinoma who had an IBTR as the first site of failure comprised the index case population base of this study. Following the identification of 25 patients with IBTR, the breast database was searched for 25 matching control patients who did not have an IBTR. The control patients were matched to the index case with respect to age (within 5 years), menopausal status, approximate date of radiation therapy, primary histology, axillary dissection, nodal status, primary tumor size, estrogen/progesterone receptor (ER/PR) status, and adjuvant chemotherapy/hormonal therapy. Both index cases and the matched control group received radiation therapy to a total dose of 64 Gy to the tumor bed. Following identification of index and control cases, the individual paraffin-embedded blocks (PEB) were evaluated for invasive ductal carcinoma with H and E staining by the pathologist. All PEB were then processed for immunohistochemical staining with a polyclonal antibody to the beta-chain of IGF-1R

  17. A chimeric receptor of the insulin-like growth factor receptor type 1 (IGFR1) and a single chain antibody specific to myelin oligodendrocyte glycoprotein activates the IGF1R signalling cascade in CG4 oligodendrocyte progenitors

    NARCIS (Netherlands)

    Annenkov, A.; Rigby, A.; Amor, S.; Zhou, D.M.; Yousaf, N.; Hemmer, B.; Chernajovsky, Y.

    2011-01-01

    In order to generate neural stem cells with increased ability to survive after transplantation in brain parenchyma we developed a chimeric receptor (ChR) that binds to myelin oligodendrocyte glycoprotein (MOG) via its ectodomain and activates the insulin-like growth factor receptor type 1 (IGF1R)

  18. Insulin-Like Growth Factor (IGF Binding Protein-2, Independently of IGF-1, Induces GLUT-4 Translocation and Glucose Uptake in 3T3-L1 Adipocytes

    Directory of Open Access Journals (Sweden)

    Biruhalem Assefa

    2017-01-01

    Full Text Available Insulin-like growth factor binding protein-2 (IGFBP-2 is the predominant IGF binding protein produced during adipogenesis and is known to increase the insulin-stimulated glucose uptake (GU in myotubes. We investigated the IGFBP-2-induced changes in basal and insulin-stimulated GU in adipocytes and the underlying mechanisms. We further determined the role of insulin and IGF-1 receptors in mediating the IGFBP-2 and the impact of IGFBP-2 on the IGF-1-induced GU. Fully differentiated 3T3-L1 adipocytes were treated with IGFBP-2 in the presence and absence of insulin and IGF-1. Insulin, IGF-1, and IGFBP-2 induced a dose-dependent increase in GU. IGFBP-2 increased the insulin-induced GU after long-term incubation. The IGFBP-2-induced impact on GU was neither affected by insulin or IGF-1 receptor blockage nor by insulin receptor knockdown. IGFBP-2 significantly increased the phosphorylation of PI3K, Akt, AMPK, TBC1D1, and PKCζ/λ and induced GLUT-4 translocation. Moreover, inhibition of PI3K and AMPK significantly reduced IGFBP-2-stimulated GU. In conclusion, IGFBP-2 stimulates GU in 3T3-L1 adipocytes through activation of PI3K/Akt, AMPK/TBC1D1, and PI3K/PKCζ/λ/GLUT-4 signaling. The stimulatory effect of IGFBP-2 on GU is independent of its binding to IGF-1 and is possibly not mediated through the insulin or IGF-1 receptor. This study highlights the potential role of IGFBP-2 in glucose metabolism.

  19. Maternal insulin-like growth factors 1 and 2 (IGF-1, IGF-2) and IGF BP-3 and the hypertensive disorders of pregnancy.

    LENUS (Irish Health Repository)

    Cooley, Sharon M

    2012-02-01

    OBJECTIVE: To investigate the relationship between levels of insulin-like growth factors 1 and 2 (IGF-1, IGF-2) and insulin-like growth factor binding protein 3 (IGFBP-3) in antenatal maternal serum and gestational hypertension and pre-eclampsia (PET). METHODS: Prospective cohort study of 1650 low-risk Caucasian women in a University teaching hospital in London. Statistical analysis was performed using commercial software (SPSS for Windows, version 6.1, SPSS, Chicago, IL), with P < 0.05 as significant. Maternal IGF 1, IGF 2 and IGF BP-3 were assessed on maternal blood at booking. Blood pressure was checked at each visit in conjunction with urine analysis. The Davey & MacGillivray 1988 classification system was used in making the diagnosis of PET. RESULTS: There was no significant correlation between maternal IGF-1 or IGFBP-3 levels and gestational hypertension or PET. However, a significant positive correlation does exist between maternal IGF-2 levels and PET. CONCLUSIONS: Maternal IGF-2 has a significant positive correlation with PET.

  20. Aging, Atherosclerosis, and IGF-1

    Science.gov (United States)

    Higashi, Yusuke; Sukhanov, Sergiy; Anwar, Asif; Shai, Shaw-Yung

    2012-01-01

    Insulin-like growth factor 1 (IGF-1) is an endocrine and autocrine/paracrine growth factor that circulates at high levels in the plasma and is expressed in most cell types. IGF-1 has major effects on development, cell growth and differentiation, and tissue repair. Recent evidence indicates that IGF-1 reduces atherosclerosis burden and improves features of atherosclerotic plaque stability in animal models. Potential mechanisms for this atheroprotective effect include IGF-1–induced reduction in oxidative stress, cell apoptosis, proinflammatory signaling, and endothelial dysfunction. Aging is associated with increased vascular oxidative stress and vascular disease, suggesting that IGF-1 may exert salutary effects on vascular aging processes. In this review, we will provide a comprehensive update on IGF-1's ability to modulate vascular oxidative stress and to limit atherogenesis and the vascular complications of aging. PMID:22491965

  1. Synthetic ligands of the elastin receptor induce elastogenesis in human dermal fibroblasts via activation of their IGF-1 receptors.

    Science.gov (United States)

    Qa'aty, Nour; Vincent, Matthew; Wang, Yanting; Wang, Andrew; Mitts, Thomas F; Hinek, Aleksander

    2015-12-01

    We have previously reported that a mixture of peptides obtained after chemical or enzymatic degradation of bovine elastin, induced new elastogenesis in human skin. Now, we investigated the elastogenic potential of synthetic peptides mimicking the elastin-derived, VGVAPG sequence, IGVAPG sequence that we found in the rice bran, and a similar peptide, VGVTAG that we identified in the IGF-1-binding protein-1 (IGFBP-1). We now demonstrate that treatment with each of these xGVxxG peptides (recognizable by the anti-elastin antibody), up-regulated the levels of elastin-encoding mRNA, tropoelastin protein, and the deposition of new elastic fibers in cultures of human dermal fibroblasts and in cultured explants of human skin. Importantly, we found that such induction of new elastogenesis may involve two parallel signaling pathways triggered after activation of IGF-1 receptor. In the first one, the xGVxxG peptides interact with the cell surface elastin receptor, thereby causing the downstream activation of the c-Src kinase and a consequent cross-activation of the adjacent IGF-1R, even in the absence of its principal ligand. In the second pathway their hydrophobic association with the N-terminal domain (VGVTAG) of the serum-derived IGFBP-1 induces conformational changes of this IGF-1 chaperone allowing for the release of its cargo and a consequent ligand-specific phosphorylation of IGF-1R. We present a novel, clinically relevant mechanism in which products of partial degradation of dermal elastin may stimulate production of new elastic fibers by dermal fibroblasts. Our findings particularly encourage the use of biologically safe synthetic xGVxxG peptides for regeneration of the injured or aged human skin. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  2. Changes of Cerebral and/or Peripheral Adenosine A1 Receptor and IGF-I Concentrations under Extended Sleep Duration in Rats

    Directory of Open Access Journals (Sweden)

    Mounir Chennaoui

    2017-11-01

    Full Text Available Extended sleep improves sustained attention and reduces sleep pressure in humans. Downregulation of adenosine A1 receptor (A1R and modulation of the neurotrophic factor insulin growth factor-1 (IGF-I in brain structures controlling attentional capacities could be involved. In the frontal cortex and hippocampus of rats, we measured adenosine A1R and IGF-I protein concentrations after photoperiod-induced sleep extension. Two groups of twelve rats were adapted over 14 days to a habitual (CON 12:12 light–dark (LD schedule and an extended (EXT 16:8 LD schedule. IGF-I content was also measured in plasma, liver, and skeletal muscle. In EXT, compared to CON rats, A1R content in the frontal cortex was significantly lower (p < 0.05, while IGF-I content was higher (p < 0.001, and no significant change was observed in the hippocampus. IGF-I content in plasma and muscle was higher (p < 0.001 and p < 0.01, while it was lower in liver (p < 0.001. The absolute weight and weight gain were higher in EXT rats (p < 0.01. These data suggest that 14 days under a 16:8 LD photoperiod respectively down- and upregulated cortical A1R and IGF-I levels. This photoperiod induced an anabolic profile with increased weight gain and circulating and muscular IGF-I levels. An extension of sleep duration might favor cerebral and peripheral anabolism, which may help attentional and physical capacities.

  3. IGF-1R Regulates the Extracellular Level of Active MMP-2, Pathological Neovascularization, and Functionality in Retinas of OIR Mouse Model.

    Science.gov (United States)

    Lorenc, Valeria E; Subirada Caldarone, Paula V; Paz, María C; Ferrer, Darío G; Luna, José D; Chiabrando, Gustavo A; Sánchez, María C

    2018-02-01

    In ischemic proliferative diseases such as retinopathies, persistent hypoxia leads to the release of numerous neovascular factors that participate in the formation of abnormal vessels and eventually cause blindness. The upregulation and activation of metalloproteinases (MMP-2 and MMP-9) represent a final common pathway in this process. Although many regulators of the neovascular process have been identified, the complete role of the insulin-like growth factor 1 (IGF-1) and its receptor (IGF-1R) appears to be significantly more complex. In this study, we used an oxygen-induced retinopathy (OIR) mouse model as well as an in vitro model of hypoxia to study the role of MMP-2 derived from Müller glial cells (MGCs) and its relation with the IGF-1/IGF-1R system. We demonstrated that MMP-2 protein expression increased in P17 OIR mice, which coincided with the active phase of the neovascular process. Also, glutamine synthetase (GS)-positive cells were also positive for MMP-2, whereas IGF-1R was expressed by GFAP-positive cells, indicating that both proteins were expressed in MGCs. In addition, in the OIR model a single intravitreal injection of the IGF-1R blocking antibody (αIR3) administered at P12 effectively prevented pathologic neovascularization, accelerated physiological revascularization, and improved retinal functionality at P17. Finally, in MGC supernatants, the blocking antibody abolished the IGF-1 effect on active MMP-2 under normoxic and hypoxic conditions without affecting the extracellular levels of pro-MMP-2. These results demonstrate, for the first time, that the IGF-1/IGF-1R system regulates active MMP-2 levels in MGCs, thus contributing to MEC remodeling during the retinal neovascular process.

  4. Insulin-like growth factor 1 (IGF-1): a growth hormone

    Science.gov (United States)

    Laron, Z

    2001-01-01

    Aim—To contribute to the debate about whether growth hormone (GH) and insulin-like growth factor 1 (IGF-1) act independently on the growth process. Methods—To describe growth in human and animal models of isolated IGF-1 deficiency (IGHD), such as in Laron syndrome (LS; primary IGF-1 deficiency and GH resistance) and IGF-1 gene or GH receptor gene knockout (KO) mice. Results—Since the description of LS in 1966, 51 patients were followed, many since infancy. Newborns with LS are shorter (42–47 cm) than healthy babies (49–52 cm), suggesting that IGF-1 has some influence on intrauterine growth. Newborn mice with IGF-1 gene KO are 30% smaller. The postnatal growth rate of patients with LS is very slow, the distance from the lowest normal centile increasing progressively. If untreated, the final height is 100–136 cm for female and 109–138 cm for male patients. They have acromicia, organomicria including the brain, heart, gonads, genitalia, and retardation of skeletal maturation. The availability of biosynthetic IGF-1 since 1988 has enabled it to be administered to children with LS. It accelerated linear growth rates to 8–9 cm in the first year of treatment, compared with 10–12 cm/year during GH treatment of IGHD. The growth rate in following years was 5–6.5 cm/year. Conclusion—IGF-1 is an important growth hormone, mediating the protein anabolic and linear growth promoting effect of pituitary GH. It has a GH independent growth stimulating effect, which with respect to cartilage cells is possibly optimised by the synergistic action with GH. PMID:11577173

  5. The level of insulin growth factor-1 receptor expression is directly correlated with the tumor uptake of {sup 111}In-IGF-1(E3R) in vivo and the clonogenic survival of breast cancer cells exposed in vitro to trastuzumab (Herceptin)

    Energy Technology Data Exchange (ETDEWEB)

    Cornelissen, Bart; McLarty, Kristin; Kersemans, Veerle [Department of Pharmaceutical Sciences, University of Toronto, Toronto, ON, M5S 3M2 (Canada); Reilly, Raymond M. [Department of Pharmaceutical Sciences, University of Toronto, Toronto, ON, M5S 3M2 (Canada); Department of Medical Imaging, University of Toronto, Toronto, ON, M5S 3M2 (Canada); Toronto General Research Institute, University Health Network Toronto, Toronto, ON, M5S 3M2 (Canada)], E-mail: raymond.reilly@utoronto.ca

    2008-08-15

    Introduction: Our objective was to define the relationships between tumor uptake of [{sup 111}In]-IGF-1 and [{sup 111}In]-IGF-1(E3R), an analogue which does not bind insulin growth factor-1 (IGF-1) binding proteins (i.e., IGFBP-3), and the level of IGF-1 receptor (IGF-1R) expression on human breast cancer (BC) xenografts in athymic mice, as well as the feasibility for tumor imaging. A second objective was to correlate IGF-1R (and HER2 density) with the cytotoxicity of trastuzumab in the absence/presence of IGFBP-3 or the IGF-1R tyrosine kinase inhibitor, AG1024. Methods: The tumor and normal tissue uptake of [{sup 111}In]-IGF-1 and [{sup 111}In]-IGF-1(E3R) were determined at 4 h postinjection in mice implanted subcutaneously with MDA-MB-231, H2N, HR2 or MCF-7/HER2-18 human BC xenografts (8.5x10{sup 4}, 1.4x10{sup 4}, 4.0x10{sup 4} and 1.0x10{sup 5} IGF-1R/cell, respectively). The effect of co-injection of IGF-1 (50 {mu}g) or IGFBP-3 (2 or 25 {mu}g) was studied. The relationship between tumor uptake of [{sup 111}In]-IGF-1(E3R) and IGF-1R density was examined. MicroSPECT/CT imaging was performed on mice with MCF-7/HER2-18 tumors injected with [{sup 111}In]-IGF-1(E3R). The surviving fraction of BC cells exposed to trastuzumab (67.5 {mu}g/ml) in the absence/presence of IGFBP-3 (1 {mu}g/ml) or the IGF-1R kinase inhibitor, AG1024 (1 or 5 {mu}g/ml), was determined. Results: [{sup 111}In]-IGF-1 was specifically taken up by MCF-7/HER2-18 xenografts; tumor uptake was decreased twofold when co-injected with IGF-1 (1.9{+-}0.1 vs. 1.0{+-}0.1 %ID/g). Co-injection of IGBP-3 decreased kidney uptake of [{sup 111}In]-IGF-1 up to twofold and increased circulating radioactivity threefold. There was a strong linear correlation (r{sup 2}=0.99) between the tumor uptake of {sup 111}In-IGF-1(E3R) and IGF-1R density. Tumor uptake ranged from 0.4{+-}0.05 %ID/g for H2N to 2.5{+-}0.5 %ID/g for MCF-7/HER2-18 xenografts. MCF-7/HER2-18 tumors were visualized by microSPECT/CT. Resistance of BC

  6. The level of insulin growth factor-1 receptor expression is directly correlated with the tumor uptake of 111In-IGF-1(E3R) in vivo and the clonogenic survival of breast cancer cells exposed in vitro to trastuzumab (Herceptin)

    International Nuclear Information System (INIS)

    Cornelissen, Bart; McLarty, Kristin; Kersemans, Veerle; Reilly, Raymond M.

    2008-01-01

    Introduction: Our objective was to define the relationships between tumor uptake of [ 111 In]-IGF-1 and [ 111 In]-IGF-1(E3R), an analogue which does not bind insulin growth factor-1 (IGF-1) binding proteins (i.e., IGFBP-3), and the level of IGF-1 receptor (IGF-1R) expression on human breast cancer (BC) xenografts in athymic mice, as well as the feasibility for tumor imaging. A second objective was to correlate IGF-1R (and HER2 density) with the cytotoxicity of trastuzumab in the absence/presence of IGFBP-3 or the IGF-1R tyrosine kinase inhibitor, AG1024. Methods: The tumor and normal tissue uptake of [ 111 In]-IGF-1 and [ 111 In]-IGF-1(E3R) were determined at 4 h postinjection in mice implanted subcutaneously with MDA-MB-231, H2N, HR2 or MCF-7/HER2-18 human BC xenografts (8.5x10 4 , 1.4x10 4 , 4.0x10 4 and 1.0x10 5 IGF-1R/cell, respectively). The effect of co-injection of IGF-1 (50 μg) or IGFBP-3 (2 or 25 μg) was studied. The relationship between tumor uptake of [ 111 In]-IGF-1(E3R) and IGF-1R density was examined. MicroSPECT/CT imaging was performed on mice with MCF-7/HER2-18 tumors injected with [ 111 In]-IGF-1(E3R). The surviving fraction of BC cells exposed to trastuzumab (67.5 μg/ml) in the absence/presence of IGFBP-3 (1 μg/ml) or the IGF-1R kinase inhibitor, AG1024 (1 or 5 μg/ml), was determined. Results: [ 111 In]-IGF-1 was specifically taken up by MCF-7/HER2-18 xenografts; tumor uptake was decreased twofold when co-injected with IGF-1 (1.9±0.1 vs. 1.0±0.1 %ID/g). Co-injection of IGBP-3 decreased kidney uptake of [ 111 In]-IGF-1 up to twofold and increased circulating radioactivity threefold. There was a strong linear correlation (r 2 =0.99) between the tumor uptake of 111 In-IGF-1(E3R) and IGF-1R density. Tumor uptake ranged from 0.4±0.05 %ID/g for H2N to 2.5±0.5 %ID/g for MCF-7/HER2-18 xenografts. MCF-7/HER2-18 tumors were visualized by microSPECT/CT. Resistance of BC cells to trastuzumab was directly associated with IGF-1R expression, despite co

  7. 18FDG-PET predicts pharmacodynamic response to OSI-906, a dual IGF-1R/IR inhibitor, in preclinical mouse models of lung cancer.

    Science.gov (United States)

    McKinley, Eliot T; Bugaj, Joseph E; Zhao, Ping; Guleryuz, Saffet; Mantis, Christine; Gokhale, Prafulla C; Wild, Robert; Manning, H Charles

    2011-05-15

    To evaluate 2-deoxy-2-[(18)F]fluoro-d-glucose positron emission tomography imaging ((18)FDG-PET) as a predictive, noninvasive, pharmacodynamic (PD) biomarker of response following administration of a small-molecule insulin-like growth factor-1 receptor and insulin receptor (IGF-1R/IR) inhibitor, OSI-906. In vitro uptake studies of (3)H-2-deoxy glucose following OSI-906 exposure were conducted evaluating correlation of dose with inhibition of IGF-1R/IR as well as markers of downstream pathways and glucose metabolism. Similarly, in vivo PD effects were evaluated in human tumor cell line xenografts propagated in athymic nude mice by (18)FDG-PET at 2, 4, and 24 hours following a single treatment of OSI-906 for the correlation of inhibition of receptor targets and downstream markers. Uptake of (3)H-2-deoxy glucose and (18)FDG was significantly diminished following OSI-906 exposure in sensitive tumor cells and subcutaneous xenografts (NCI-H292) but not in an insensitive model lacking IGF-1R expression (NCI-H441). Diminished PD (18)FDG-PET, collected immediately following the initial treatment agreed with inhibition of pIGF-1R/pIR, reduced PI3K (phosphoinositide 3-kinase) and MAPK (mitogen activated protein kinase) pathway activity, and predicted tumor growth arrest as measured by high-resolution ultrasound imaging. (18)FDG-PET seems to serve as a rapid, noninvasive PD marker of IGF-1R/IR inhibition following a single dose of OSI-906 and should be explored clinically as a predictive clinical biomarker in patients undergoing IGF-1R/IR-directed cancer therapy. ©2011 AACR.

  8. IGF-1 promotes the development and cytotoxic activity of human NK cells

    Science.gov (United States)

    Ni, Fang; Sun, Rui; Fu, Binqing; Wang, Fuyan; Guo, Chuang; Tian, Zhigang; Wei, Haiming

    2013-01-01

    Insulin-like growth factor 1 (IGF-1) is a critical regulator of many physiological functions, ranging from longevity to immunity. However, little is known about the role of IGF-1 in natural killer cell development and function. Here, we identify an essential role for IGF-1 in the positive regulation of human natural killer cell development and cytotoxicity. Specifically, we show that human natural killer cells have the ability to produce IGF-1 and that differential endogenous IGF-1 expression leads to disparate cytotoxicity in human primary natural killer cells. Moreover, miR-483-3p is identified as a critical regulator of IGF-1 expression in natural killer cells. Overexpression of miR-483-3p has an effect similar to IGF-1 blockade and decreased natural killer cell cytotoxicity, whereas inhibition of miR-483-3p has the opposite effect, which is reversible with IGF-1 neutralizing antibody. These findings indicate that IGF-1 and miR-483-3p belong to a new class of natural killer cell functional modulators and strengthen the prominent role of IGF-1 in innate immunity. PMID:23403580

  9. Tumor-targeting magnetic lipoplex delivery of short hairpin RNA suppresses IGF-1R overexpression of lung adenocarcinoma A549 cells in vitro and in vivo.

    Science.gov (United States)

    Wang, Chunmao; Ding, Chao; Kong, Minjian; Dong, Aiqiang; Qian, Jianfang; Jiang, Daming; Shen, Zhonghua

    2011-07-08

    Liposomal magnetofection potentiates gene transfection by applying a magnetic field to concentrate magnetic lipoplexes onto target cells. Magnetic lipoplexes are self-assembling ternary complexes of cationic lipids with plasmid DNA associated with superparamagnetic iron oxide nanoparticles (SPIONs). Type1 insulin-like growth factor receptor (IGF-1R), an important oncogene, is frequently overexpressed in lung cancer and mediates cancer cell proliferation and tumor growth. In this study, we evaluated the transfection efficiency (percentage of transfected cells) and therapeutic potential (potency of IGF-1R knockdown) of liposomal magnetofection of plasmids expressing GFP and shRNAs targeting IGF-1R (pGFPshIGF-1Rs) in A549 cells and in tumor-bearing mice as compared to lipofection using Lipofectamine 2000. Liposomal magnetofection provided a threefold improvement in transgene expression over lipofection and transfected up to 64.1% of A549 cells in vitro. In vitro, IGF-1R specific-shRNA transfected by lipofection inhibited IGF-1R protein by 56.1±6% and by liposomal magnetofection by 85.1±3%. In vivo delivery efficiency of the pGFPshIGF-1R plasmid into the tumor was significantly higher in the liposomal magnetofection group than in the lipofection group. In vivo IGF-1R specific-shRNA by lipofection inhibited IGF-1R protein by an average of 43.8±5.3%; that by liposomal magnetofection inhibited IGF-1R protein by 43.4±5.7%, 56.3±9.6%, and 72.2±6.8%, at 24, 48, and 72 h, respectively, after pGFPshIGF-1R injection. Our findings indicate that liposomal magnetofection may be a promising method that allows the targeting of gene therapy to lung cancer. Copyright © 2011 Elsevier Inc. All rights reserved.

  10. Cyclic glycine-proline regulates IGF-1 homeostasis by altering the binding of IGFBP-3 to IGF-1

    OpenAIRE

    Guan, Jian; Gluckman, Peter; Yang, Panzao; Krissansen, Geoff; Sun, Xueying; Zhou, Yongzhi; Wen, Jingyuan; Phillips, Gemma; Shorten, Paul R.; McMahon, Chris D.; Wake, Graeme C.; Chan, Wendy H. K.; Thomas, Mark F.; Ren, April; Moon, Steve

    2014-01-01

    The homeostasis of insulin-like growth factor-1 (IGF-1) is essential for metabolism, development and survival. Insufficient IGF-1 is associated with poor recovery from wounds whereas excessive IGF-1 contributes to growth of tumours. We have shown that cyclic glycine-proline (cGP), a metabolite of IGF-1, can normalise IGF-1 function by showing its efficacy in improving the recovery from ischemic brain injury in rats and inhibiting the growth of lymphomic tumours in mice. Further investigation ...

  11. IGF-1 Receptor and adhesion signaling: an important axis in determining cancer cell phenotype and therapy resistance.

    Directory of Open Access Journals (Sweden)

    Orla T Cox

    2015-07-01

    Full Text Available IGF-1R expression and activation levels generally cannot be correlated in cancer cells, suggesting that cellular proteins may modulate IGF-1R activity. Strong candidates for such modulation are found in cell-matrix and cell-cell adhesion signaling complexes. Activated IGF-1R is present at focal adhesions, where it can stabilize β1 integrin and participate in signaling complexes that promote invasiveness associated with epithelial mesenchymal transition (EMT, and resistance to therapy. Whether IGF-1R contributes to EMT or to non-invasive tumor growth may be strongly influenced by the degree of ECM engagement and the presence or absence of key proteins in IGF-1R-cell adhesion complexes. One such protein is PDLIM2, which promotes both cell polarization and EMT by regulating the stability of transcription factors including NFκB, STATs and beta catenin. PDLIM2 exhibits tumor suppressor activity, but is also highly expressed in certain invasive cancers. It is likely that distinct adhesion complex proteins modulate IGF-1R signaling during cancer progression or adaptive responses to therapy. Thus, identifying the key modulators will be important for developing effective therapeutic strategies and predictive biomarkers.

  12. Role of insulin-like growth factor-1 (IGF-1) pathway in the pathogenesis of Graves' orbitopathy

    DEFF Research Database (Denmark)

    Smith, Terry J; Hegedüs, Laszlo; Douglas, Raymond S

    2012-01-01

    with GD. These abnormal patterns of IGF-1R display are also found in rheumatoid arthritis and carry functional consequences. In addition, activating IgGs capable of displacing IGF-1 from IGF-1R have also been detected in patients with these diseases. IGF-1R forms a complex with TSHR which is necessary...

  13. Cross-talk between IGF-1 and estrogen receptors attenuates intracellular changes in ventral spinal cord 4.1 motoneuron cells due to interferon-gamma exposure

    Science.gov (United States)

    Park, Sookyoung; Nozaki, Kenkichi; Smith, Joshua A.; Krause, James S.; Banik, Naren L.

    2014-01-01

    Insulin-like growth factor-1 (IGF-1) is a neuroprotective growth factor that promotes neuronal survival by inhibition of apoptosis. In order to examine whether IGF-1 exerts cytoprotective effects against extracellular inflammatory stimulation, ventral spinal cord 4.1 (VSC4.1) motoneuron cells were treated with interferon-gamma (IFN-γ). Our data demonstrated apoptotic changes, increased calpain:calpastatin and Bax:Bcl-2 ratios, and expression of apoptosis related proteases (caspase-3 and −12) in motoneurons rendered by IFN-γ in a dose-dependent manner. Post-treatment with IGF-1 attenuated these changes. In addition, IGF-1 treatment of motoneurons exposed to IFN-γ decreased expression of inflammatory markers (cyclooxygenase-2 and nuclear factor-kappa B:inhibitor of kappa B ratio). Furthermore, IGF-1 attenuated the loss of expression of IGF-1 receptors (IGF-1Rα and IGF-1Rβ) and estrogen receptors (ERα and ERβ) induced by IFN-γ. To determine whether the protective effects of IGF-1 are associated with ERs, ERs antagonist ICI and selective siRNA targeted against ERα and ERβ were used in VSC4.1 motoneurons. Distinctive morphological changes were observed following siRNA knockdown of ERα and ERβ. In particular, apoptotic cell death assessed by TUNEL assay was enhanced in both ERα and ERβ-silenced VSC4.1 motoneurons following IFN-γ and IGF-1 exposure. These results suggest that IGF-1 protects motoneurons from inflammatory insult by a mechanism involving pivotal interactions with ERα and ERβ. PMID:24188094

  14. Poly(ADP-ribose) polymerase as a novel regulator of 17β-estradiol-induced cell growth through a control of the estrogen receptor/IGF-1 receptor/PDZK1 axis.

    Science.gov (United States)

    Kim, Hogyoung; Tarhuni, Abdelmetalab; Abd Elmageed, Zakaria Y; Boulares, A Hamid

    2015-07-17

    We and others have extensively investigated the role of PARP-1 in cell growth and demise in response to pathophysiological cues. Most of the clinical trials on PARP inhibitors are targeting primarily estrogen receptor (ER) negative cancers with BRCA-deficiency. It is surprising that the role of the enzyme has yet to be investigated in ER-mediated cell growth. It is noteworthy that ER is expressed in the majority of breast cancers. We recently showed that the scaffolding protein PDZK1 is critical for 17β-estradiol (E2)-induced growth of breast cancer cells. We demonstrated that E2-induced PDZK1 expression is indirectly regulated by ER and requires IGF-1 receptor (IGF-1R). The breast cancer cell lines MCF-7 and BT474 were used as ER(+) cell culture models. Thieno[2,3-c]isoquinolin-5-one (TIQ-A) and olaparib (AZD2281) were used as potent inhibitors of PARP. PARP-1 knockdown by shRNA was used to show specificity of the effects to PARP-1. In this study, we aimed to determine the effect of PARP inhibition on estrogen-induced growth of breast cancer cells and examine whether the potential effect is linked to PDZK1 and IGF-1R expression. Our results show that PARP inhibition pharmacologically by TIQ-A or olaparib or by PARP-1 knockdown blocked E2-dependent growth of MCF-7 cells. Such inhibitory effect was also observed in olaparib-treated BT474 cells. The effect of PARP inhibition on cell growth coincided with an efficient reduction in E2-induced PDZK1 expression. This effect was accompanied by a similar decrease in the cell cycle protein cyclin D1. PARP appeared to regulate E2-induced PDZK1 at the mRNA level. Such regulation may be linked to a modulation of IGF-1R as PARP inhibition pharmacologically or by PARP-1 knockdown efficiently reduced E2-induced expression of the receptor at the protein and mRNA levels. Overall, our results show for the first time that PARP regulates E2-mediated cell growth by controlling the ER/IGF-1R/PDZK1 axis. These findings suggest that the

  15. Distribution of IGF receptors in the plasma membrane of proximal tubular cells

    International Nuclear Information System (INIS)

    Hammerman, M.R.; Rogers, S.

    1987-01-01

    To characterize the distribution of receptors for insulin-like growth factors I and II (IGF I and II) in the plasma membrane of the renal proximal tubular cell, the authors measured binding of 125 I-labeled IGF I and 125 I-labeled IGF II to proximal tubular basolateral and brush-border membranes and characterized IGF I-stimulated phosphorylation of detergent-solubilized membranes. 125 I-IGF bound primarily to a 135,000 relative molecular weight (M r ) protein and IGF II to a 260,000 M r protein in isolated membranes. Binding of 125 I-IGF I was severalfold greater in basolateral than in brush-border membranes. IGF I-stimulated phosphorylation of the 92,000 M r β-subunit of its receptors could be demonstrated only in basolateral membranes. These findings are consistent with an asymmetrical distribution of receptors for IGF I in the plasma membrane of the renal proximal tubular cell, localization being primary on the basolateral side. In contrast, binding of 125 I-IGF II to isolated basolateral and brush-border membranes was equivalent, suggesting that receptors for this peptide are distributed more symmetrically in the plasma membrane. The findings suggest that the action of IGF I in proximal tubule are mediated via interaction of circulating peptide with specific receptors in the basolateral membrane. However, the findings established the potential for actions of IGF II to be exerted in proximal tubule via interaction with both basolateral and/or brush-border membrane receptors

  16. Elevated Serum Levels of IGF-1 Are Sufficient to Establish Normal Body Size and Skeletal Properties Even in the Absence of Tissue IGF-1

    OpenAIRE

    Elis, Sebastien; Courtland, Hayden-William; Wu, Yingjie; Rosen, Clifford J; Sun, Hui; Jepsen, Karl J; Majeska, Robert J; Yakar, Shoshana

    2010-01-01

    Use of recombinant insulin-like growth factor 1 (IGF-1) as a treatment for primary IGF-1 deficiency in children has become increasingly common. When untreated, primary IGF-1 deficiency may lead to a range of metabolic disorders, including lipid abnormalities, insulin resistance, and decreased bone density. To date, results of this therapy are considered encouraging; however, our understanding of the role played by IGF-1 during development remains limited. Studies on long-term treatment with r...

  17. The impact of the IGF-1 system of cancer cells on radiation response - An in vitro study.

    Science.gov (United States)

    Venkatachalam, Senthiladipan; Mettler, Esther; Fottner, Christian; Miederer, Matthias; Kaina, Bernd; Weber, Matthias M

    2017-12-01

    Overexpression of the insulin-like growth factor-1 receptor (IGF-1R) is associated with increased cell proliferation, differentiation, transformation, and tumorigenicity. Additionally, signaling involved in the resistance of cancer cells to radiotherapy originates from IGF-1R. The purpose of this study was to investigate the role of the IGF-1 system in the radiation response and further evaluate its effect on the expression of DNA repair pathway genes. To inhibit the IGF-1 system, we stably transfected the Caco-2 cell line to express a kinase-deficient IGF-1R mutant. We then studied the effects of this mutation on cell growth, the response to radiation, and clonogenic survival, as well as using a cell viability assay to examine DNA damage and repair. Finally, we performed immunofluorescence for γ-H2AX to examine double-strand DNA breaks and evaluated the expression of 84 key genes involved in DNA repair with a real-time PCR array. Mutant IGF-1R cells exhibited significantly blunted cell growth and viability, compared to wild-type cells, as well as reduced clonogenic survival after γ-irradiation. However, mutant IGF-1R cells did not show any significant delays in the repair of radiation-induced DNA double-strand breaks. Furthermore, expression of mutant IGF-1R significantly down-regulated the mRNA levels of BRCA2, a major protein involved in homologous recombination DNA repair. These results indicate that blocking the IGF-1R-mediated signaling cascade, through the expression of a kinase-deficient IGF-1R mutant, reduces cell growth and sensitizes cancer cells to ionizing radiation. Therefore, the IGF-1R system could be a potential target to enhance radio-sensitivity and the efficacy of cancer treatments.

  18. Tumor-targeted Nanobullets: Anti-EGFR nanobody-liposomes loaded with anti-IGF-1R kinase inhibitor for cancer treatment.

    Science.gov (United States)

    van der Meel, Roy; Oliveira, Sabrina; Altintas, Isil; Haselberg, Rob; van der Veeken, Joris; Roovers, Rob C; van Bergen en Henegouwen, Paul M P; Storm, Gert; Hennink, Wim E; Schiffelers, Raymond M; Kok, Robbert J

    2012-04-30

    The epidermal growth factor receptor (EGFR) is a validated target for anti-cancer therapy and several EGFR inhibitors are used in the clinic. Over the years, an increasing number of studies have reported on the crosstalk between EGFR and other receptors that can contribute to accelerated cancer development or even acquisition of resistance to anti-EGFR therapies. Combined targeting of EGFR and insulin-like growth factor 1 receptor (IGF-1R) is a rational strategy to potentiate anti-cancer treatment and possibly retard resistance development. In the present study, we have pursued this by encapsulating the kinase inhibitor AG538 in anti-EGFR nanobody-liposomes. The thus developed dual-active nanobody-liposomes associated with EGFR-(over)expressing cells in an EGFR-specific manner and blocked both EGFR and IGF-1R activation, due to the presence of the EGFR-blocking nanobody EGa1 and the anti-IGF-1R kinase inhibitor AG538 respectively. AG538-loaded nanobody-liposomes induced a strong inhibition of tumor cell proliferation even upon short-term exposure followed by a drug-free wash-out period. Therefore, AG538-loaded nanobody-liposomes are a promising anti-cancer formulation due to efficient intracellular delivery of AG538 in combination with antagonistic and downregulating properties of the EGa1 nanobody-liposomes. Copyright © 2011 Elsevier B.V. All rights reserved.

  19. Distinct signalling properties of insulin receptor substrate (IRS)-1 and IRS-2 in mediating insulin/IGF-1 action.

    Science.gov (United States)

    Rabiee, Atefeh; Krüger, Marcus; Ardenkjær-Larsen, Jacob; Kahn, C Ronald; Emanuelli, Brice

    2018-07-01

    Insulin/IGF-1 action is driven by a complex and highly integrated signalling network. Loss-of-function studies indicate that the major insulin/IGF-1 receptor substrate (IRS) proteins, IRS-1 and IRS-2, mediate different biological functions in vitro and in vivo, suggesting specific signalling properties despite their high degree of homology. To identify mechanisms contributing to the differential signalling properties of IRS-1 and IRS-2 in the mediation of insulin/IGF-1 action, we performed comprehensive mass spectrometry (MS)-based phosphoproteomic profiling of brown preadipocytes from wild type, IRS-1 -/- and IRS-2 -/- mice in the basal and IGF-1-stimulated states. We applied stable isotope labeling by amino acids in cell culture (SILAC) for the accurate quantitation of changes in protein phosphorylation. We found ~10% of the 6262 unique phosphorylation sites detected to be regulated by IGF-1. These regulated sites included previously reported substrates of the insulin/IGF-1 signalling pathway, as well as novel substrates including Nuclear Factor I X and Semaphorin-4B. In silico prediction suggests the protein kinase B (PKB), protein kinase C (PKC), and cyclin-dependent kinase (CDK) as the main mediators of these phosphorylation events. Importantly, we found preferential phosphorylation patterns depending on the presence of either IRS-1 or IRS-2, which was associated with specific sets of kinases involved in signal transduction downstream of these substrates such as PDHK1, MAPK3, and PKD1 for IRS-1, and PIN1 and PKC beta for IRS-2. Overall, by generating a comprehensive phosphoproteomic profile from brown preadipocyte cells in response to IGF-1 stimulation, we reveal both common and distinct insulin/IGF-1 signalling events mediated by specific IRS proteins. Copyright © 2018 Elsevier Inc. All rights reserved.

  20. Experimental approach to IGF-1 therapy in CCl4-induced acute liver damage in healthy controls and mice with partial IGF-1 deficiency.

    Science.gov (United States)

    Morales-Garza, Luis A; Puche, Juan E; Aguirre, Gabriel A; Muñoz, Úrsula; García-Magariño, Mariano; De la Garza, Rocío G; Castilla-Cortazar, Inma

    2017-05-04

    Cell necrosis, oxidative damage, and fibrogenesis are involved in cirrhosis development, a condition in which insulin-like growth factor 1 (IGF-1) levels are diminished. This study evaluates whether the exogenous administration of low doses of IGF-1 can induce hepatoprotection in acute carbon tetrachloride (CCl 4 )-induced liver damage compared to healthy controls (Wt Igf +/+ ). Additionally, the impact of IGF-1 deficiency on a damaged liver was investigated in mice with a partial deficit of this hormone (Hz Igf1 +/- ). Three groups of 25 ± 5-week-old healthy male mice (Wt Igf +/+ ) were included in the protocol: untreated controls (Wt). Controls that received CCl 4 (Wt + CCl 4 ) and Wt + CCl 4 were treated subcutaneously with IGF-1 (2 µg/100 g body weight/day) for 10 days (Wt + CCl 4  + IGF1). In parallel, three IGF-1-deficient mice (Hz Igf1 +/- ) groups were studied: untreated Hz, Hz + CCl 4 , and Hz + CCl 4  + IGF-1. Microarray and real-time quantitative polymerase chain reaction (RT-qPCR) analyses, serum aminotransferases levels, liver histology, and malondialdehyde (MDA) levels were assessed at the end of the treatment in all groups. All data represent mean ± SEM. An altered gene coding expression pattern for proteins of the extracellular matrix, fibrosis, and cellular protection were found, as compared to healthy controls, in which IGF-1 therapy normalized in the series including healthy mice. Liver histology showed that Wt + CCl 4  + IGF1 mice had less oxidative damage, fibrosis, lymphocytic infiltrate, and cellular changes when compared to the Wt + CCl 4 . Moreover, there was a correlation between MDA levels and the histological damage score (Pearson's r = 0.858). In the IGF-1-deficient mice series, similar findings were identified, denoting a much more vulnerable hepatic parenchyma. IGF1 treatment improved the biochemistry, histology, and genetic expression of pro-regenerative and cytoprotective factors in both series

  1. Serum IGF-1 is insufficient to restore skeletal size in the total absence of the growth hormone receptor

    Science.gov (United States)

    Wu, Yingjie; Sun, Hui; Basta-Pljakic, Jelena; Cardoso, Luis; Kennedy, Oran D; Jasper, Hector; Domené, Horacio; Karabatas, Liliana; Guida, Clara; Schaffler, Mitchell B; Rosen, Clifford J; Yakar, Shoshana

    2013-01-01

    States of growth hormone (GH) resistance, such those observed in Laron’s dwarf patients, are characterized by mutations in the GH receptor (GHR), decreased serum and tissue IGF-1 levels, impaired glucose tolerance, and impaired skeletal acquisition. IGF-1 replacement therapy in such patients increases growth velocity but does not normalize growth. Herein we combined the GH-resistant (GHR knockout, GHRKO) mouse model with mice expressing the hepatic Igf-1 transgene (HIT) to generate the GHRKO-HIT mouse model. In GHRKOHIT mice, serum IGF-1 levels were restored via transgenic expression of Igf-1 allowing us to study how endocrine IGF-1 affects growth, metabolic homeostasis, and skeletal integrity. We show that in a GH-resistant state, normalization of serum IGF-1 improved body adiposity and restored glucose tolerance but was insufficient to support normal skeletal growth, resulting in an osteopenic skeletal phenotype. The inability of serum IGF-1 to restore skeletal integrity in the total absence of GHR likely resulted from reduced skeletal Igf-1 gene expression, blunted GH-mediated effects on the skeleton that are independent of serum or tissue IGF-1, and from poor delivery of IGF-1 to the tissues. These findings are consistent with clinical data showing that IGF-I replacement therapy in patients with Laron’s syndrome does not achieve full skeletal growth. PMID:23456957

  2. IGF-1 and Survival in ESRD

    Science.gov (United States)

    Jia, Ting; Gama Axelsson, Thiane; Heimbürger, Olof; Bárány, Peter; Stenvinkel, Peter; Qureshi, Abdul Rashid

    2014-01-01

    Summary Background and objectives IGF-1 deficiency links to malnutrition in CKD patients; however, it is not clear to what extent it associates with survival among these patients. Design, setting, participants, & measurements Serum IGF-1 and other biochemical, clinical (subjective global assessment), and densitometric (dual energy x-ray absorptiometry) markers of nutritional status and mineral and bone metabolism were measured in a cohort of 365 Swedish clinically stable CKD stage 5 patients (median age of 53 years) initiating dialysis between 1994 and 2009; in 207 patients, measurements were also taken after 1 year of dialysis. Deaths were registered during a median follow-up of 5 years. Associations of mortality with baseline IGF-1 and changes of IGF-1 after 1 year of dialysis were evaluated by Cox models. Results At baseline, IGF-1 concentrations associated negatively with age, diabetes mellitus, cardiovascular disease, poor nutritional status, IL-6, and osteoprotegerin and positively with body fat mass, bone mineral density, serum phosphate, calcium, and fibroblast growth factor-23. At 1 year, IGF-1 had increased by 33%. In multivariate regression, low age, diabetes mellitus, and high serum phosphate and calcium associated with IGF-1 at baseline, and in a mixed model, these factors, together with high fat body mass, associated with changes of IGF-1 during the first 1 year of dialysis. Adjusting for calendar year of inclusion, age, sex, diabetes mellitus, cardiovascular disease, IL-6, and poor nutritional status, a 1 SD higher level of IGF-1 at baseline associated with lower mortality risk (hazard ratio, 0.57; 95% confidence interval, 0.32 to 0.98). Persistently low or decreasing IGF-1 levels during the first 1 year on dialysis predicted worse survival (adjusted hazard ratio, 2.19; 95% confidence interval, 1.06 to 4.50). Conclusion In incident dialysis patients, low serum IGF-1 associates with body composition and markers of mineral and bone metabolism, and it

  3. Cross-talk between IGF-1 and estrogen receptors attenuates intracellular changes in ventral spinal cord 4.1 motoneuron cells because of interferon-gamma exposure.

    Science.gov (United States)

    Park, Sookyoung; Nozaki, Kenkichi; Smith, Joshua A; Krause, James S; Banik, Naren L

    2014-03-01

    Insulin-like growth factor-1 (IGF-1) is a neuroprotective growth factor that promotes neuronal survival by inhibition of apoptosis. To examine whether IGF-1 exerts cytoprotective effects against extracellular inflammatory stimulation, ventral spinal cord 4.1 (VSC4.1) motoneuron cells were treated with interferon-gamma (IFN-γ). Our data demonstrated apoptotic changes, increased calpain:calpastatin and Bax:Bcl-2 ratios, and expression of apoptosis-related proteases (caspase-3 and -12) in motoneurons rendered by IFN-γ in a dose-dependent manner. Post-treatment with IGF-1 attenuated these changes. In addition, IGF-1 treatment of motoneurons exposed to IFN-γ decreased expression of inflammatory markers (cyclooxygenase-2 and nuclear factor-kappa B:inhibitor of kappa B ratio). Furthermore, IGF-1 attenuated the loss of expression of IGF-1 receptors (IGF-1Rα and IGF-1Rβ) and estrogen receptors (ERα and ERβ) induced by IFN-γ. To determine whether the protective effects of IGF-1 are associated with ERs, ERs antagonist ICI and selective siRNA targeted against ERα and ERβ were used in VSC4.1 motoneurons. Distinctive morphological changes were observed following siRNA knockdown of ERα and ERβ. In particular, apoptotic cell death assessed by TUNEL assay was enhanced in both ERα and ERβ-silenced VSC4.1 motoneurons following IFN-γ and IGF-1 exposure. These results suggest that IGF-1 protects motoneurons from inflammatory insult by a mechanism involving pivotal interactions with ERα and ERβ. © 2013 International Society for Neurochemistry.

  4. IGF-1 prevents simvastatin-induced myotoxicity in C2C12 myotubes.

    Science.gov (United States)

    Bonifacio, Annalisa; Sanvee, Gerda M; Brecht, Karin; Kratschmar, Denise V; Odermatt, Alex; Bouitbir, Jamal; Krähenbühl, Stephan

    2017-05-01

    Statins are generally well tolerated, but treatment with these drugs may be associated with myopathy. The mechanisms of statin-associated myopathy are not completely understood. Statins inhibit AKT phosphorylation by an unclear mechanism, whereas insulin-like growth factor (IGF-1) activates the IGF-1/AKT signaling pathway and promotes muscle growth. The aims of the study were to investigate mechanisms of impaired AKT phosphorylation by simvastatin and to assess effects of IGF-1 on simvastatin-induced myotoxicity in C2C12 myotubes. C2C12 mouse myotubes were exposed to 10 μM simvastatin and/or 10 ng/mL IGF-1 for 18 h. Simvastatin inhibited the IGF-1/AKT signaling pathway, resulting in increased breakdown of myofibrillar proteins, impaired protein synthesis and increased apoptosis. Simvastatin inhibited AKT S473 phosphorylation, indicating reduced activity of mTORC2. In addition, simvastatin impaired stimulation of AKT T308 phosphorylation by IGF-1, indicating reduced activation of the IGF-1R/PI3K pathway by IGF-1. Nevertheless, simvastatin-induced myotoxicity could be at least partially prevented by IGF-1. The protective effects of IGF-1 were mediated by activation of the IGF-1R/AKT signaling cascade. Treatment with IGF-1 also suppressed muscle atrophy markers, restored protein synthesis and inhibited apoptosis. These results were confirmed by normalization of myotube morphology and protein content of C2C12 cells exposed to simvastatin and treated with IGF-1. In conclusion, impaired activity of AKT can be explained by reduced function of mTORC2 and of the IGF-1R/PI3K pathway. IGF-1 can prevent simvastatin-associated cytotoxicity and metabolic effects on C2C12 cells. The study gives insight into mechanisms of simvastatin-associated myotoxicity and provides potential targets for therapeutic intervention.

  5. E-Peptides Control Bioavailability of IGF-1

    Science.gov (United States)

    Piszczek, Agnieszka; Perlas, Emarald; Winn, Nadine; Nastasi, Tommaso; Rosenthal, Nadia

    2012-01-01

    Insulin-like growth factor 1 (IGF-1) is a potent cytoprotective growth factor that has attracted considerable attention as a promising therapeutic agent. Transgenic over-expression of IGF-1 propeptides facilitates protection and repair in a broad range of tissues, although transgenic mice over-expressing IGF-1 propeptides display little or no increase in IGF-1 serum levels, even with high levels of transgene expression. IGF-1 propeptides are encoded by multiple alternatively spliced transcripts including C-terminal extension (E) peptides, which are highly positively charged. In the present study, we use decellularized mouse tissue to show that the E-peptides facilitate in vitro binding of murine IGF-1 to the extracellular matrix (ECM) with varying affinities. This property is independent of IGF-1, since proteins consisting of the E-peptides fused to relaxin, a related member of the insulin superfamily, bound equally avidly to decellularized ECM. Thus, the E-peptides control IGF-1 bioavailability by preventing systemic circulation, offering a potentially powerful way to tether IGF-1 and other therapeutic proteins to the site of synthesis and/or administration. PMID:23251442

  6. miR-139 is up-regulated in osteoarthritis and inhibits chondrocyte proliferation and migration possibly via suppressing EIF4G2 and IGF1R

    Energy Technology Data Exchange (ETDEWEB)

    Hu, Weihua; Zhang, Weikai; Li, Feng; Guo, Fengjing; Chen, Anmin, E-mail: chenanmin6072@126.com

    2016-05-27

    Osteoarthritis (OA) is one of the most progressive articular cartilage erosions. microRNAs (miRNAs) play pivotal roles in OA modulation, but the role of miR-139 in OA remains elusive. This study aims to reveal the effects and possible mechanism of miR-139 in OA and chondrocytes. The levels of miR-139 and its possible targets eukaryotic translation initiation factor 4 gamma 2 (EIF4G2) and insulin-like growth factor 1 receptor (IGF1R) were detected by qRT-PCR in the articular cartilages of 20 OA patients and 20 non-OA patients. Human chondrocyte CHON-001 cells were transfected with miR-139 mimic or inhibitor, as well as the siRNAs of EIF4G2 and IGF1R. Cell viability by MTT assay, proliferation by colony formation assay and migration by Transwell assay were performed. Results showed that miR-139 was up-regulated, while EIF4G2 and IGF1R mRNAs down-regulated in OA cartilages (P < 0.001), and negative correlations existed between the level of miR-139 and EIF4G2 or IGF1R. Overexpression of miR-139 in CHON-001 cells suppressed both mRNA and protein levels of EIF4G2 and IGF1R, and inhibited cell viability, colony formation number and cell migration, while miR-139 inhibitor induced the opposite effects. Knockdown of EIF4G2 or IGF1R in CHON-001 cells reversed the effects of miR-139 inhibitor on cell viability, colony formation and cell migration. These results indicate that miR-139 is capable of inhibiting chondrocyte proliferation and migration, thus being a possible therapeutic target for OA. The mechanism of miR-139 in chondrocytes may be related to its regulation on EIF4G2 and IGF1R.

  7. Igf1r+/CD34+ immature ICC are putative adult progenitor cells, identified ultrastructurally as fibroblast-like ICC in Ws/Ws rat colon

    DEFF Research Database (Denmark)

    Wang, X Y; Albertí, E; White, E J

    2009-01-01

    by ICC in the wild-type rat colon, suggesting them to be immature ICC. In addition, a marked increase in immunoreactivity for insulin-like growth factor 1 receptor (Igf1r) occurred, co-localized with CD34 but not with c-Kit. A significantly higher number of Igf1r(+)/CD34(+) cells were found in Ws....../Ws compared to wild-type rat colons. These CD34(+)/Igf1r(+) cells in the Ws/Ws colon occupied the same space as FL-ICC. Hence we propose that a subset of immature ICC (FL-ICC) consists of adult progenitor cells. Immunohistochemistry revealed a reduction of neurons positive for neuronal nitric oxide synthase...

  8. Tumor-targeting magnetic lipoplex delivery of short hairpin RNA suppresses IGF-1R overexpression of lung adenocarcinoma A549 cells in vitro and in vivo

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Chunmao; Ding, Chao; Kong, Minjian [Department of Cardiothoracic Surgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009 (China); Dong, Aiqiang, E-mail: dr_dongaiqiang@sina.com [Department of Cardiothoracic Surgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009 (China); Qian, Jianfang; Jiang, Daming; Shen, Zhonghua [Department of Cardiothoracic Surgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009 (China)

    2011-07-08

    Highlights: {yields} We compared lipofection with magnetofection about difference of transfection efficiency on delivery a therapeutic gene in vitro and in vivo. {yields} We investigated the difference of shRNA induced by magnetofection and lipofection into A549 cell and subcutaneous tumor to knockdown IGF-1R overexpressed in A549 cell and A549 tumor. {yields} We investigated in vivo shRNA silenced IGF-1R overexpression 24, 48, and 72 h after shRNA intravenous injection into tumor-bearing mice by way of magnetofection and lipofection. {yields} Our results showed that magnetofection could achieve therapeutic gene targeted delivery into special site, which contributed to targeted gene therapy of lung cancers. -- Abstract: Liposomal magnetofection potentiates gene transfection by applying a magnetic field to concentrate magnetic lipoplexes onto target cells. Magnetic lipoplexes are self-assembling ternary complexes of cationic lipids with plasmid DNA associated with superparamagnetic iron oxide nanoparticles (SPIONs). Type1insulin-like growth factor receptor (IGF-1R), an important oncogene, is frequently overexpressed in lung cancer and mediates cancer cell proliferation and tumor growth. In this study, we evaluated the transfection efficiency (percentage of transfected cells) and therapeutic potential (potency of IGF-1R knockdown) of liposomal magnetofection of plasmids expressing GFP and shRNAs targeting IGF-1R (pGFPshIGF-1Rs) in A549 cells and in tumor-bearing mice as compared to lipofection using Lipofectamine 2000. Liposomal magnetofection provided a threefold improvement in transgene expression over lipofection and transfected up to 64.1% of A549 cells in vitro. In vitro, IGF-1R specific-shRNA transfected by lipofection inhibited IGF-1R protein by 56.1 {+-} 6% and by liposomal magnetofection by 85.1 {+-} 3%. In vivo delivery efficiency of the pGFPshIGF-1R plasmid into the tumor was significantly higher in the liposomal magnetofection group than in the

  9. Tumor-targeting magnetic lipoplex delivery of short hairpin RNA suppresses IGF-1R overexpression of lung adenocarcinoma A549 cells in vitro and in vivo

    International Nuclear Information System (INIS)

    Wang, Chunmao; Ding, Chao; Kong, Minjian; Dong, Aiqiang; Qian, Jianfang; Jiang, Daming; Shen, Zhonghua

    2011-01-01

    Highlights: → We compared lipofection with magnetofection about difference of transfection efficiency on delivery a therapeutic gene in vitro and in vivo. → We investigated the difference of shRNA induced by magnetofection and lipofection into A549 cell and subcutaneous tumor to knockdown IGF-1R overexpressed in A549 cell and A549 tumor. → We investigated in vivo shRNA silenced IGF-1R overexpression 24, 48, and 72 h after shRNA intravenous injection into tumor-bearing mice by way of magnetofection and lipofection. → Our results showed that magnetofection could achieve therapeutic gene targeted delivery into special site, which contributed to targeted gene therapy of lung cancers. -- Abstract: Liposomal magnetofection potentiates gene transfection by applying a magnetic field to concentrate magnetic lipoplexes onto target cells. Magnetic lipoplexes are self-assembling ternary complexes of cationic lipids with plasmid DNA associated with superparamagnetic iron oxide nanoparticles (SPIONs). Type1insulin-like growth factor receptor (IGF-1R), an important oncogene, is frequently overexpressed in lung cancer and mediates cancer cell proliferation and tumor growth. In this study, we evaluated the transfection efficiency (percentage of transfected cells) and therapeutic potential (potency of IGF-1R knockdown) of liposomal magnetofection of plasmids expressing GFP and shRNAs targeting IGF-1R (pGFPshIGF-1Rs) in A549 cells and in tumor-bearing mice as compared to lipofection using Lipofectamine 2000. Liposomal magnetofection provided a threefold improvement in transgene expression over lipofection and transfected up to 64.1% of A549 cells in vitro. In vitro, IGF-1R specific-shRNA transfected by lipofection inhibited IGF-1R protein by 56.1 ± 6% and by liposomal magnetofection by 85.1 ± 3%. In vivo delivery efficiency of the pGFPshIGF-1R plasmid into the tumor was significantly higher in the liposomal magnetofection group than in the lipofection group. In vivo IGF-1R

  10. Combinational Therapy Enhances the Effects of Anti-IGF-1R mAb Figitumumab to Target Small Cell Lung Cancer.

    Directory of Open Access Journals (Sweden)

    Hongxin Cao

    Full Text Available Small cell lung cancer (SCLC is a recalcitrant malignancy with distinct biologic properties. Antibody targeting therapy has been actively investigated as a new drug modality.We tested the expression of IGF-1R and calculated the survival in 61 SCLC patients. We also evaluated the anti-tumor effects of anti-IGF-1R monoclonal antibody Figitumumab (CP on SCLC, and tried two drug combinations to improve CP therapy.Our clinical data suggested that high IGF-1R expression was correlated with low SCLC patient survival. We then demonstrated the effect of CP was likely through IGF-1R blockage and down-regulation without IGF-1R auto-phosphorylation and PI3K/AKT activation. However, we observed elevated MEK/ERK activation upon CP treatment in SCLC cells, and this MEK/ERK activation was enhanced by ß-arrestin1 knockdown while attenuated by ß-arrestin2 knockdown. We found both MEK/ERK inhibitor and metformin could enhance CP treatment in SCLC cells. We further illustrated the additive effect of metformin was likely through promoting further IGF-1R down-regulation.Our results highlighted the potential of anti-IGF-1R therapy and the adjuvant therapy strategy with either MEK/ERK inhibitor or metformin to target SCLC, warranting further studies.

  11. Circulating levels of IGF-1, IGFBP-3, and IGF-1/IGFBP-3 molar ratio and colorectal adenomas: A meta-analysis.

    Science.gov (United States)

    Yoon, Yeong Sook; Keum, NaNa; Zhang, Xuehong; Cho, Eunyoung; Giovannucci, Edward L

    2015-12-01

    Insulin-like growth factor-1(IGF-1) promotes cell proliferation and inhibits apoptosis, and is thereby implicated in carcinogenesis. Insulin-like growth factor binding protein-3 (IGFBP-3) may antagonize IGF-1 action, leading to inhibition of the potential tumorigenicity of IGF-1. We conducted this meta-analysis to estimate the association between IGF-1, IGFBP-3 and IGF-1/IGFBP-3 ratio and the risk of colorectal adenomas (CRAs). Further, we investigated whether this association was different between occurrent and recurrent CRA, by adjustment for obesity, and by advanced CRA. Pubmed and Embase were searched up to April, 2015 to identify relevant observational studies and summary odds ratio (OR) and the corresponding 95% confidence interval (95% CI) was estimated using a random-effects model. A total of 12 studies (11 studies including 3038 cases for IGF-1, 12 studies including 3208 cases for IGFBP-3, and 7 studies including 1867 cases for IGF-1/IGFBP-3 ratio) were included in this meta-analysis. The summary ORs of occurrent CRA for the highest versus lowest category of IGF-1, IGFBP-3 and IGF-1/IGFBP-3 ratio were 1.13 (95% CI: 0.95-1.34), 0.99 (0.84-1.16), and 1.05 (0.86-1.29), respectively. Higher IGF-1 and IGF-1/IGFBP-3 ratio were significantly associated with decreased risk of recurrent CRA (OR for IGF-1=0.60 [95% CI: 0.42-0.85]; IGF-1/IGFBP-3 ratio=0.65 [0.44-0.96]). A stratified analysis by advancement of occurrent CRA produced a significant summary OR of IGF-1 for advanced CRA (OR=2.21 [1.08-4.52]) but not for non-advanced CRA (OR=0.89 [0.55-1.45]). We did not find significant publication bias or heterogeneity. Circulating levels of IGF-1, IGFBP-3 and their molar ratio were not associated with the risk of occurrence of CRA, but IGF-1 was associated with the increased risk for occurrence of advanced CRA. Copyright © 2015. Published by Elsevier Ltd.

  12. Mechanisms Underlying Testicular Damage and Dysfunction in Mice With Partial IGF-1 Deficiency and the Effectiveness of IGF-1 Replacement Therapy.

    Science.gov (United States)

    Castilla-Cortázar, Inma; Gago, Alberto; Muñoz, Úrsula; Ávila-Gallego, Elena; Guerra-Menéndez, Lucía; Sádaba, María Cruz; García-Magariño, Mariano; Olleros Santos-Ruiz, María; Aguirre, G A; Puche, Juan Enrique

    2015-12-01

    To determine whether insulin-like growth factor (IGF-1) deficiency can cause testicular damage and to examine changes of the testicular morphology and testicular function-related gene expression caused by IGF-1 deficiency. Therefore, this study aims to determine the benefits of low doses of IGF-1 and to explore the mechanisms underlying the IGF-1 replacement therapy. A murine model of IGF-1 deficiency was used to avoid any factor that could contribute to testicular damage. Testicular weight, score of histopathological damage, and gene expressions were studied in 3 experimental groups of mice: controls (wild-type Igf1(+/+)), heterozygous Igf1(+/-) with partial IGF-1 deficiency, and heterozygous Igf1(+/-) treated with IGF-1. Results show that the partial IGF-1 deficiency induced testicular damage and altered expression of genes involved in IGF-1 and growth hormone signaling and regulation, testicular hormonal function, extracellular matrix establishment and its regulation, angiogenesis, fibrogenesis, inflammation, and cytoprotection. In addition, proteins involved in tight junction expression were found to be reduced. However, low doses of IGF-1 restored the testicular damage and most of these parameters. IGF-1 deficiency caused the damage of the blood-testis barrier and testicular structure and induced the abnormal testicular function-related gene expressions. However, low doses of IGF-1 constitute an effective replacement therapy that restores the described testicular damage. Data herein show that (1) cytoprotective activities of IGF-1 seem to be mediated by heat shock proteins and that (2) connective tissue growth factor could play a relevant role together with IGF-1 in the extracellular matrix establishment. Copyright © 2015 Elsevier Inc. All rights reserved.

  13. IGF-1-induced MMP-11 expression promotes the proliferation and invasion of gastric cancer cells through the JAK1/STAT3 signaling pathway.

    Science.gov (United States)

    Su, Chao; Wang, Wenchang; Wang, Cunchuan

    2018-05-01

    The present study aimed to investigate the association between insulin-like growth factor-1 (IGF-1) and matrix metalloproteinase-11 (MMP-11) expression in gastric cancer (GC) and the underlying mechanisms in SGC-7901 cells. Reverse transcription-quantitative polymerase chain reaction analysis revealed that the expression of IGF-1 and MMP-11 was significantly upregulated in GC tissues compared with normal gastric tissue. Furthermore, IGF-1 significantly and dose-dependently promoted MMP-11. Western blotting revealed that the addition of IGF-1 to SGC-7901 cells led to an evident enhancement in signal transducer and activator of transcription 3 (STAT3), IGF-1R and Janus kinase 1 (JAK1) phosphorylation at 20 and 40 min. A decrease in the extent of the elevated expression of MMP-11 and the enhanced phosphorylation of STAT3, JAK1 and IGF-1 receptor (IGF-1R) induced by IGF-1 in SGC-7901 cells were observed following treatment with NT157 (an IGF-1R inhibitor). Furthermore, piceatannol (a JAK1 inhibitor) or small interfering RNA against STAT3 reduced the extent of the increased expression of MMP-11 induced by IGF-1 in SGC-7901 cells. Piceatannol treatment induced the dose-dependent decline in the enhancement of STAT3 phosphorylation induced by IGF-1, indicating that the JAK1/STAT3 pathway may be implicated in the elevated expression of MMP-11 induced by IGF-1 in SGC-7901 cells. Finally, IGF-1 treatment significantly promoted the proliferation and invasion of SGC-7901 cells, which was inhibited following NT157, piceatannol or si-STAT3 treatment. The present study therefore demonstrated that IGF-1-induced MMP-11 may have facilitated the proliferation and invasion of SGC-7901 cells via the JAK1/STAT3 pathway.

  14. Investigation on the role of IGF-1 signal transduction in the biological radiation responses

    Energy Technology Data Exchange (ETDEWEB)

    Jung, U Hee; Jo, Sung Kee; Park, Hae Ran; Oh, Soo Jin; Cho, Eun Hee; Eom, Hyun Soo; Ju, Eun Jin

    2009-05-15

    Effects of {gamma}-irradiation on the IGF-1 related gene expressions and activations in various cell lines - Various expression patterns of IGF-1 and IGF-1R following {gamma}-irradiation were observed according to the cell lines - The increased expressions of IGF-1 and IGF-1R were observed in Balb/3T3 and NIH/3T3 cells - Among the IGF-1 downstream signaling molecules, the phosphorylated ERK5 were not changed by {gamma}-irradiation in all three examined cell lines, whereas the phosphorylated p65 were increased by {gamma} -irradiation in all cell lines. The role of IGF-1 and p38 signaling in {gamma}-irradiated mouse embryonic fibroblast (MEF) cells - In MEF cells, IGF-1 signaling molecules were decreased and p21/phosphorylated p38 were increased by {gamma}-irradiation - The experiments with IGF-1R inhibitor (AG1024) and p38 inhibitor (SB203580) revealed that IGF-1 signaling is involved but not essential in radiation-induced cell growth arrest and senescence and that p38 MAP kinase play a important role in this cellular radiation response. The role of IGF-1 and p38 signaling in {gamma}-irradiated mouse fibroblast (NIH/3T3) cell - In NIH/3T3 cells, IGF-1 signaling molecules and p21/phosphorylated p38 were increased by {gamma} -irradiation. - However, the experiments with IGF-1R inhibitor (AG1024) and p38 inhibitor (SB203580) revealed that IGF-1 and p38 signaling do not play a crucial role in radiation-induced cell growth arrest and senescence in NIH/3T3 cells. Effects of {gamma}-irradiation on the expressions and activations on the genes related to the IGF-1 signaling in mouse tissues - In {gamma}-irradiated mice, the increased expressions of IGF-1 and IGF-1R were observed in the lung and kidney at 2 months after irradiation, and in all the tissues examined (lung, liver and kidney) at 6 months after irradiation. - In the lung of {gamma}-irradiated mice at 6 months after irradiation, the increases of IGF-1R, phosphorylated FOXO3a, p65, p38, p21 were observed. - The

  15. Investigation on the role of IGF-1 signal transduction in the biological radiation responses

    International Nuclear Information System (INIS)

    Jung, U Hee; Jo, Sung Kee; Park, Hae Ran; Oh, Soo Jin; Cho, Eun Hee; Eom, Hyun Soo; Ju, Eun Jin

    2009-05-01

    Effects of γ-irradiation on the IGF-1 related gene expressions and activations in various cell lines - Various expression patterns of IGF-1 and IGF-1R following γ-irradiation were observed according to the cell lines - The increased expressions of IGF-1 and IGF-1R were observed in Balb/3T3 and NIH/3T3 cells - Among the IGF-1 downstream signaling molecules, the phosphorylated ERK5 were not changed by γ-irradiation in all three examined cell lines, whereas the phosphorylated p65 were increased by γ -irradiation in all cell lines. The role of IGF-1 and p38 signaling in γ-irradiated mouse embryonic fibroblast (MEF) cells - In MEF cells, IGF-1 signaling molecules were decreased and p21/phosphorylated p38 were increased by γ-irradiation - The experiments with IGF-1R inhibitor (AG1024) and p38 inhibitor (SB203580) revealed that IGF-1 signaling is involved but not essential in radiation-induced cell growth arrest and senescence and that p38 MAP kinase play a important role in this cellular radiation response. The role of IGF-1 and p38 signaling in γ-irradiated mouse fibroblast (NIH/3T3) cell - In NIH/3T3 cells, IGF-1 signaling molecules and p21/phosphorylated p38 were increased by γ -irradiation. - However, the experiments with IGF-1R inhibitor (AG1024) and p38 inhibitor (SB203580) revealed that IGF-1 and p38 signaling do not play a crucial role in radiation-induced cell growth arrest and senescence in NIH/3T3 cells. Effects of γ-irradiation on the expressions and activations on the genes related to the IGF-1 signaling in mouse tissues - In γ-irradiated mice, the increased expressions of IGF-1 and IGF-1R were observed in the lung and kidney at 2 months after irradiation, and in all the tissues examined (lung, liver and kidney) at 6 months after irradiation. - In the lung of γ-irradiated mice at 6 months after irradiation, the increases of IGF-1R, phosphorylated FOXO3a, p65, p38, p21 were observed. - The patterns of altered expressions showed significant

  16. Monoclonal antibody to the type I insulin-like growth factor (IGF-I) receptor blocks IGF-I receptor-mediated DNA synthesis: clarification of the mitogenic mechanisms of IGF-I and insulin in human skin fibroblasts

    International Nuclear Information System (INIS)

    Flier, J.S.; Usher, P.; Moses, A.C.

    1986-01-01

    Insulin and insulin-like growth factor type I (IGF-I) stimulate an overlapping spectrum of biological responses in human skin fibroblasts. Although insulin and IGF-I are known to stimulate the incorporation of [ 3 H]thymidine into DNA in these cells, the identify of the receptor(s) that mediates this effect has not been fully clarified. The mouse anti-human IGF-I receptor antibody αIR-3 binds with specificity to IGF-I but not to insulin receptors in human placental membranes; it also specifically inhibits the binding of 125 I-labeled IGF-I but not 125 I-labeled insulin to suspensions of human skin fibroblasts in a dose-dependent manner. αIR-3 competitively inhibits IGF-I-mediated stimulation of [ 3 H]thymidine incorporation into DNA. This inhibition is dependent on the concentration of αIR-3 and in the presence of a fixed antibody concentration can be partially overcome by high concentrations of IGF-I. In contrast, at concentrations of 3 H]thymidine incorporation is not inhibited by αIR-3. However, the incremental effects of higher concentrations (> 1 μg/ml) of insulin on [ 3 H]thymidine incorporation are inhibited by αIR-3. αIR-3 is a highly specific antagonist of IGF-I receptor-mediated mitogenesis in human skin fibroblasts. By using this antibody, it is shown directly that insulin can act through the IGF-I receptor to stimulate DNA synthesis but can also activate this effect through the insulin receptor itself

  17. Clinical significance of proliferation, apoptosis and senescence of nasopharyngeal cells by the simultaneously blocking EGF, IGF-1 receptors and Bcl-xl genes

    International Nuclear Information System (INIS)

    Dai, Guodong; Peng, Tao; Zhou, Xuhong; Zhu, Jun; Kong, Zhihua; Ma, Li; Xiong, Zhi; Yuan, Yulin

    2013-01-01

    Highlight: •Construction of shRNA segments expression vectors is valid by the investigation of RT-PCR for IGF1R, EGFR and Bcl-xl mRNA and protein expression. •Studies have suggested that the vectors in blocking these genes of the growth factor receptors and anti- apoptosis is capable of breaking the balance of tumor growth so that tumor trend apoptosis and senescence. •Simultaneously blocking multiple genes that are abnormally expressed may be more effective in treating cancer cells than silencing a single gene. -- Abstract: Background: In previous work, we constructed short hairpin RNA (shRNA) expression plasmids that targeted human EGF and IGF-1 receptors messenger RNA, respectively, and demonstrated that these vectors could induce apoptosis of human nasopharyngeal cell lines (CNE2) and inhibit ligand-induced pAkt and pErk activation. Method: We have constructed multiple shRNA expression vectors of targeting EGFR, IGF1R and Bcl-xl, which were transfected to the CNE2 cells. The mRNA expression was assessed by RT-PCR. The growth of the cells, cell cycle progression, apoptosis of the cells, senescent tumor cells and the proteins of EGFR, IGF1R and Bcl-xl were analyzed by MTT, flow cytometry, cytochemical therapy or Western blot. Results: In group of simultaneously blocking EGFR, IGF1R and Bcl-xl genes, the mRNA of EGFR, IGF1R and Bcl-xl expression was decreased by (66.66 ± 3.42)%, (73.97 ± 2.83)% and (64.79 ± 2.83)%, and the protein expressions was diminished to (67.69 ± 4.02)%, (74.32 ± 2.30)%, and (60.00 ± 3.34)%, respectively. Meanwhile, the cell apoptosis increased by 65.32 ± 0.18%, 65.16 ± 0.25% and 55.47 ± 0.45%, and senescent cells increased by 1.42 ± 0.15%, 2.26 ± 0.15% and 3.22 ± 0.15% in the second, third and fourth day cultures, respectively. Conclusions: Simultaneously blocking EGFR, IGF1R and Bcl-xl genes is capable of altering the balance between proliferating versus apoptotic and senescent cells in the favor of both of apoptosis and

  18. Clinical significance of proliferation, apoptosis and senescence of nasopharyngeal cells by the simultaneously blocking EGF, IGF-1 receptors and Bcl-xl genes

    Energy Technology Data Exchange (ETDEWEB)

    Dai, Guodong [Anatomy and Embryology, Wuhan University School of Medicine, Wuhan, Hubei 430071 (China); Peng, Tao; Zhou, Xuhong [Department of Otolaryngology-Head and Neck Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071 (China); Zhu, Jun; Kong, Zhihua; Ma, Li; Xiong, Zhi [Anatomy and Embryology, Wuhan University School of Medicine, Wuhan, Hubei 430071 (China); Yuan, Yulin, E-mail: yuanyulin19620120@126.com [Anatomy and Embryology, Wuhan University School of Medicine, Wuhan, Hubei 430071 (China)

    2013-11-01

    Highlight: •Construction of shRNA segments expression vectors is valid by the investigation of RT-PCR for IGF1R, EGFR and Bcl-xl mRNA and protein expression. •Studies have suggested that the vectors in blocking these genes of the growth factor receptors and anti- apoptosis is capable of breaking the balance of tumor growth so that tumor trend apoptosis and senescence. •Simultaneously blocking multiple genes that are abnormally expressed may be more effective in treating cancer cells than silencing a single gene. -- Abstract: Background: In previous work, we constructed short hairpin RNA (shRNA) expression plasmids that targeted human EGF and IGF-1 receptors messenger RNA, respectively, and demonstrated that these vectors could induce apoptosis of human nasopharyngeal cell lines (CNE2) and inhibit ligand-induced pAkt and pErk activation. Method: We have constructed multiple shRNA expression vectors of targeting EGFR, IGF1R and Bcl-xl, which were transfected to the CNE2 cells. The mRNA expression was assessed by RT-PCR. The growth of the cells, cell cycle progression, apoptosis of the cells, senescent tumor cells and the proteins of EGFR, IGF1R and Bcl-xl were analyzed by MTT, flow cytometry, cytochemical therapy or Western blot. Results: In group of simultaneously blocking EGFR, IGF1R and Bcl-xl genes, the mRNA of EGFR, IGF1R and Bcl-xl expression was decreased by (66.66 ± 3.42)%, (73.97 ± 2.83)% and (64.79 ± 2.83)%, and the protein expressions was diminished to (67.69 ± 4.02)%, (74.32 ± 2.30)%, and (60.00 ± 3.34)%, respectively. Meanwhile, the cell apoptosis increased by 65.32 ± 0.18%, 65.16 ± 0.25% and 55.47 ± 0.45%, and senescent cells increased by 1.42 ± 0.15%, 2.26 ± 0.15% and 3.22 ± 0.15% in the second, third and fourth day cultures, respectively. Conclusions: Simultaneously blocking EGFR, IGF1R and Bcl-xl genes is capable of altering the balance between proliferating versus apoptotic and senescent cells in the favor of both of apoptosis and

  19. Does Metformin affect ER, PR, IGF-1R, β-catenin and PAX-2 expression in women with diabetes mellitus and endometrial cancer?

    Science.gov (United States)

    Markowska, Anna; Pawałowska, Monika; Filas, Violetta; Korski, Konstanty; Gryboś, Marian; Sajdak, Stefan; Olejek, Anita; Bednarek, Wiesława; Spiewankiewicz, Beata; Lubin, Jolanta; Markowska, Janina

    2013-12-05

    Diabetes mellitus, as a risk factor for endometrial cancer (EC), causes an increase in insulin and IGF-1 concentrations in the blood serum. The increase in insulin and IGF-1 are considered mitogenic factors contributory to cancer development. Studies suggest that metformin has preventive activity, decreasing mortality and the risk of neoplasms. Since estrogen (ER), progesterone (PR) and IGF-1 (IGF-1R) receptor expression and β-catenin and PAX-2 mutations are significant in the development of endometrial cancer, it was decided to study these factors in patients with endometrial cancer and type 2 diabetes mellitus (DM2), and to establish the effects of metformin on their expression. The expression of ER, PR, IGF-1R, β-catenin and PAX-2 have been immunohistochemically investigated in 86 type I endometrial cancer specimens. Patients were grouped according to the presence of DM2 and the type of hypoglycemic treatment administered. Comparing EC patients with DM2 and normal glycemic status, we found increased IGF-1R expression in women with DM2. A decrease in ER expression was noted in women with EC and DM2 receiving metformin as compared to women treated with insulin (p = 0.004). There was no statistically significant difference in PR, IGF-1R, β-catenin and PAX-2 expression among women receiving metformin and other hypoglycemic treatment. Although epidemiological studies suggest the beneficial role of metformin in many human cancers, there are still few studies confirming its favorable effect on endometrial cancer. Decreased ER expression in patients receiving metformin needs further research to allow evaluation of its clinical significance.

  20. GPER1-mediated IGFBP-1 induction modulates IGF-1-dependent signaling in tamoxifen-treated breast cancer cells.

    Science.gov (United States)

    Vaziri-Gohar, Ali; Houston, Kevin D

    2016-02-15

    Tamoxifen, a selective estrogen receptor modulator, is a commonly prescribed adjuvant therapy for estrogen receptor-α (ERα)-positive breast cancer patients. To determine if extracellular factors contribute to the modulation of IGF-1 signaling after tamoxifen treatment, MCF-7 cells were treated with IGF-1 in conditioned medium (CM) obtained from 4-OHT-treated MCF-7 cells and the accumulation of phospho-Akt (S473) was measured. CM inhibited IGF-1-dependent cell signaling and suggesting the involvement of extracellular factors (ie. IGFBPs). A significant increase in IGFBP-1 mRNA and extracellular IGFBP-1 protein was observed in 4-OHT-treated MCF-7 cells. Knockdown experiments demonstrated that both GPER1 and CREB mediate IGFBP-1 induction. Furthermore, experiments showed that 4-OHT-dependent IGFBP-1 transcription is downstream of GPER1-activation in breast cancer cells. Additionally, neutralization and knockdown experiments demonstrated a role for IGFBP-1 in the observed inhibition of IGF-1 signaling. These results suggested that 4-OHT inhibits IGF-1 signaling via GPER1 and CREB mediated extracellular IGFBP-1 accumulation in breast cancer cells. Copyright © 2015 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

  1. CD99 triggering induces methuosis of Ewing sarcoma cells through IGF-1R/RAS/Rac1 signaling

    OpenAIRE

    Manara, Maria Cristina; Terracciano, Mario; Mancarella, Caterina; Sciandra, Marika; Guerzoni, Clara; Pasello, Michela; Grilli, Andrea; Zini, Nicoletta; Picci, Piero; Colombo, Mario P.; Morrione, Andrea; Scotlandi, Katia

    2016-01-01

    CD99 is a cell surface molecule that has emerged as a novel target for Ewing sarcoma (EWS), an aggressive pediatric bone cancer. This report provides the first evidence of methuosis in EWS, a non-apoptotic form of cell death induced by an antibody directed against the CD99 molecule. Upon mAb triggering, CD99 induces an IGF-1R/RAS/Rac1 complex, which is internalized into RAB5-positive endocytic vacuoles. This complex is then dissociated, with the IGF-1R recycling to the cell membrane while CD9...

  2. IGF-1 modulates gene expression of proteins involved in inflammation, cytoskeleton, and liver architecture.

    Science.gov (United States)

    Lara-Diaz, V J; Castilla-Cortazar, I; Martín-Estal, I; García-Magariño, M; Aguirre, G A; Puche, J E; de la Garza, R G; Morales, L A; Muñoz, U

    2017-05-01

    Even though the liver synthesizes most of circulating IGF-1, it lacks its receptor under physiological conditions. However, according to previous studies, a damaged liver expresses the receptor. For this reason, herein, we examine hepatic histology and expression of genes encoding proteins of the cytoskeleton, extracellular matrix, and cell-cell molecules and inflammation-related proteins. A partial IGF-1 deficiency murine model was used to investigate IGF-1's effects on liver by comparing wild-type controls, heterozygous igf1 +/- , and heterozygous mice treated with IGF-1 for 10 days. Histology, microarray for mRNA gene expression, RT-qPCR, and lipid peroxidation were assessed. Microarray analyses revealed significant underexpression of igf1 in heterozygous mice compared to control mice, restoring normal liver expression after treatment, which then normalized its circulating levels. IGF-1 receptor mRNA was overexpressed in Hz mice liver, while treated mice displayed a similar expression to that of the controls. Heterozygous mice showed overexpression of several genes encoding proteins related to inflammatory and acute-phase proteins and underexpression or overexpression of genes which coded for extracellular matrix, cytoskeleton, and cell junction components. Histology revealed an altered hepatic architecture. In addition, liver oxidative damage was found increased in the heterozygous group. The mere IGF-1 partial deficiency is associated with relevant alterations of the hepatic architecture and expression of genes involved in cytoskeleton, hepatocyte polarity, cell junctions, and extracellular matrix proteins. Moreover, it induces hepatic expression of the IGF-1 receptor and elevated acute-phase and inflammation mediators, which all resulted in liver oxidative damage.

  3. IGF-1 Receptor Expression on Circulating Osteoblast Progenitor Cells Predicts Tissue-Based Bone Formation Rate and Response to Teriparatide in Premenopausal Women With Idiopathic Osteoporosis.

    Science.gov (United States)

    Cohen, Adi; Kousteni, Stavroula; Bisikirska, Brygida; Shah, Jayesh G; Manavalan, J Sanil; Recker, Robert R; Lappe, Joan; Dempster, David W; Zhou, Hua; McMahon, Donald J; Bucovsky, Mariana; Kamanda-Kosseh, Mafo; Stubby, Julie; Shane, Elizabeth

    2017-06-01

    We have previously reported that premenopausal women with idiopathic osteoporosis (IOP) have profound microarchitectural deficiencies and heterogeneous bone remodeling. Those with the lowest bone formation rate have higher baseline serum insulin-like growth factor-1 (IGF-1) levels and less robust response to teriparatide. Because IGF-1 stimulates bone formation and is critical for teriparatide action on osteoblasts, these findings suggest a state of IGF-1 resistance in some IOP women. To further investigate the hypothesis that osteoblast and IGF-1-related mechanisms mediate differential responsiveness to teriparatide in IOP, we studied circulating osteoblast progenitor (COP) cells and their IGF-1 receptor (IGF-1R) expression. In premenopausal women with IOP, peripheral blood mononuclear cells (PBMCs) were obtained at baseline (n = 25) and over 24 months of teriparatide treatment (n = 11). Flow cytometry was used to identify and quantify COPs (non-hematopoetic lineage cells expressing osteocalcin and RUNX2) and to quantify IGF-1R expression levels. At baseline, both the percent of PBMCs that were COPs (%COP) and COP cell-surface IGF-1R expression correlated directly with several histomorphometric indices of bone formation in tetracycline-labeled transiliac biopsies. In treated subjects, both %COP and IGF-1R expression increased promptly after teriparatide, returning toward baseline by 18 months. Although neither baseline %COP nor increase in %COP after 3 months predicted the bone mineral density (BMD) response to teriparatide, the percent increase in IGF-1R expression on COPs at 3 months correlated directly with the BMD response to teriparatide. Additionally, lower IGF-1R expression after teriparatide was associated with higher body fat, suggesting links between teriparatide resistance, body composition, and the GH/IGF-1 axis. In conclusion, these assays may be useful to characterize bone remodeling noninvasively and may serve to predict early response to

  4. miR-425 inhibits melanoma metastasis through repression of PI3K-Akt pathway by targeting IGF-1.

    Science.gov (United States)

    Liu, Pei; Hu, Yaotian; Ma, Ling; Du, Min; Xia, Lin; Hu, Zhensheng

    2015-10-01

    miR-425 is a potential tumor suppressor in cancer, but its role in melanoma is still unknown. We aim to investigate miR-425 expression in melanoma tissues and cell lines. Next, cell proliferation, cell cycle, apoptosis and metastasis will be studied using lentivirus-mediated gain-of-function studies. The predicted results are stable miR-425 inhibits cell proliferation and metastasis and induced cell apoptosis. It is predicted that IGF-1 is a potential target gene of miR-495 by bioinformatics analysis. Then luciferase assay analysis identifies IGF-1 as a new direct target gene of miR-425 and miR-425 inhibits melanoma cancer progression via IGF-1. Collectively, our findings suggested that miR-425 may function as a tumor suppressor in melanoma by targeting IGF-1. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  5. Long-pulse gastric electrical stimulation protects interstitial cells of Cajal in diabetic rats via IGF-1 signaling pathway.

    Science.gov (United States)

    Li, Hai; Chen, Yan; Liu, Shi; Hou, Xiao-Hua

    2016-06-21

    To investigate the effects of different parameters of gastric electrical stimulation (GES) on interstitial cells of Cajal (ICCs) and changes in the insulin-like growth factor 1 (IGF-1) signal pathway in streptozotocin-induced diabetic rats. Male rats were randomized into control, diabetic (DM), diabetic with sham GES (DM + SGES), diabetic with GES1 (5.5 cpm, 100 ms, 4 mA) (DM + GES1), diabetic with GES2 (5.5 cpm, 300 ms, 4 mA) (DM + GES2) and diabetic with GES3 (5.5 cpm, 550 ms, 2 mA) (DM + GES3) groups. The expression levels of c-kit, M-SCF and IGF-1 receptors were evaluated in the gastric antrum using Western blot analysis. The distribution of ICCs was observed using immunolabeling for c-kit, while smooth muscle cells and IGF-1 receptors were identified using α-SMA and IGF-1R antibodies. Serum level of IGF-1 was tested using enzyme-linked immunosorbent assay. Gastric emptying was delayed in the DM group but improved in all GES groups, especially in the GES2 group. The expression levels of c-kit, M-SCF and IGF-1R were decreased in the DM group but increased in all GES groups. More ICCs (c-kit(+)) and smooth muscle cells (α-SMA(+)/IGF-1R(+)) were observed in all GES groups than in the DM group. The average level of IGF-1 in the DM group was markedly decreased, but it was up-regulated in all GES groups, especially in the GES2 group. The results suggest that long-pulse GES promotes the regeneration of ICCs. The IGF-1 signaling pathway might be involved in the mechanism underlying this process, which results in improved gastric emptying.

  6. The single IGF-1 partial deficiency is responsible for mitochondrial dysfunction and is restored by IGF-1 replacement therapy.

    Science.gov (United States)

    Olleros Santos-Ruiz, M; Sádaba, M C; Martín-Estal, I; Muñoz, U; Sebal Neira, C; Castilla-Cortázar, I

    2017-08-01

    We previously described in cirrhosis and aging, both conditions of IGF-1 deficiency, a clear hepatic mitochondrial dysfunction with increased oxidative damage. In both conditions, the hepatic mitochondrial function was improved with low doses of IGF-1. The aim of this work was to explore if the only mere IGF-1 partial deficiency, without any exogenous insult, is responsible for hepatic mitochondrial dysfunction. Heterozygous (igf1 +/- ) mice were divided into two groups: untreated and treated mice with low doses of IGF-1. WT group was used as controls. Parameters of hepatic mitochondrial function were determined by flow cytometry, antioxidant enzyme activities were determined by spectrophotometry, and electron chain transport enzyme levels were determined by immunohistochemistry and immunofluorescence analyses. Liver expression of genes coding for proteins involved in mitochondrial protection and apoptosis was studied by microarray analysis and RT-qPCR. Hz mice showed a significant reduction in hepatic mitochondrial membrane potential (MMP) and ATPase activity, and an increase in intramitochondrial free radical production and proton leak rates, compared to controls. These parameters were normalized by IGF-1 replacement therapy. No significant differences were found between groups in oxygen consumption and antioxidant enzyme activities, except for catalase, whose activity was increased in both Hz groups. Relevant genes coding for proteins involved in mitochondrial protection and survival were altered in Hz group and were reverted to normal in Hz+IGF-1 group. The mere IGF-1 partial deficiency is per se associated with hepatic mitochondrial dysfunction sensitive to IGF-1 replacement therapy. Results in this work prove that IGF-1 is involved in hepatic mitochondrial protection, because it is able to reduce free radical production, oxidative damage and apoptosis. All these IGF-1 actions are mediated by the modulation of the expression of genes encoding citoprotective

  7. A randomized, phase II study of the anti-insulin-like growth factor receptor type 1 (IGF-1R) monoclonal antibody robatumumab (SCH 717454) in patients with advanced colorectal cancer

    International Nuclear Information System (INIS)

    Lin, Edward H; Lenz, Heinz-Josef; Saleh, Mansoor N; Mackenzie, Mary J; Knost, James A; Pathiraja, Kumudu; Langdon, Ronald B; Yao, Siu-Long; Lu, Brian D

    2014-01-01

    Overexpression of insulin-like growth factor receptor type 1 (IGF-1R) may promote tumor development and progression in some cancer patients. Our objective was to assess tumor uptake of fluorodeoxyglucose by positron-emission tomography in patients with chemotherapy-refractory colorectal cancer treated with an anti-insulin-like growth factor receptor type 1 (anti-IGF-1R) monoclonal antibody, robatumumab. This was a randomized, open-label study with two periods (P1 and P2). Patients were randomized 3:1 into treatment arms R/R and C/R that received, respectively, one cycle of 0.3 mg/kg robatumumab or one or more cycles of second-line chemotherapy in P1, followed in either case by 10 mg/kg robatumumab biweekly in P2. The primary measure of fluorodeoxyglucose uptake was maximum standardized uptake value (SUV max ). The primary endpoint was the proportion of patients in the R/R arm having a mean percent decrease from baseline in SUV max (DiSUV) greater than 20% 12–14 days postdose in P2. Secondary endpoints included Response Evaluation Criteria in Solid Tumors (RECIST)-defined tumor response and pharmacodynamic measures of target engagement. Among 41 patients who were evaluable for the primary endpoint, seven (17%, 95% CI 7%–32%) had DiSUV greater than 20%. Fifty robatumumab-treated patients were evaluable for RECIST-defined tumor response and six (12%) had stable disease lasting greater than or equal to 7 weeks in P2. Pharmacodynamic endpoints indicated target engagement after dosing with 10 mg/kg robatumumab, but not 0.3 mg/kg. The most frequently reported adverse events were fatigue/asthenia, nausea, anorexia, and gastrointestinal disturbances. In this study, few patients with chemotherapy-refractory colorectal cancer appeared to benefit from treatment with the IGF-1R antagonist robatumumab

  8. Serum levels of IGF-1 and IGF-BP3 are associated with event-free survival in adult Ewing sarcoma patients treated with chemotherapy

    Directory of Open Access Journals (Sweden)

    de Groot S

    2017-06-01

    Full Text Available Stefanie de Groot,1 Hans Gelderblom,1 Marta Fiocco,2,3 Judith VMG Bovée,4 Jacobus JM van der Hoeven,1 Hanno Pijl,5 Judith R Kroep1 1Department of Medical Oncology, 2Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, 3Mathematical Department, Leiden University, 4Department of Pathology, 5Department of Endocrinology, Leiden University Medical Center, Leiden, the Netherlands Background: Activation of the insulin-like growth factor 1 (IGF-1 pathway is involved in cell growth and proliferation and is associated with tumorigenesis, tumor progression, and therapy resistance in solid tumors. We examined whether variability in serum levels of IGF-1, IGF-2, and IGF-binding protein 3 (IGF-BP3 can predict event-free survival (EFS and overall survival (OS in Ewing sarcoma patients treated with chemotherapy.Patients and methods: Serum levels of IGF-1, IGF-2, and IGF-BP3 of 22 patients with localized or metastasized Ewing sarcoma treated with six cycles of vincristine/ifosfamide/doxorubicin/etoposide (VIDE chemotherapy were recorded. Baseline levels were compared with presixth cycle levels using paired t-tests and were tested for associations with EFS and OS. Continuous variables were dichotomized according to the Contal and O’Quigley procedure. Survival analyses were performed using Cox regression analysis.Results: High baseline IGF-1 and IGF-BP3 serum levels were associated with EFS (hazard ratio [HR] 0.075, 95% confidence interval [CI] 0.009–0.602 and HR 0.090, 95% CI 0.011–0.712, respectively in univariate and multivariate analyses (HR 0.063, 95% CI 0.007–0.590 and HR 0.057, 95% CI 0.005–0.585, respectively. OS was improved, but this was not statistically significant. IGF-BP3 and IGF-2 serum levels increased during treatment with VIDE chemotherapy (P=0.055 and P=0.023, respectively.Conclusion: High circulating serum levels of IGF-1 and IGF-BP3 and the molar ratio of IGF-1:IGF-BP3 serum levels were associated

  9. The proto-oncogene product c-Crk associates with insulin receptor substrate-1 and 4PS. Modulation by insulin growth factor-I (IGF) and enhanced IGF-I signaling.

    Science.gov (United States)

    Beitner-Johnson, D; Blakesley, V A; Shen-Orr, Z; Jimenez, M; Stannard, B; Wang, L M; Pierce, J; LeRoith, D

    1996-04-19

    The Crk proto-oncogene product is an SH2 and SH3 domain-containing adaptor protein which we have previously shown to become rapidly tyrosine phosphorylated in response to stimulation with insulin-like growth factor I (IGF-I) in NIH-3T3 cells. In order to further characterize the role of Crk in the IGF-I signaling pathway, NIH-3T3 and 293 cells were stably transfected with an expression vector containing the Crk cDNA. The various resultant 3T3-Crk clones expressed Crk at approximately 2-15-fold higher levels than parental 3T3 cells. In 3T3-Crk cells, Crk immunoreactivity was detected in insulin receptor substrate-1 (IRS-1) immunoprecipitates. Stimulation with IGF-I resulted in a dissociation of Crk protein from IRS-1. In contrast, the association of the related adaptor protein Grb2 with IRS-1 was enhanced by IGF-I stimulation. Similar results were obtained in stably transfected 293-Crk cells, which express both IRS-1 and the IRS-1-related signaling protein 4PS. In these cells, IRS-1 and 4PS both associated with Crk, and this association was also decreased by IGF-I treatment, whereas the association of Grb2 with IRS-1 and 4PS was enhanced by IGF-I. Overexpression of Crk also enhanced IGF-I-induced mitogenesis of NIH-3T3 cells, as measured by [3H]thymidine incorporation. The levels of IGF-I-induced mitogenesis were proportional to the level of Crk expression. These results suggest that Crk is a positive effector of IGF-I signaling, and may mediate its effects via interaction with IRS-1 and/or 4PS.

  10. Phosphatidylinositol 3-Kinase (PI3K) Activity Bound to Insulin-like Growth Factor-I (IGF-I) Receptor, which Is Continuously Sustained by IGF-I Stimulation, Is Required for IGF-I-induced Cell Proliferation*

    Science.gov (United States)

    Fukushima, Toshiaki; Nakamura, Yusaku; Yamanaka, Daisuke; Shibano, Takashi; Chida, Kazuhiro; Minami, Shiro; Asano, Tomoichiro; Hakuno, Fumihiko; Takahashi, Shin-Ichiro

    2012-01-01

    Continuous stimulation of cells with insulin-like growth factors (IGFs) in G1 phase is a well established requirement for IGF-induced cell proliferation; however, the molecular components of this prolonged signaling pathway that is essential for cell cycle progression from G1 to S phase are unclear. IGF-I activates IGF-I receptor (IGF-IR) tyrosine kinase, followed by phosphorylation of substrates such as insulin receptor substrates (IRS) leading to binding of signaling molecules containing SH2 domains, including phosphatidylinositol 3-kinase (PI3K) to IRS and activation of the downstream signaling pathways. In this study, we found prolonged (>9 h) association of PI3K with IGF-IR induced by IGF-I stimulation. PI3K activity was present in this complex in thyrocytes and fibroblasts, although tyrosine phosphorylation of IRS was not yet evident after 9 h of IGF-I stimulation. IGF-I withdrawal in mid-G1 phase impaired the association of PI3K with IGF-IR and suppressed DNA synthesis the same as when PI3K inhibitor was added. Furthermore, we demonstrated that Tyr1316-X-X-Met of IGF-IR functioned as a PI3K binding sequence when this tyrosine is phosphorylated. We then analyzed IGF signaling and proliferation of IGF-IR−/− fibroblasts expressing exogenous mutant IGF-IR in which Tyr1316 was substituted with Phe (Y1316F). In these cells, IGF-I stimulation induced tyrosine phosphorylation of IGF-IR and IRS-1/2, but mutated IGF-IR failed to bind PI3K and to induce maximal phosphorylation of GSK3β and cell proliferation in response to IGF-I. Based on these results, we concluded that PI3K activity bound to IGF-IR, which is continuously sustained by IGF-I stimulation, is required for IGF-I-induced cell proliferation. PMID:22767591

  11. The pro-Forms of Insulin-Like Growth Factor I (IGF-I) Are Predominant in Skeletal Muscle and Alter IGF-I Receptor Activation

    Science.gov (United States)

    Durzyńska, Julia; Philippou, Anastassios; Brisson, Becky K.; Nguyen-McCarty, Michelle

    2013-01-01

    IGF-I is a key regulator of muscle development and growth. The pre-pro-peptide produced by the Igf1gene undergoes several posttranslational processing steps to result in a secreted mature protein, which is thought to be the obligate ligand for the IGF-I receptor (IGF-IR). The goals of this study were to determine what forms of IGF-I exist in skeletal muscle, and whether the mature IGF-I protein was the only form able to activate the IGF-IR. We measured the proportion of IGF-I species in murine skeletal muscle and found that the predominant forms were nonglycosylated pro-IGF-I and glycosylated pro-IGF-I, which retained the C-terminal E peptide extension, instead of mature IGF-I. These forms were validated using samples subjected to viral expression of IGF-I combined with furin and glycosidase digestion. To determine whether the larger molecular weight IGF-I forms were also ligands for the IGF-IR, we generated each specific form through transient transfection of 3T3 cells and used the enriched media to perform kinase receptor activation assays. Compared with mature IGF-I, nonglycosylated pro-IGF-I had similar ability to activate the IGF-IR, whereas glycosylation of pro-IGF-I significantly reduced receptor activation. Thus, it is important to understand not only the quantity, but also the proportion of IGF-I forms produced, to evaluate the true biological activity of this growth factor. PMID:23407451

  12. [Effects of pulsed magnetic field on insulin-like growth factor-1 (IGF-1) in cerebrospinal fluid and effects of IGF-1 on functional recovery].

    Science.gov (United States)

    Song, Cheng-xian; Fan, Jian-zhong; Wu, Hong-ying; Wei, Yi; Zhen, Jian-rong

    2010-10-01

    To study the effects of pulsed magnetic field on insulin-like growth factor-1 (IGF-1) level in the cerebrospinal fluid (CSF) and the association of IGF-1 alterations with the activities of daily living (ADL) of patients with brain injury. Sixty-five patients with brain injury were divided randomly into the control group (n=30) and magnetic therapy group (n=35), both receiving conventional therapy and in the latter group, daily pulsed magnetic field treatment (20-40 mT, 50 Hz, 20 min per time, 1 time per day) for 14 consecutive days were administered. On the first and 14th days of the treatment, 2 ml CSF was collected from the cases patients for IGF-1 measurement by radioimmunoassay, and Barthel index (BI) was used to assess the ADL of the patients. After a 14-day treatment, IGF-1 level in the CSF were significantly increased in the magnetic group in comparison with the level before the treatment and with those in the control group (P0.05). The scores of BI increased significantly in both groups after the treatment (Pmagnetic therapy group (P<0.05). A significant positive correlation was found between IGF-1 level in the CSF and BI in these patients (r=0.283, P=0.022). Pulsed magnetic field might increase IGF-1 level in the CSF of patients with brain injury to promote the recovery of the patients ADL, suggesting its potential clinical value in the treatment of brain injury.

  13. Role of heterotrimeric G protein and calcium in cardiomyocyte hypertrophy induced by IGF-1.

    Science.gov (United States)

    Carrasco, Loreto; Cea, Paola; Rocco, Paola; Peña-Oyarzún, Daniel; Rivera-Mejias, Pablo; Sotomayor-Flores, Cristian; Quiroga, Clara; Criollo, Alfredo; Ibarra, Cristian; Chiong, Mario; Lavandero, Sergio

    2014-04-01

    In the heart, insulin-like growth factor-1 (IGF-1) is a peptide with pro-hypertrophic and anti-apoptotic actions. The pro-hypertrophic properties of IGF-1 have been attributed to the extracellular regulated kinase (ERK) pathway. Recently, we reported that IGF-1 also increases intracellular Ca(2+) levels through a pertussis toxin (PTX)-sensitive G protein. Here we investigate whether this Ca(2+) signal is involved in IGF-1-induced cardiomyocyte hypertrophy. Our results show that the IGF-1-induced increase in Ca(2+) level is abolished by the IGF-1 receptor tyrosine kinase inhibitor AG538, PTX and the peptide inhibitor of Gβγ signaling, βARKct. Increases in the activities of Ca(2+) -dependent enzymes calcineurin, calmodulin kinase II (CaMKII), and protein kinase Cα (PKCα) were observed at 5 min after IGF-1 exposure. AG538, PTX, βARKct, and the dominant negative PKCα prevented the IGF-1-dependent phosphorylation of ERK1/2. Participation of calcineurin and CaMKII in ERK phosphorylation was discounted. IGF-1-induced cardiomyocyte hypertrophy, determined by cell size and β-myosin heavy chain (β-MHC), was prevented by AG538, PTX, βARKct, dominant negative PKCα, and the MEK1/2 inhibitor PD98059. Inhibition of calcineurin with CAIN did not abolish IGF-1-induced cardiac hypertrophy. We conclude that IGF-1 induces hypertrophy in cultured cardiomyocytes by activation of the receptor tyrosine kinase activity/βγ-subunits of a PTX-sensitive G protein/Ca(2+) /PKCα/ERK pathway without the participation of calcineurin. © 2013 Wiley Periodicals, Inc.

  14. Maternal insulin-like growth factors 1 and 2 (IGF-1, IGF-2) and IGF BP-3 and the hypertensive disorders of pregnancy.

    LENUS (Irish Health Repository)

    Cooley, Sharon M

    2010-07-01

    To investigate the relationship between levels of insulin-like growth factors 1 and 2 (IGF-1, IGF-2) and insulin-like growth factor binding protein 3 (IGFBP-3) in antenatal maternal serum and gestational hypertension and pre-eclampsia (PET).

  15. IGF-1 deficiency impairs neurovascular coupling in mice: implications for cerebromicrovascular aging.

    Science.gov (United States)

    Toth, Peter; Tarantini, Stefano; Ashpole, Nicole M; Tucsek, Zsuzsanna; Milne, Ginger L; Valcarcel-Ares, Noa M; Menyhart, Akos; Farkas, Eszter; Sonntag, William E; Csiszar, Anna; Ungvari, Zoltan

    2015-12-01

    Aging is associated with marked deficiency in circulating IGF-1, which has been shown to contribute to age-related cognitive decline. Impairment of moment-to-moment adjustment of cerebral blood flow (CBF) via neurovascular coupling is thought to play a critical role in the genesis of age-related cognitive impairment. To establish the link between IGF-1 deficiency and cerebromicrovascular impairment, neurovascular coupling mechanisms were studied in a novel mouse model of IGF-1 deficiency (Igf1(f/f) -TBG-Cre-AAV8) and accelerated vascular aging. We found that IGF-1-deficient mice exhibit neurovascular uncoupling and show a deficit in hippocampal-dependent spatial memory test, mimicking the aging phenotype. IGF-1 deficiency significantly impaired cerebromicrovascular endothelial function decreasing NO mediation of neurovascular coupling. IGF-1 deficiency also impaired glutamate-mediated CBF responses, likely due to dysregulation of astrocytic expression of metabotropic glutamate receptors and impairing mediation of CBF responses by eicosanoid gliotransmitters. Collectively, we demonstrate that IGF-1 deficiency promotes cerebromicrovascular dysfunction and neurovascular uncoupling mimicking the aging phenotype, which are likely to contribute to cognitive impairment. © 2015 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

  16. Growth inhibition of human pancreatic cancer cells by lipofection mediated IGF-1R antisense oligodeoxynucletides in combination with ionizing radiation

    International Nuclear Information System (INIS)

    Pan Yaozhen; Sun Chengyi; Wang Yuzhi

    2004-01-01

    Objective: To study the growth inhibition of human pancreatic cancer cells (PC-3) by lipofection-mediated and ionizing radiation improving transfection of IGF-1R antisense oligodeoxynucletides (ASON) in vitro. Methods: Colonigenicity of PC-3 cells in vitro after 60 Co γ-radiation was observed for ascertaining their radiosensitivity and optimal radiation dose was selected according to the radiation sensitivity. PC-3 cells were transfected by two ways: 1) by lipofection-mediated IGF-1R ASON combined with ionizing radiation. 2) by lipo-ASON alone without ionizing radiation. Cell growth was assessed by MTT method. The expression of IGF-1R at mRNA level was examined by RT-PCR. Flow cytometry was used to demonstrate apoptotic changes in lipo-ASON-treated cells. Results: The inhibitory efficiency of lipo-ASON combined with ionizing radiation was higher than that without ionizing radiation (P < 0.05). The apoptotic efficiency and the decreased level of IGF-1R at mRNA were significantly improved (P < 0.05). Conclusion: Lipofection-mediated and ionizing radiation-promoted transfection of IGF-1R antisense oligodeoxynucletides (ASON) significantly decreases IGF-1R at mRNA level and induces apoptosis of human pancreatic cancer cells in vitro

  17. A Novel Role of IGF1 in Apo2L/TRAIL-Mediated Apoptosis of Ewing Tumor Cells

    Directory of Open Access Journals (Sweden)

    Frans van Valen

    2012-01-01

    Full Text Available Insulin-like growth factor 1 (IGF1 reputedly opposes chemotoxicity in Ewing sarcoma family of tumor (ESFT cells. However, the effect of IGF1 on apoptosis induced by apoptosis ligand 2 (Apo2L/tumor necrosis factor (TNF- related apoptosis-inducing ligand (TRAIL remains to be established. We find that opposite to the partial survival effect of short-term IGF1 treatment, long-term IGF1 treatment amplified Apo2L/TRAIL-induced apoptosis in Apo2L/TRAIL-sensitive but not resistant ESFT cell lines. Remarkably, the specific IGF1 receptor (IGF1R antibody α-IR3 was functionally equivalent to IGF1. Short-term IGF1 incubation of cells stimulated survival kinase AKT and increased X-linked inhibitor of apoptosis (XIAP protein which was associated with Apo2L/TRAIL resistance. In contrast, long-term IGF1 incubation resulted in repression of XIAP protein through ceramide (Cer formation derived from de novo synthesis which was associated with Apo2L/TRAIL sensitization. Addition of ceramide synthase (CerS inhibitor fumonisin B1 during long-term IGF1 treatment reduced XIAP repression and Apo2L/TRAIL-induced apoptosis. Noteworthy, the resistance to conventional chemotherapeutic agents was maintained in cells following chronic IGF1 treatment. Overall, the results suggest that chronic IGF1 treatment renders ESFT cells susceptible to Apo2L/TRAIL-induced apoptosis and may have important implications for the biology as well as the clinical management of refractory ESFT.

  18. IGF-1 levels are significantly correlated with patient-reported measures of sexual function.

    Science.gov (United States)

    Pastuszak, A W; Liu, J S; Vij, A; Mohamed, O; Sathyamoorthy, K; Lipshultz, L I; Khera, M

    2011-01-01

    Growth hormone (GH) supplementation may help to preserve erectile function. We assessed whether serum insulin-like growth factor 1 (IGF-1) levels, a surrogate for GH levels, correlate with sexual function scores in 65 men who completed the Sexual Health Inventory for Men (SHIM) and Expanded Prostate Cancer Index Composite (EPIC) questionnaires, and had serum IGF-1 and testosterone levels determined. Median±s.d. IGF-1 level, SHIM and EPIC scores were 235.0±86.4, 19.5±8.7 and 56.4±28.3 mg ml(-1), respectively. IGF-1 levels and total SHIM score correlate significantly (r=0.31, P=0.02), as do IGF-1 levels and all individual SHIM question scores, and IGF-1 levels and the sexual domain of the EPIC questionnaire (r=0.30, P=0.02). No correlation was observed between IGF-1 levels and Gleason score, IGF-1 and testosterone level or SHIM score and testosterone level. These data support a potential role for the GH axis in erectile function.

  19. IGF-IR promotes prostate cancer growth by stabilizing α5β1 integrin protein levels.

    Directory of Open Access Journals (Sweden)

    Aejaz Sayeed

    Full Text Available Dynamic crosstalk between growth factor receptors, cell adhesion molecules and extracellular matrix is essential for cancer cell migration and invasion. Integrins are transmembrane receptors that bind extracellular matrix proteins and enable cell adhesion and cytoskeletal organization. They also mediate signal transduction to regulate cell proliferation and survival. The type 1 insulin-like growth factor receptor (IGF-IR mediates tumor cell growth, adhesion and inhibition of apoptosis in several types of cancer. We have previously demonstrated that β1 integrins regulate anchorage-independent growth of prostate cancer (PrCa cells by regulating IGF-IR expression and androgen receptor-mediated transcriptional functions. Furthermore, we have recently reported that IGF-IR regulates the expression of β1 integrins in PrCa cells. We have dissected the mechanism through which IGF-IR regulates β1 integrin expression in PrCa. Here we report that IGF-IR is crucial for PrCa cell growth and that β1 integrins contribute to the regulation of proliferation by IGF-IR. We demonstrate that β1 integrin regulation by IGF-IR does not occur at the mRNA level. Exogenous expression of a CD4 - β1 integrin cytoplasmic domain chimera does not interfere with such regulation and fails to stabilize β1 integrin expression in the absence of IGF-IR. This appears to be due to the lack of interaction between the β1 cytoplasmic domain and IGF-IR. We demonstrate that IGF-IR stabilizes the β1 subunit by protecting it from proteasomal degradation. The α5 subunit, one of the binding partners of β1, is also downregulated along with β1 upon IGF-IR knockdown while no change is observed in the expression of the α2, α3, α4, α6 and α7 subunits. Our results reveal a crucial mechanistic role for the α5β1 integrin, downstream of IGF-IR, in regulating cancer growth.

  20. Plasma and tissue insulin-like growth factor-I receptor (IGF-IR) as a prognostic marker for prostate cancer and anti-IGF-IR agents as novel therapeutic strategy for refractory cases: a review.

    Science.gov (United States)

    Ozkan, Emine Elif

    2011-09-15

    Cancer database analysis indicates that prostate cancer is one of the most seen cancers in men meanwhile composing the leading cause of morbidity and mortality among developed countries. Current available therapies are surgery, radiotherapy and androgene ablation for prostate carcinoma. The response rate is as high nearly 90% however, most of these recur or become refractory and androgene independent (AI). Therefore recent studies intensified on molecular factors playing role on development of prostate carcinoma and novel treatment strategies targetting these factors and their receptors. Insulin-like growth factor-I (IGF-I) and its primary receptor insulin-like growth factor receptor-I (IGF-IR) are among these factors. Biologic functions and role in malign progression are primarily achieved via IGF-IR which is a type 2 tyrosine kinase receptor. IGF-IR plays an important role in mitogenesis, angiogenesis, transformation, apoptosis and cell motility. It also generates intensive proliferative signals leading to carcinogenesis in prostate tissue. So IGF-IR and its associated signalling system have provoked considerable interest over recent years as a novel therapeutic target in cancer. In this paper it is aimed to sum up the lately published literature searching the relation of IGF-IR and prostate cancer in terms of incidence, pathologic features, and prognosis. This is followed by a discussion of the different possible targets within the IGF-1R system, and drugs developed to interact at each target. A systems-based approach is then used to review the in vitro and in vivo data in the published literature of the following compounds targeting IGF-1R components using specific examples: growth hormone releasing hormone antagonists (e.g. JV-1-38), growth hormone receptor antagonists (e.g. pegvisomant), IGF-1R antibodies (e.g. CP-751,871, AVE1642/EM164, IMC-A12, SCH-717454, BIIB022, AMG 479, MK-0646/h7C10), and IGF-1R tyrosine kinase inhibitors (e.g. BMS-536942, BMS-554417

  1. IGF-I and branchial IGF receptor expression and localization during salinity acclimation in striped bass

    DEFF Research Database (Denmark)

    Tipsmark, Christian Kølbaek; Luckenbach, John Adam; Madsen, Steffen

    2007-01-01

    The initial response of the IGF-I system and the expression and cellular localization of IGF type-I receptor (IGF-IR) were studied in the gill of a euryhaline teleost during salinity acclimation. Exposure of striped bass (Morone saxatilis) to hyperosmotic and hypoosmotic challenges induced small...... in either plasma IGF-I, liver, or gill IGF-I mRNA, or gill IGF-IR mRNA levels. In a separate experiment, FW-acclimated fish were injected with saline or IGF-I prior to a 24-h SW challenge. Rapid regain of osmotic balance following SW transfer was hindered by IGF-I. Immunohistochemistry revealed...

  2. Systemic analysis of different colorectal cancer cell lines and TCGA datasets identified IGF-1R/EGFR-PPAR-CASPASE axis as important indicator for radiotherapy sensitivity.

    Science.gov (United States)

    Chen, Lin; Zhu, Zhe; Gao, Wei; Jiang, Qixin; Yu, Jiangming; Fu, Chuangang

    2017-09-05

    Insulin-like growth factor 1 receptor (IGF-1R) is proved to contribute the development of many types of cancers. But, little is known about its roles in radio-resistance of colorectal cancer (CRC). Here, we demonstrated that low IGF-1R expression value was associated with the better radiotherapy sensitivity of CRC. Besides, through Quantitative Real-time PCR (qRT-PCR), the elevated expression value of epidermal growth factor receptor (EGFR) was observed in CRC cell lines (HT29, RKO) with high radio-sensitivity compared with those with low sensitivity (SW480, LOVO). The irradiation induced apoptosis rates of wild type and EGFR agonist (EGF) or IGF-1R inhibitor (NVP-ADW742) treated HT29 and SW480 cells were quantified by flow cytometry. As a result, the apoptosis rate of EGF and NVP-ADW742 treated HT29 cells was significantly higher than that of those wild type ones, which indicated that high EGFR and low IGF-1R expression level in CRC was associated with the high sensitivity to radiotherapy. We next conducted systemic bioinformatics analysis of genome-wide expression profiles of CRC samples from the Cancer Genome Atlas (TCGA). Differential expression analysis between IGF-1R and EGFR abnormal CRC samples, i.e. CRC samples with higher IGF-1R and lower EGFR expression levels based on their median expression values, and the rest of CRC samples identified potential genes contribute to radiotherapy sensitivity. Functional enrichment of analysis of those differential expression genes (DEGs) in the Database for Annotation, Visualization and Integrated Discovery (DAVID) indicated PPAR signaling pathway as an important pathway for the radio-resistance of CRC. Our study identified the potential biomarkers for the rational selection of radiotherapy for CRC patients. Copyright © 2017 Elsevier B.V. All rights reserved.

  3. Serum levels of bioactive IGF1 and physiological markers of ageing in healthy adults.

    Science.gov (United States)

    Vestergaard, Poul Frølund; Hansen, Mette; Frystyk, Jan; Espelund, Ulrick; Christiansen, Jens S; Jørgensen, Jens Otto Lunde; Fisker, Sanne

    2014-02-01

    Senescent changes in body composition and muscle strength are accompanied by reduced production of GH and IGF1, but the causal relationship remains elusive. We speculate that serum bioactive IGF1, measured by the IGF1 kinase receptor activation assay, is closer related to human physiological ageing than total IGF1 measured by immunoassay. We conducted a cross-sectional study in 150 adult males and females, between 20 and 70 years. After an overnight fasting, serum levels of bioactive IGF1, total IGF1 and IGF-binding protein 1 (IGFBP1) and IGFBP3 were assessed. Furthermore, body composition and muscle strength was measured. Total IGF1 levels were higher in females (P=0.048). Bioactive IGF1 were identical in males and females (P=0.31), decreasing with age. Total IGF1 tended to decrease more with age compared with bioactive IGF1 (-1.48 vs -0.89 percent/year, P=0.052). Total body fat (TBF) was lower and BMI was higher in males (Page. Knee extension and elbow flexion force were higher in males (P=0.001 and P=0.001), but decreased with age in both genders.  Total but not bioactive IGF1 was positively correlated to TBF, knee extension and muscle function in males. In multiple linear regression, only age predicted total IGF1, whereas age and IGFBP1 predicted bioactive IGF1. Bioactive IGF1 tends to decrease to a lesser extent than total IGF1 with age and was not correlated with measures of body composition or muscle strength. Therefore, levels of circulating bioactive IGF1 does not appear to be a better biomarker of physiological ageing than total IGF1.

  4. IGF-1 Regulates Vertebral Bone Aging Through Sex-Specific and Time-Dependent Mechanisms.

    Science.gov (United States)

    Ashpole, Nicole M; Herron, Jacquelyn C; Mitschelen, Matthew C; Farley, Julie A; Logan, Sreemathi; Yan, Han; Ungvari, Zoltan; Hodges, Erik L; Csiszar, Anna; Ikeno, Yuji; Humphrey, Mary Beth; Sonntag, William E

    2016-02-01

    Advanced aging is associated with increased risk of bone fracture, especially within the vertebrae, which exhibit significant reductions in trabecular bone structure. Aging is also associated with a reduction in circulating levels of insulin-like growth factor (IGF-1). Studies have suggested that the reduction in IGF-1 compromises healthspan, whereas others report that loss of IGF-1 is beneficial because it increases healthspan and lifespan. To date, the effect of decreases in circulating IGF-1 on vertebral bone aging has not been thoroughly investigated. Here, we delineate the consequences of a loss of circulating IGF-1 on vertebral bone aging in male and female Igf(f/f) mice. IGF-1 was reduced at multiple specific time points during the mouse lifespan: early in postnatal development (crossing albumin-cyclic recombinase [Cre] mice with Igf(f/f) mice); and in early adulthood and in late adulthood using hepatic-specific viral vectors (AAV8-TBG-Cre). Vertebrae bone structure was analyzed at 27 months of age using micro-computed tomography (μCT) and quantitative bone histomorphometry. Consistent with previous studies, both male and female mice exhibited age-related reductions in vertebral bone structure. In male mice, reduction of circulating IGF-1 induced at any age did not diminish vertebral bone loss. Interestingly, early-life loss of IGF-1 in females resulted in a 67% increase in vertebral bone volume fraction, as well as increased connectivity density and increased trabecular number. The maintenance of bone structure in the early-life IGF-1-deficient females was associated with increased osteoblast surface and an increased ratio of osteoprotegerin/receptor-activator of NF-κB-ligand (RANKL) levels in circulation. Within 3 months of a loss of IGF-1, there was a 2.2-fold increase in insulin receptor expression within the vertebral bones of our female mice, suggesting that local signaling may compensate for the loss of circulating IGF-1. Together, these data

  5. Relative IGF-1 and IGF-2 gene expression in maternal and fetal tissues from diabetic swine

    International Nuclear Information System (INIS)

    Wolverton, C.K.; Leaman, D.W.; White, M.E.; Ramsay, T.G.

    1990-01-01

    Fourteen pregnant, crossbred gilts were utilized in this study. Seven gilts were injected with alloxan (50 mg/kg) at day 75 of gestation to induce diabetes. Gilts underwent caesarean section on day 105 of gestation. Samples were collected from maternal skeletal muscle, adipose tissue, uterus and endometrium; and from fetal skeletal muscle, adipose tissue, placenta, liver, lung, kidney, heart, brain and spleen. Tissues were frozen in liquid nitrogen for later analysis of IGF-1 and IGF-2 gene expression. Samples were pooled and total RNA was isolated using the guanidine isothiocynate method. Total mRNA was analyzed by dot blot hybridization. Blots were probed with 32 P-cDNA for porcine IGF-1 and rat IGF-2. IGF-1 gene expression in maternal tissues was unaffected by diabetes. Maternal diabetes increased IGF-2 mRNA in maternal adipose tissue but exhibited no effect in muscle or uterus. Expression of IGF-2 by maternal endometrium was decreased by diabetes. Maternal diabetes induced an increase in IGF-1 gene expression in muscle and placenta while causing an increase in IGF-2 expression in fetal liver and placenta. IGF-2 mRNA was lower in lung from fetuses of diabetic mothers than in controls. These results suggest that maternal diabetes alters IGF-1 and IGF-2 gene expression in specific tissues and differential regulation of these genes appears to exist in the mother and developing fetus

  6. MicroRNA-133a Inhibits Osteosarcoma Cells Proliferation and Invasion via Targeting IGF-1R

    Directory of Open Access Journals (Sweden)

    Guangnan Chen

    2016-02-01

    Full Text Available Background/Aims: MicroRNAs (miRNAs are a class of small noncoding RNAs that regulate gene expression by repressing translation or cleaving RNA transcripts in a sequence-specific manner. Downregulated microRNAs and their roles in cancer development have attracted much attention. A growing body of evidence showed that microRNA-133a (miR-133a has inhibitory effects on cell proliferation, migration, invasion, and metastasis of osteosarcoma. Methods: MiR-133a expression in human osteosarcoma cell lines and human normal osteoblastic cell line hFOB was investigated by real-time PCR (RT-PCR. The role of miR-133a in human osteosarcoma growth and invasion was assessed in cell lines in vitro and in vivo. Then, luciferase reporter assay validated IGF-1R as a downstream and functional target of miR-133a, and functional studies revealed that the anti-tumor effect of miR-133a was probably due to targeting and repressing of IGF-1R expression. Results: MiR-133a was lower expressed in human osteosarcoma cell lines than human normal osteoblastic cell line hFOB and its effect on inhibiting proliferation, invasion and metastasis is mediated by its direct interaction with the IGF-1R. Furthermore, the tumour-suppressive function of miR-133a probably contributed to inhibiting the activation AKT and ERK signaling pathway. Conclusion: MiR-133a suppresses osteosarcoma progression and metastasis by targeting IGF-1R in human osteosarcoma cells, providing a novel candidate prognostic factor and a potential anti-metastasis therapeutic target in osteosarcoma.

  7. Upregulation of miR-150* and miR-630 induces apoptosis in pancreatic cancer cells by targeting IGF-1R.

    Directory of Open Access Journals (Sweden)

    Lulu Farhana

    Full Text Available MicroRNAs have been implicated in many critical cellular processes including apoptosis. We have previously found that apoptosis in pancreatic cancer cells was induced by adamantyl retinoid-related (ARR molecule 3-Cl-AHPC. Here we report that 3-Cl-AHPC-dependent apoptosis involves regulating a number of microRNAs including miR-150* and miR-630. 3-Cl-AHPC stimulated miR-150* expression and caused decreased expression of c-Myb and IGF-1R in the pancreatic cancer cells. 3-Cl-AHPC-mediated reduction of c-Myb resulted in diminished binding of c-Myb with IGF-1R and Bcl-2 promoters, thereby causing repression of their transcription and protein expression. Over-expression of miR-150* also resulted in diminished levels of c-Myb and Bcl-2 proteins. Furthermore, the addition of the miRNA inhibitor 2'-O-methylated miR-150 blocked 3-Cl-AHPC-mediated increase in miR-150* levels and abrogated loss of c-Myb protein. Knockdown of c-Myb in PANC-1 cells resulted in enhanced apoptosis both in the presence or absence of 3-Cl-AHPC confirming the anti-apoptotic property of c-Myb. Overexpression of miR-630 also induced apoptosis in the pancreatic cancer cells and inhibited target protein IGF-1R mRNA and protein expression. Together these results implicate key roles for miR-150* and miR-630 and their targeting of IGF-1R to promote apoptosis in pancreatic cancer cells.

  8. Inhibition of EGFR or IGF-1R signaling enhances radiation response in head and neck cancer models but concurrent inhibition has no added benefit

    International Nuclear Information System (INIS)

    Raju, Uma; Molkentine, David P; Valdecanas, David R; Deorukhkar, Amit; Mason, Kathryn A; Buchholz, Thomas A; Meyn, Raymond E; Ang, Kie-Kian; Skinner, Heath

    2015-01-01

    Interaction between the epidermal growth factor receptor (EGFR) and the insulin-like growth factor receptor (IGF-1R) has been well established in many cancer types. We investigated the effects of cetuximab (EGFR antibody) and IMC-A12 (IGF-1R antibody) on the response of head and neck squamous cell carcinoma (HNSCC) to radiation therapy (RT). The effects of cetuximab and IMC-A12 on cell viability and radiosensitivity were determined by clonogenic cell survival assay. Formation of nuclear γ-H2AX and 53BP1 foci was monitored by immunofluorescence. Alterations in target signaling were analyzed by Western blots. In vivo tumor growth delay assay was performed to determine the efficacy of triple therapy with IMC-A12, cetuximab, and RT. In vitro data showed that cetuximab differentially affected the survival and the radiosensitivity of HNSCC cells. Cetuximab suppressed DNA repair that was evident by the prolonged presence of nuclear γ-H2AX and 53BP1 foci. IMC-A12 did not have any effect on the cell survival. However, it increased the radiosensitivity of one of the cell lines. EGFR inhibition increased IGF-1R expression levels and also the association between EGFR and IGF-1R. Addition of IMC-A12 to cetuximab did not increase the radiosensitivity of these cells. Tumor xenografts exhibited enhanced response to RT in the presence of either cetuximab or IMC-A12. Concurrent treatment regimen failed to further enhance the tumor response to cetuximab and/or RT. Taken together our data suggest that concomitant inhibition of both EGFR and IGF-1R pathways did not yield additional therapeutic benefit in overcoming resistance to RT

  9. Membrane-associated insulin-like growth factor (IGF binding structures in placental cells

    Directory of Open Access Journals (Sweden)

    ROMANA MASNIKOSA

    2003-11-01

    Full Text Available The biological activities of IGF-I and –II are mediated mainly by the type 1 IGF receptor (IGF 1R and controlled by their interaction with soluble proteins, the IGF binding proteins (IGFBPs. Although there is a growing body of evidence that some IGFBPs may be cell surface-bound, published data concerning cell association of IGFBP-1 are scarce and none of them concern placental cells. The cell membranes used in this study were isolated from term human placentae. Detergent-solubilized membranes were shown to contain two types of IGF binding structures that were separated by gel filtration on a Sephadex G-100 column. Proteins in the first peak were eluted at V0 (Mr > 100 kD and they bound IGF-I with greater specificity and affinity than IGF-II and insulin. Most likely, they represented the IGF 1R. Small proteins (Mr ~ 45 kD were eluted with the membrane proteins in the second maximum. They were able to bind IGF-I and IGF-II, but not insulin. The identity of these proteins was shown to be IGFBP-1 on the basis of their reaction with specific anti-IGFBP-1 antibodies. To the best of our knowledge, the existence of IGFBP-1 associated with human placental cell membranes has not been reported in the literature before. Colocalisation of IGFBP-1 with IGF 1R in cell membranes could provide efficient modulation of IGF 1R receptor-ligand interactions.

  10. Inhibition of p70S6K1 Activation by Pdcd4 Overcomes the Resistance to an IGF-1R/IR Inhibitor in Colon Carcinoma Cells.

    Science.gov (United States)

    Zhang, Yan; Wang, Qing; Chen, Li; Yang, Hsin-Sheng

    2015-03-01

    Agents targeting insulin-like growth factor 1 receptor (IGF-1R) are being actively examined in clinical trials. Although there has been some initial success of single-agent targeting IGF-1R, attempts in later studies failed because of resistance. This study aimed to understand the effects of programmed cell death 4 (Pdcd4) on the chemosensitivity of the IGF-1R inhibitor OSI-906 in colorectal cancer cells and the mechanism underlying this impact. Using OSI-906-resistant and -sensitive colorectal cancer cells, we found that the Pdcd4 level directly correlates with cell chemosensitivity to OSI-906. In addition, tumors derived from Pdcd4 knockdown cells resist the growth inhibitory effect of OSI-906 in a colorectal cancer xenograft mouse model. Moreover, Pdcd4 enhances the antiproliferative effect of OSI-906 in resistant cells through suppression of p70S6K1 activation. Knockdown of p70S6K1, but not p70S6K2, significantly increases the chemosensitivity of OSI-906 in cultured colorectal cancer cells. Furthermore, the combination of OSI-906 and PF-4708671, a p70S6K1 inhibitor, efficiently suppresses the growth of OSI-906-resistant colon tumor cells in vitro and in vivo. Taken together, activation of p70S6K1 that is inhibited by Pdcd4 is essential for resistance to the IGF-1R inhibitor in colon tumor cells, and the combinational treatment of OSI-906 and PF-4708671 results in enhanced antiproliferation effects in colorectal cancer cells in vitro and in vivo, providing a novel venue to overcome the resistance to the IGF-1R inhibitor in treating colorectal cancer. ©2015 American Association for Cancer Research.

  11. Insulin-like growth factor (IGF)-I binding to a cell membrane associated IGF binding protein-3 acid-labile subunit complex in human anterior pituitary gland

    NARCIS (Netherlands)

    Wilczak, N; Kuhl, N; Chesik, D; Geerts, A; Luiten, P; De Keyser, J

    The binding characteristics of [(125) I]insulin-like growth factor (IGF)-I were studied in human brain and pituitary gland. Competition binding studies with DES(1-3)IGF-I and R-3 -IGF-I, which display high affinity for the IGF-I receptor and low affinity for IGF binding proteins (IGFBPs), were

  12. Co-targeting the HER and IGF/insulin receptor axis in breast cancer, with triple targeting with endocrine therapy for hormone-sensitive disease.

    Science.gov (United States)

    Chakraborty, Ashok; Hatzis, Christos; DiGiovanna, Michael P

    2017-05-01

    Interactions between HER2, estrogen receptor (ER), and insulin-like growth factor I receptor (IGF1R) are implicated in resistance to monotherapies targeting these receptors. We have previously shown in pre-clinical studies synergistic anti-tumor effects for co-targeting each pairwise combination of HER2, IGF1R, and ER. Strikingly, synergy for HER2/IGF1R targeting occurred not only in a HER2+ model, but also in a HER2-normal model. The purpose of the current study was therefore to determine the generalizability of synergistic anti-tumor effects of co-targeting HER2/IGF1R, the anti-tumor activity of triple-targeting HER2/IGF1R/ER in hormone-dependent cell lines, and the effect of using the multi-targeting drugs neratinib (pan-HER) and BMS-754807 (dual IGF1R/insulin receptor). Proliferation and apoptosis assays were performed in a large panel of cell lines representing varying receptor expression levels. Mechanistic effects were studied using phospho-protein immunoblotting. Analyses of drug interaction effects were performed using linear mixed-effects regression models. Enhanced anti-proliferative effects of HER/IGF-insulin co-targeting were seen in most, though not all, cell lines, including HER2-normal lines. For ER+ lines, triple targeting with inclusion of anti-estrogen generally resulted in the greatest anti-tumor effects. Double or triple targeting generally resulted in marked increases in apoptosis in the sensitive lines. Mechanistic studies demonstrated that the synergy between drugs was correlated with maximal inhibition of Akt and ERK pathway signaling. Dual HER/IGF-insulin targeting, and triple targeting with inclusion of anti-estrogen drugs, shows striking anti-tumor activity across breast cancer types, and drugs with broader receptor specificity may be more effective than single receptor selective drugs, particularly for ER- cells.

  13. Insulin-like Growth Factor 1 (IGF-1) Stabilizes Nascent Blood Vessels*

    Science.gov (United States)

    Jacobo, Sarah Melissa P.; Kazlauskas, Andrius

    2015-01-01

    Here we report that VEGF-A and IGF-1 differ in their ability to stabilize newly formed blood vessels and endothelial cell tubes. Although VEGF-A failed to support an enduring vascular response, IGF-1 stabilized neovessels generated from primary endothelial cells derived from various vascular beds and mouse retinal explants. In these experimental systems, destabilization/regression was driven by lysophosphatidic acid (LPA). Because previous studies have established that Erk antagonizes LPA-mediated regression, we considered whether Erk was an essential component of IGF-dependent stabilization. Indeed, IGF-1 lost its ability to stabilize neovessels when the Erk pathway was inhibited pharmacologically. Furthermore, stabilization was associated with prolonged Erk activity. In the presence of IGF-1, Erk activity persisted longer than in the presence of VEGF or LPA alone. These studies reveal that VEGF and IGF-1 can have distinct inputs in the angiogenic process. In contrast to VEGF, IGF-1 stabilizes neovessels, which is dependent on Erk activity and associated with prolonged activation. PMID:25564613

  14. IGF-1, IGFBP-1, and IGFBP-3 polymorphisms predict circulating IGF levels but not breast cancer risk: findings from the Breast and Prostate Cancer Cohort Consortium (BPC3.

    Directory of Open Access Journals (Sweden)

    Alpa V Patel

    2008-07-01

    Full Text Available IGF-1 has been shown to promote proliferation of normal epithelial breast cells, and the IGF pathway has also been linked to mammary carcinogenesis in animal models. We comprehensively examined the association between common genetic variation in the IGF1, IGFBP1, and IGFBP3 genes in relation to circulating IGF-I and IGFBP-3 levels and breast cancer risk within the NCI Breast and Prostate Cancer Cohort Consortium (BPC3. This analysis included 6,912 breast cancer cases and 8,891 matched controls (n = 6,410 for circulating IGF-I and 6,275 for circulating IGFBP-3 analyses comprised primarily of Caucasian women drawn from six large cohorts. Linkage disequilibrium and haplotype patterns were characterized in the regions surrounding IGF1 and the genes coding for two of its binding proteins, IGFBP1 and IGFBP3. In total, thirty haplotype-tagging single nucleotide polymorphisms (htSNP were selected to provide high coverage of common haplotypes; the haplotype structure was defined across four haplotype blocks for IGF1 and three for IGFBP1 and IGFBP3. Specific IGF1 SNPs individually accounted for up to 5% change in circulating IGF-I levels and individual IGFBP3 SNPs were associated up to 12% change in circulating IGFBP-3 levels, but no associations were observed between these polymorphisms and breast cancer risk. Logistic regression analyses found no associations between breast cancer and any htSNPs or haplotypes in IGF1, IGFBP1, or IGFBP3. No effect modification was observed in analyses stratified by menopausal status, family history of breast cancer, body mass index, or postmenopausal hormone therapy, or for analyses stratified by stage at diagnosis or hormone receptor status. In summary, the impact of genetic variation in IGF1 and IGFBP3 on circulating IGF levels does not appear to substantially influence breast cancer risk substantially among primarily Caucasian postmenopausal women.

  15. The Direct Binding of Insulin-like Growth Factor-1 (IGF-1) to Integrin αvβ3 Is Involved in IGF-1 Signaling*

    OpenAIRE

    Saegusa, Jun; Yamaji, Satoshi; Ieguchi, Katsuaki; Wu, Chun-Yi; Lam, Kit S.; Liu, Fu-Tong; Takada, Yoko K.; Takada, Yoshikazu

    2009-01-01

    It has been proposed that ligand occupancy of integrin αvβ3 with extracellular matrix ligands (e.g. vitronectin) plays a critical role in insulin-like growth factor-1 (IGF-1) signaling. We found that expression of αvβ3 enhanced IGF-1-induced proliferation of Chinese hamster ovary cells in serum-free conditions (in the absence of vitronectin). We hypothesized that the direct integrin binding to IGF-1 may play a role in IGF-1 signaling. We demonstrated that αvβ3 specifically and directly bound ...

  16. Correlation between GH and IGF-1 during treatment for acromegaly.

    Science.gov (United States)

    Oldfield, Edward H; Jane, John A; Thorner, Michael O; Pledger, Carrie L; Sheehan, Jason P; Vance, Mary Lee

    2017-06-01

    OBJECTIVE The relationship between growth hormone (GH) and insulin-like growth factor-1 (IGF-1) in patients with acromegaly as serial levels drop over time after treatment has not been examined previously. Knowledge of this relationship is important to correlate pretreatment levels that best predict response to treatment. To examine the correlation between GH and IGF-1 and IGF-1 z-scores over a wide range of GH levels, the authors examined serial GH and IGF-1 levels at intervals before and after surgery and radiosurgery for acromegaly. METHODS This retrospective analysis correlates 414 pairs of GH and IGF-1 values in 93 patients with acromegaly. RESULTS Absolute IGF-1 levels increase linearly with GH levels only up to a GH of 4 ng/ml, and with IGF-1 z-scores only to a GH level of 1 ng/ml. Between GH levels of 1 and 10 ng/ml, increases in IGF-1 z-scores relative to changes in GH diminish and then plateau at GH concentrations of about 10 ng/ml. From patient to patient there is a wide range of threshold GH levels beyond which IGF-1 increases are no longer linear, GH levels at which the IGF-1 response plateaus, IGF-1 levels at similar GH values after the IGF-1 response plateaus, and of IGF-1 levels at similar GH levels. CONCLUSIONS In acromegaly, although IGF-1 levels represent a combination of the integrated effects of GH secretion and GH action, the tumor produces GH, not IGF-1. Nonlinearity between GH and IGF-1 occurs at GH levels far below those previously recognized. To monitor tumor activity and tumor viability requires measurement of GH levels.

  17. DNA Methylation Changes in the IGF1R Gene in Birth Weight Discordant Adult Monozygotic Twins

    DEFF Research Database (Denmark)

    Tsai, Pei-Chien; Van Dongen, Jenny; Tan, Qihua

    2015-01-01

    persists into adulthood. To investigate this further, we performed epigenome-wide association analyses of blood DNA methylation using Infinium HumanMethylation450 BeadChip profiles in 71 adult monozygotic (MZ) twin pairs who were extremely discordant for birth weight. A signal mapping to the IGF1R gene (cg...... were not significant. However, a meta-analysis across the four independent samples, in total 216 birth-weight discordant MZ twin pairs, showed a significant positive association between birth weight and DNA methylation differences at IGF1R (random-effects meta-analysis p = .04), and the effect...... was particularly pronounced in older twins (random-effects meta-analysis p = .008, 98 older birth-weight discordant MZ twin pairs). The results suggest that severe intra-uterine growth differences (birth weight discordance >20%) are associated with methylation changes in the IGF1R gene in adulthood, independent...

  18. Superoxide anion radicals induce IGF-1 resistance through concomitant activation of PTP1B and PTEN

    Science.gov (United States)

    Singh, Karmveer; Maity, Pallab; Krug, Linda; Meyer, Patrick; Treiber, Nicolai; Lucas, Tanja; Basu, Abhijit; Kochanek, Stefan; Wlaschek, Meinhard; Geiger, Hartmut; Scharffetter-Kochanek, Karin

    2015-01-01

    The evolutionarily conserved IGF-1 signalling pathway is associated with longevity, metabolism, tissue homeostasis, and cancer progression. Its regulation relies on the delicate balance between activating kinases and suppressing phosphatases and is still not very well understood. We report here that IGF-1 signalling in vitro and in a murine ageing model in vivo is suppressed in response to accumulation of superoxide anions () in mitochondria, either by chemical inhibition of complex I or by genetic silencing of -dismutating mitochondrial Sod2. The -dependent suppression of IGF-1 signalling resulted in decreased proliferation of murine dermal fibroblasts, affected translation initiation factors and suppressed the expression of α1(I), α1(III), and α2(I) collagen, the hallmarks of skin ageing. Enhanced led to activation of the phosphatases PTP1B and PTEN, which via dephosphorylation of the IGF-1 receptor and phosphatidylinositol 3,4,5-triphosphate dampened IGF-1 signalling. Genetic and pharmacologic inhibition of PTP1B and PTEN abrogated -induced IGF-1 resistance and rescued the ageing skin phenotype. We thus identify previously unreported signature events with , PTP1B, and PTEN as promising targets for drug development to prevent IGF-1 resistance-related pathologies. PMID:25520316

  19. IGF-1 induces SOCS-2 but not SOCS-1 and SOCS-3 transcription in juvenile Nile tilapia (Oreochromis niloticus).

    Science.gov (United States)

    Liu, Cai-Zhi; Luo, Yuan; Limbu, Samwel Mchele; Chen, Li-Qiao; Du, Zhen-Yu

    2018-05-20

    Insulin-like growth factor-1 (IGF-1) plays a crucial role in regulating growth in vertebrates whereas suppressors of cytokine signaling (SOCS) act as feedback inhibitors of the GH/IGF-1 axis. Although SOCS-2 binds the IGF-1 receptor and inhibits IGF-1-induced STAT3 activation, presently there is no clear evidence as to whether IGF-1 could induce SOCS gene expression. The current study aimed to determine whether IGF-1 could induce the transcription of SOCS in juvenile Nile tilapia ( Oreochromis niloticus ). We show that there is a common positive relationship between the mRNA expression of IGF-I and SOCS-2 under different nutritional statuses and stimulants, but not the mRNA expression of SOCS-1 and SOCS-3 Furthermore, rhIGF-1 treatment and transcriptional activity assay confirmed the hypothesis that IGF-1 could induce SOCS-2 expression, whereas it had no effect or even decreased the expression of SOCS-1 and SOCS-3 Overall, we obtained evidence that the transcription of SOCS-2, but not SOCS-1 or SOCS-3, could be induced by IGF signaling, suggesting that SOCS-2 serves as a feedback suppressor of the IGF-1 axis in juvenile Nile tilapia. © 2018. Published by The Company of Biologists Ltd.

  20. Matrix metalloproteinase-1 facilitates MSC migration via cleavage of IGF-2/IGFBP2 complex.

    Science.gov (United States)

    Guan, Shou P; Lam, Alan T L; Newman, Jennifer P; Chua, Kevin L M; Kok, Catherine Y L; Chong, Siao T; Chua, Melvin L K; Lam, Paula Y P

    2018-01-01

    The specific mechanism underlying the tumor tropism of human mesenchymal stem cells (MSCs) for cancer is not well defined. We previously showed that the migration potential of MSCs correlated with the expression and protease activity of matrix metalloproteinase (MMP)-1. Furthermore, highly tumor-tropic MSCs expressed higher levels of MMP-1 and insulin-like growth factor (IGF)-2 than poorly migrating MSCs. In this study, we examined the functional roles of IGF-2 and MMP-1 in mediating the tumor tropism of MSCs. Exogenous addition of either recombinant IGF-2 or MMP-1 could stimulate MSC migration. The correlation between IGF-2, MMP-1 expression, and MSC migration suggests that MMP-1 may play a role in regulating MSC migration via the IGF-2 signaling cascade. High concentrations of IGF binding proteins (IGFBPs) can inhibit IGF-stimulated functions by blocking its binding to its receptors and proteolysis of IGFBP is an important mechanism for the regulation of IGF signaling. We thus hypothesized that MMP-1 acts as an IGFBP2 proteinase, resulting in the cleavage of IGF-2/IGFBP2 complex and extracellular release of free IGF-2. Indeed, our results showed that conditioned media from highly migrating MSCs, which expressed high levels of MMP-1, cleaved the IGF-2/IGFBP2 complex. Taken together, these results showed that the MMP-1 secreted by highly tumor-tropic MSCs cleaved IGF-2/IGFBP2 complex. Free IGF-2 released from the complex may facilitate MSC migration toward tumor.

  1. Insulin-like growth factor-I (IGF-1), IGF-binding protein-3 (IGFBP-3) and mammographic features.

    Science.gov (United States)

    Izzo, L; Meggiorini, M L; Nofroni, I; Pala, A; De Felice, C; Meloni, P; Simari, T; Izzo, S; Pugliese, F; Impara, L; Merlini, G; Di Cello, P; Cipolla, V; Forcione, A R; Paliotta, A; Domenici, L; Bolognese, A

    2012-05-01

    The IGF system has recently been shown to play an important role in the regulation of breast tumor cell proliferation. However, also breast density is currently considered as the strongest breast cancer risk factor. It is not yet clear whether these factors are interrelated and if and how they are influenced by menopausal status. The purpose of this study was to examine the possible effects of IGF-1 and IGFBP-3 and IGF-1/IGFBP-3 molar ratio on mammographic density stratified by menopausal status. A group of 341 Italian women were interviewed to collect the following data: family history of breast cancer, reproductive and menstrual factors, breast biopsies, previous administration of hormonal contraceptive therapy, hormone replacement therapy (HRT) in menopause and lifestyle information. A blood sample was drawn for determination of IGF-1, IGFBP-3 levels. IGF-1/ IGFBP-3 molar ratio was then calculated. On the basis of recent mammograms the women were divided into two groups: dense breast (DB) and non-dense breast (NDB). Student's t-test was employed to assess the association between breast density and plasma level of IGF-1, IGFBP-3 and molar ratio. To assess if this relationship was similar in subgroups of pre- and postmenopausal women, the study population was stratified by menopausal status and Student's t-test was performed. Finally, multivariate analysis was employed to evaluate if there were confounding factors that might influence the relationship between growth factors and breast density. The analysis of the relationship between mammographic density and plasma level of IGF-1, IGFBP-3 and IGF-1/ IGFBP-3 molar ratio showed that IGF-1 levels and molar ratio varied in the two groups resulting in higher mean values in the DB group (IGF-1: 109.6 versus 96.6 ng/ml; p= 0.001 and molar ratio 29.4 versus 25.5 ng/ml; p= 0.001) whereas IGFBP-3 showed similar values in both groups (DB and NDB). Analysis of plasma level of IGF-1, IGFBP-3 and IGF-1/IGFBP-3 molar ratio

  2. Insulin-Like Growth Factor (IGF System in Liver Diseases

    Directory of Open Access Journals (Sweden)

    Agnieszka Adamek

    2018-04-01

    Full Text Available Hepatocyte differentiation, proliferation, and apoptosis are affected by growth factors produced in liver. Insulin-like growth factor 1 and 2 (IGF1 and IGF2 act in response to growth hormone (GH. Other IGF family components include at least six binding proteins (IGFBP1 to 6, manifested by both IGFs develop due to interaction through the type 1 receptor (IGF1R. The data based on animal models and/or in vitro studies suggest the role of IGF system components in cellular aspects of hepatocarcinogenesis (cell cycle progression, uncontrolled proliferation, cell survival, migration, inhibition of apoptosis, protein synthesis and cell growth, and show that systemic IGF1 administration can reduce fibrosis and ameliorate general liver function. In epidemiologic and clinicopathological studies on chronic liver disease (CLD, lowered serum levels, decreased tissue expression of IGF1, elevated production of IGF1R and variable IGF2 expression has been noted, from the start of preneoplastic alterations up to the developed hepatocellular carcinoma (HCC stage. These changes result in well-known clinical symptoms of IGF1 deficiency. This review summarized the current data of the complex role of IGF system components in the most common CLD (nonalcoholic fatty liver disease, cirrhosis, and hepatocellular carcinoma. Better recognition and understanding of this system can contribute to discovery of new and improved versions of current preventive and therapeutic actions in CLD.

  3. Inhibition of tumor growth by targeted anti-EGFR/IGF-1R Nanobullets depends on efficient blocking of cell survival pathways

    NARCIS (Netherlands)

    van der Meel, Roy; Oliveira, Sabrina; Altintas, Isil; Heukers, R.; Pieters, Ebel H.E.; van Bergen en Henegouwen, Paul M.P.; Storm, Gerrit; Hennink, Wim E.; Kok, Robbert J.; Schiffelers, Raymond M.

    2013-01-01

    The clinical efficacy of epidermal growth factor receptor (EGFR)-targeted inhibitors is limited due to resistance mechanisms of the tumor such as activation of compensatory pathways. Crosstalk between EGFR and insulin-like growth factor 1 (IGF-1R) signaling has been frequently described to be

  4. Regulation of Kisspeptin Synthesis and Release in the Preoptic/Anterior Hypothalamic Region of Prepubertal Female Rats: Actions of IGF-1 and Alcohol.

    Science.gov (United States)

    Hiney, Jill K; Srivastava, Vinod K; Vaden Anderson, Danielle N; Hartzoge, Nicole L; Dees, William L

    2018-01-01

    Alcohol (ALC) causes suppressed secretion of prepubertal luteinizing hormone-releasing hormone (LHRH). Insulin-like growth factor-1 (IGF-1) and kisspeptin (Kp) are major regulators of LHRH and are critical for puberty. IGF-1 may be an upstream mediator of Kp in the preoptic area and rostral hypothalamic area (POA/RHA) of the rat brain, a region containing both Kp and LHRH neurons. We investigated the ability of IGF-1 to stimulate prepubertal Kp synthesis and release in POA/RHA, and the potential inhibitory effects of ALC. Immature female rats were administered either ALC (3 g/kg) or water via gastric gavage at 0730 hours. At 0900 hours, both groups were subdivided where half received either saline or IGF-1 into the brain third ventricle. A second dose of ALC (2 g/kg) or water was administered at 1130 hours. Rats were killed 6 hours after injection and POA/RHA region collected. IGF-1 stimulated Kp, an action blocked by ALC. Upstream to Kp, IGF-1 receptor (IGF-1R) activation, as demonstrated by the increase in insulin receptor substrate 1, resulted in activation of Akt, tuberous sclerosis 2, ras homologue enriched in brain, and mammalian target of rapamycin (mTOR). ALC blocked the central action of IGF-1 to induce their respective phosphorylation. IGF-1 specificity and ALC specificity for the Akt-activated mTOR pathway were demonstrated by the absence of effects on PRAS40. Furthermore, IGF-1 stimulated Kp release from POA/RHA incubated in vitro. IGF-1 stimulates prepubertal Kp synthesis and release following activation of a mTOR signaling pathway, and ALC blocks this pathway at the level of IGF-1R. Copyright © 2017 by the Research Society on Alcoholism.

  5. Differential Regulation of Hippocampal IGF-1-Associated Signaling Proteins by Dietary Restriction in Aging Mouse.

    Science.gov (United States)

    Hadem, Ibanylla Kynjai Hynniewta; Sharma, Ramesh

    2017-08-01

    Time-dependent alterations in several biological processes of an organism may be characterized as aging. One of the effects of aging is the decline in cognitive functions. Dietary restriction (DR), an intervention where the consumption of food is lessened but without malnutrition, is a well-established mechanism that has a wide range of important outcomes including improved health span, delayed aging, and extension of lifespan of various species. It also plays a beneficial role in protecting against age-dependent deterioration of cognitive functions, and has neuroprotective properties against neurodegenerative diseases. Insulin-like growth factor (IGF)-1 plays an important role in the regulation of cellular and tissue functions, and relating to the aging process the most important pathway of IGF-1 is the phosphatidylinositol 3-kinase (PI3K) and protein kinase B (Akt/PKB) signaling cascade. Although many have studied the changes in the level of IGF-1 and its effect on neural proliferation, the downstream signaling proteins have not been fully elucidated. Hence in the present investigation, the IGF-1 gene expression and the normal endogenous levels of IGF1R (IGF-1 receptor), PI3K, Akt, pAkt, and pFoxO in the hippocampus of young, adult, and old mice were determined using real-time PCR and Western blot analyses. The effects of DR on these protein levels were also studied. Results showed a decrease in the levels of IGF-1, IGF1R, PI3K, and pAkt, while pFoxO level increased with respect to age. Under DR, these protein levels are maintained in adult mice, but old mice displayed diminished expression levels of these proteins as compared to ad libitum-fed mice. Maintenance of PI3K/Akt pathway results in the phosphorylation of FoxOs, necessary for the enhancement of neural proliferation and survival in adult mice. The down-regulation of IGF-I signaling, as observed in old mice, leads to increasing the activity of FoxO factors that may be important for the neuroprotective

  6. IGF-1 induces the epithelial-mesenchymal transition via Stat5 in hepatocellular carcinoma.

    Science.gov (United States)

    Zhao, Chuanzong; Wang, Qian; Wang, Ben; Sun, Qi; He, Zhaobin; Hong, Jianguo; Kuehn, Florian; Liu, Enyu; Zhang, Zongli

    2017-12-19

    It has been reported that the epithelial-mesenchymal transition (EMT) plays an important role in hepatocellular carcinoma (HCC). However, the relationship between the insulin-like growth factor-1 (IGF-1) and EMT of HCC was not fully elucidated. In the present work, we found that the expression of N-cadherin, Vimentin, Snail1, Snail2, and Twist1 was positively associated with IGF-1R expression, while E-cadherin expression was negatively associated with IGF-1 expression in human HCC samples. Furthermore, we observed that IGF-1 up-regulated the expression of N-cadherin, Vimentin, Snail1, Snail2 and Twist1, and down-regulated the expression of E-cadherin. In addition, Stat5 was induced in IGF-1-treated HepG2 and Hep3B cells, and Stat5 inhibition or siRNA significantly affected IGF-1-induced EMT in HepG2 and Hep3B cells. In conclusion, IGF-1 induces EMT of HCC via Stat5 signaling pathway. Thus, IGF-1/Stat5 can be recommended as a potential and novel therapeutic strategy for HCC patients.

  7. Regulation of insulin-like growth factor (IGF) I receptor expression during muscle cell differentiation. Potential autocrine role of IGF-II.

    OpenAIRE

    Rosenthal, S M; Brunetti, A; Brown, E J; Mamula, P W; Goldfine, I D

    1991-01-01

    Muscle is an important target tissue for insulin-like growth factor (IGF) action. The presence of specific, high affinity IGF receptors, as well as the expression of IGF peptides and binding proteins by muscle suggest that a significant component of IGF action in this tissue is mediated through autocrine and/or paracrine mechanisms. To explore autocrine/paracrine action of IGFs in muscle, we studied the regulation of the IGF-I receptor and the expression of IGF peptides during differentiation...

  8. Suckling induced insulin-like growth factor-1 (IGF-1) release in mother rats.

    Science.gov (United States)

    Lékó, András H; Cservenák, Melinda; Dobolyi, Árpád

    2017-12-01

    Lactation involves significant neuroendocrine changes. The elevated prolactin (PRL) release from the pituitary, induced markedly by suckling, is the most relevant example. Suckling also causes a significant and rapid elevation in growth hormone (GH) levels. GH is necessary for milk synthesis as milk yield is stopped completely in the absence of PRL and GH, while the absence of PRL alone causes only a 50% reduction. Insulin-like growth factor-1 (IGF-1) plays an important role in the GH axis. GH exerts its effects through IGF-1 in the periphery, for example in the mammary gland. In addition, IGF-1 is responsible for the long-loop feedback control of GH secretion. IGF-1 secretion has not been established yet in mothers. Therefore, in the present study, we investigated the effect of suckling on serum IGF-1 level in rat mothers and correlated it with serum PRL levels. We examined a potential mechanism of the regulation of IGF-1 level during suckling by administering IGF-1 into the lateral ventricle of rat mothers continuously for 12days, or acutely, right before the start of suckling. We described that suckling affected IGF-1 release based on one-way repeated measures ANOVA (F=10.8 and pIGF-1 level 30min after the start of suckling (pIGF-1 release. The prolonged central IGF-1 administration diminished the suckling-induced IGF-1 surge (F=9.19 and pIGF-1 release either by elevating PRL or GH. Long-loop feedback via IGF-1 in the GH axis can diminish this action. Copyright © 2017 Elsevier Ltd. All rights reserved.

  9. IGF-1: The Jekyll & Hyde of the aging brain.

    Science.gov (United States)

    Gubbi, Sriram; Quipildor, Gabriela Farias; Barzilai, Nir; Huffman, Derek M; Milman, Sofiya

    2018-05-08

    The IGF-1 signaling pathway has emerged as a major regulator of the aging process, from rodents to humans. However, given the pleiotropic actions of IGF-1, its role in the aging brain remains complex and controversial. While IGF-1 is clearly essential for normal development of the central nervous system, conflicting evidence has emerged from preclinical and human studies regarding its relationship to cognitive function, as well as cerebrovascular and neurodegenerative disorders. This review delves into the current state of the evidence examining the role of IGF-1 in the aging brain, encompassing preclinical and clinical studies. A broad examination of the data indicates that IGF-1 may indeed play opposing roles in the aging brain, depending on the underlying pathology and context. Some evidence suggests that in the setting of neurodegenerative diseases that manifest with abnormal protein deposition in the brain, such as Alzheimer's disease, reducing IGF-1 signaling may serve a protective role by slowing disease progression and augmenting clearance of pathologic proteins to maintain cellular homeostasis. In contrast, inducing IGF-1 deficiency has also been implicated in dysregulated function of cognition and the neurovascular system, suggesting that some IGF-1 signaling may be necessary for normal brain function. Furthermore, states of acute neuronal injury, which necessitate growth, repair and survival signals to persevere, typically demonstrate salutary effects of IGF-1 in that context. Appreciating the dual, at times opposing "Dr. Jekyll" and "Mr. Hyde" characteristics of IGF-1 in the aging brain, will bring us closer to understanding its impact and devising more targeted IGF-1-related interventions.

  10. Crosstalk between TEMs and endothelial cells modulates angiogenesis and metastasis via IGF1-IGF1R signalling in epithelial ovarian cancer.

    Science.gov (United States)

    Wang, Xinjing; Zhu, Qinyi; Lin, Yingying; Wu, Li; Wu, Xiaoli; Wang, Kai; He, Qizhi; Xu, Congjian; Wan, Xiaoping; Wang, Xipeng

    2017-10-24

    Epithelial ovarian cancer (EOC) is the leading cause of death from gynaecologic malignancies and has a poor prognosis due to metastasis. Drugs targeting the angiogenesis pathway significantly improve patient outcome. However, the key factors linking angiogenesis and metastasis have not been elucidated. In this study, we found Tie2 expressing monocytes (CD14 + Tie2 + , TEMs) as key contributors to angiogenesis and metastasis of EOC. Tissue slides were evaluated by immunofluorescence for the presence of total tissue macrophages and TEMs. The correlation between microvascular density (MVD) values and the TEMs number or ratio was calculated in both ovarian cancer tissues and peritoneum. The rate of TEMs in monocytes was evaluated in the peripheral blood of female healthy donors, benign cysts patients, and EOC patients using flow cytometry. The TEMs rate in ascites from EOC patients was also evaluated by flow cytometry. The concentration of Ang2, as the ligand of Tie2, was examined by ELISA in serum samples of EOC patients, benign cysts patients, and ascites samples of EOC patients. The effects of Ang2 on the migration and the cytokine expression of TEMs were further examined. The pro- angiogenesis activity of TEMs via IGF1 was performed in both in vivo and in vitro. And the IGF1 blocking test was performed using neutralising antibody. TEMs were significantly higher in tumour foci, peripheral blood and ascites in EOC patients. The proportion of TEMs among total tissue macrophages was positively correlated with tumour MVD. In vivo animal results showed that TEMs promoted EOC angiogenesis and metastasis. Further functional and mechanisms studies revealed that concentration of angiopoietin 2 (Ang2), a ligand of Tie2, was elevated in EOC ascites which further recruit TEMs in a dose-dependent manner as a powerful chemokine to TEMs. Recruited TEMs promoted endothelial cell function through IGF1-activated downstream signalling. Blocking secreted IGF1 using inhibiting antibody

  11. MVP expression is related to IGF1-R in cervical carcinoma patients treated by radiochemotherapy.

    Science.gov (United States)

    Lloret, Marta; Lara, Pedro Carlos; Bordón, Elisa; Rey, Agustin; Falcón, Orlando; Apolinario, Rosa Maria; Clavo, Bernardino; Ruiz, Ana

    2008-09-01

    To assess the expression of MVP in cervix carcinoma patients treated by radiochemotherapy, its relation to clinical and pathologic prognostic factors and its role in predicting clinical outcome. In addition the relation to IGF-1R expression in this cohort of patients will be explored. Sixty consecutive patients suffering from localized cervix carcinoma were prospectively included in this study from July 1999 to December 2003. Follow-up was closed in November 2007. Patients were staged following the TNM classification. All patients received pelvic radiation (45-64.80 Gy in 1.8-2 Gy fractions) followed brachytherapy and concomitant cisplatin at 40 mg/m(2)/week doses. MVP expression was studied by immunohistochemistry in paraffin-embedded tumour tissue. MVP was expressed in 58 patients (96.7%) and no relation was found with clinicopathological variables. High MVP expression was related to high IGF1-R expression (p=0.023). Complete response after treatment was observed in 50 patients (83.3%). Clinical stage of the disease and clinical response to radiochemotherapy were the most important prognostic factors related to survival. High MVP and IGF-1R tumour expression was strongly related to poor local and regional disease-free survival (p=0.006), distant disease-free survival (p=0.050), disease-free survival (p=0.006), and cause-specific survival (p=0.007) in patients achieving a complete response. MVP and IGF-1R expression were related in clinical cervical tumours and confer reduced long-term local control in patients who achieved clinical complete response to radiochemotherapy.

  12. IGF-II-mediated downregulation of peroxisome proliferator-activated receptor-γ coactivator-1α in myoblast cells involves PI3K/Akt/FoxO1 signaling pathway.

    Science.gov (United States)

    Mu, Xiaoyu; Qi, Weihong; Liu, Yunzhang; Zhou, Jianfeng; Li, Yun; Rong, Xiaozhi; Lu, Ling

    2017-08-01

    Insulin-like growth factor II (IGF-II) can stimulate myogenesis and is critically involved in skeletal muscle differentiation. The presence of negative regulators of this process, however, is not well explored. Here, we showed that in myoblast cells, IGF-II negatively regulated peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) mRNA expression, while constitutive expression of PGC-1α induced myoblast differentiation. These results suggest that the negative regulation of PGC-1α by IGF-II may act as a negative feedback mechanism in IGF-II-induced myogenic differentiation. Reporter assays demonstrated that IGF-II suppresses the basal PGC-1α promoter activity. Blocking the IGF-II signaling pathway increased the endogenous PGC-1α levels. In addition, pharmacological inhibition of PI3 kinase activity prevented the downregulation of PGC-1α but the activation of mTOR was not required for this process. Importantly, further analysis showed that forkhead transcription factor FoxO1 contributes to mediating the effects of IGF-II on PGC-1 promoter activity. These findings indicate that IGF-II reduces PGC-1α expression in skeletal muscle cells through a mechanism involving PI3K-Akt-FoxO1 but not p38 MAPK or Erk1/2 MAPK pathways.

  13. Circulating IGF1 regulates hippocampal IGF1 levels and brain gene expression during adolescence

    OpenAIRE

    Yan, Han; Mitschelen, Matthew; Bixler, Georgina V; Brucklacher, Robert M; Farley, Julie A; Han, Song; Freeman, Willard M; Sonntag, William E

    2011-01-01

    GH and its anabolic mediator, IGF1, are important not only in somatic growth but also in the regulation of brain function. Even though GH treatment has been used clinically to improve body composition and exercise capacity in adults, its influence on central nervous system function has only recently been recognized. This is also the case for children with childhood-onset GH deficiency (GHD) where GH has been used to stimulate bone growth and enhance final adult height. Circulating IGF1 is tra...

  14. Telomerase activity promotes osteoblast differentiation by modulating IGF-signaling pathway

    DEFF Research Database (Denmark)

    Saeed, Hamid; Qiu, Weimin; Li, Chen

    2015-01-01

    -regulation of several components of insulin-like growth factor (IGF) signaling. Specifically, a significant increase in IGF-induced AKT phosphorylation and alkaline phosphatase (ALP) activity were observed in hMSC-TERT. Enhanced ALP activity was reduced in presence of IGF1 receptor inhibitor: picropodophyllin....... In addition, telomerase deficiency caused significant reduction in IGF signaling proteins in osteoblastic cells cultured from telomerase deficient mice (Terc (-/-)). The low bone mass exhibited by Terc (-/-) mice was associated with significant reduction in serum levels of IGF1 and IGFBP3 as well as reduced...... skeletal mRNA expression of Igf1, Igf2, Igf2r, Igfbp5 and Igfbp6. IGF1-induced osteoblast differentiation was also impaired in Terc (-/-) MSC. In conclusion, our data demonstrate that impaired IGF/AKT signaling contributes to the observed decreased bone mass and bone formation exhibited by telomerase...

  15. The trajectory of IGF-1 across age and duration of type 1 diabetes.

    Science.gov (United States)

    Palta, Mari; LeCaire, Tamara J; Sadek-Badawi, Mona; Herrera, Victor M; Danielson, Kirstie K

    2014-11-01

    Individuals with type 1 diabetes may have low IGF-1, related to insulinopenia and insulin resistance. There are few longitudinal studies of IGF-1 levels to establish its pattern in type 1 diabetes with duration and age, and to examine whether IGF-1 tracks within individuals over time. We examine age and duration trends, and the relationship of IGF-1 to gender, glycaemic control, insulin level and other factors. Participants in the Wisconsin Diabetes Registry Study, an incident cohort study of type 1 diabetes diagnosed May 1987-April 1992, were followed for up to 18 years with IGF-1 samples up to age 45 for women and age 37 for men. IGF-1 is lower with type 1 diabetes than in normative samples. Although, the pattern across age resembles that in normative samples with a peak in adolescence and slow decline after age 20, the adolescent peak is delayed for women with type 1 diabetes. There was low to moderate tracking of IGF-1 within an individual. Higher insulin dose was associated with higher IGF-1 as was puberty, and female gender. Adjusted for these factors, IGF-1 declined rapidly across early diabetes duration. Lower HbA1c was most strongly related to higher IGF-1 at Tanner stages 1 and 2. IGF-1 is low in type 1 diabetes, with a delayed adolescent peak in women and is especially influenced by glycaemic control in early and pre-adolescence. High variability within an individual is likely a challenge in investigating associations between IGF-1 and long-term outcomes, and may explain contradictory findings. Copyright © 2014 John Wiley & Sons, Ltd.

  16. Comparison of IGF-1 (insulin like growth factor-1) levels in bovine serum sampled three times during the day using validated equine IGF-1 elisa

    OpenAIRE

    Mrkun J.; Kosec M.; Zrimšek Petra

    2009-01-01

    Cows in negative energy balance exhibit reduced fertility, mediated by metabolic signals that influence the reproductive system. Measurement of IGF-1 contributes to the diagnosis of negative energy balance. The aim of this study was to investigate possible variations in IGF-1 levels in samples taken at different times of the day. Equine IGF-1 ELISA was used for measuring IGF-1 in bovine samples. Statistical analysis was applied to the results. Using scatter diagrams fitted with Deming regress...

  17. The relevance of the M6P/IGF2R status for the tumorigenicity and invasiveness of liver and skin cancer cells

    International Nuclear Information System (INIS)

    Puxbaum, V.

    2010-01-01

    The mannose 6-phosphate/insulin-like growth factor 2 receptor (M6P/IGF2R), a multifunctional membrane-associated protein, plays a central role in targeting of lysosomal enzymes and controlling of the bioavailability of insulin-like growth factor II (IGF-II). In addition to intracellular sorting and endocytosis of M6P-containing ligands and IGF-II, the receptor also interacts with urokinase-type plasminogen activator receptor (uPAR) and plasminogen at the cell surface. M6P/IGF2R is considered a putative tumor suppressor, and its expression may modulate the invasiveness of cancer cells. Importantly, the M6P/IGF2R gene is frequently lost or mutated in a wide range of malignant tumors including hepatocellular and squamous cell carcinomas. However, the impact of the receptor on tumor invasion and metastasis is still poorly understood. FRL14 and SCC-VII cells are M6P/IGF2R deficient and thus secrete large amounts of lysosomal enzymes. Reconstitution of functional M6P/IGF2R expression restores transport of lysosomal enzymes to these compartments and drastically reduces the invasive potential of the cells. In addition, the presence of ectopic M6P/IGF2R compromises the growth of FRL14 and SCC-VII cells both in vitro and in vivo. Conversely, M6P/IGF2R knock-down in receptor-positive MIM-1-4 hepatocytes leads to increased lysosomal enzyme secretion and enhanced invasiveness. To assess the relevance of different ligand-binding sites for the biological activities of M6P/IGF2R, several mutant forms of the receptor were stably expressed in FRL14 and SCC-VII cells. Functional M6P-binding sites proved to be important for the anti-invasive potential of M6P/IGF2R, whereas the interactions of the receptor with IGF-II and uPAR/plasminogen were found to be dispensable for its biological activities. These results suggest that the M6P/IGF2R status influences the metastatic propensity of hepatocellular and squamous cell carcinomas, and that functional M6P-binding sites are crucial for the

  18. Forkhead box A1 (FOXA1) is a key mediator of insulin-like growth factor I (IGF-I) activity.

    Science.gov (United States)

    Potter, Adam S; Casa, Angelo J; Lee, Adrian V

    2012-01-01

    The insulin-like growth factor receptor (IGF-IR) has been implicated in a number of human tumors, including breast cancer. Data from human breast tumors has demonstrated that IGF-IR is over-expressed and hyper-phosphorylated. Additionally, microarray analysis has shown that IGF-I treatment of MCF7 cells leads to a gene signature comprised of induced and repressed genes, which correlated with luminal B tumors. FOXA1, a forkhead family transcription factor, has been shown to be crucial for mammary ductal morphogenesis, similar to IGF-IR, and expressed at high levels in luminal subtype B breast tumors. Here, we investigated the relationship between FOXA1 and IGF-I action in breast cancer cells. We show that genes regulated by IGF-I are enriched for FOXA1 binding sites, and knock down of FOXA1 blocked the ability of IGF-I to regulate gene expression. IGF-I treatment of MCF7 cells increased the half-life of FOXA1 protein and this increase in half-life appeared to be dependent on canonical IGF-I signal transduction through both MAPK and AKT pathways. Finally, knock down of FOXA1 led to a decreased ability of IGF-I to induce proliferation and protect against apoptosis. Together, these results demonstrate that IGF-I can increase the stability of FOXA1 protein expression and place it as a critical mediator of IGF-I regulation of gene expression and IGF-I-mediated biological responses. Copyright © 2011 Wiley Periodicals, Inc.

  19. Genetic and Dietary Determinants of Insulin-Like Growth Factor (IGF)-1 and IGF Binding Protein (BP)-3 Levels among Chinese Women

    Science.gov (United States)

    Li, Hui; McCullough, Lauren E.; Qi, Ya-na; Li, Jia-yuan; Zhang, Jing; Miller, Erline; Yang, Chun-xia; Smith, Jennifer S.

    2014-01-01

    Background Higher insulin-like growth factor (IGF)-1 and lower IGF binding protein (BP)-3 levels have been associated with higher commoncancer risk, including breast cancer. Dietary factors, genetic polymorphisms, and the combination of both may influence circulating IGF-1 and IGFBP-3 serum concentrations. Methods From September 2011 to July 2012, we collected demographic, reproductive and dietary data on 143 women (≥40 years). We genotyped IGF-1 rs1520220 and IGFBP-3 rs2854744 and measured circulating IGF-1 and IGFBP-3 levels in serum. Covariance analyses were used to estimate the associations of serum levels of IGF-1 and IGFBP-3, and the molar ratio of IGF-1to IGFBP-3 with IGF-1 rs1520220 and IGFBP-3 rs2854744 genotypes. We subsequently assessed the combined influence of genetics and diet (daily intake of protein, fat and soy isoflavones) on IGF-1 and IGFBP-3 levels. Results Among women aged less than 50 years, circulating IGF-1 serum levels were significantly lower for those with CC genotype for IGF-1 rs1520220 than levels for those with the GC or GG genotypes (in recessive model: P = 0.007).In gene-diet analyses among these women, we found carrying CC genotype for IGF-1 rs1520220 and high soy isoflavone intake tend to be associated with lower circulating IGF-1 levels synthetically (P = 0.002). Women with GG or GC genotypes for IGF-1 rs1520220 and with low intake of soy isoflavones had the highest levels of circulating IGF-1 (geometric mean [95% CI]: 195 [37, 1021] µg/L). Comparatively, women with both the CC genotype and high soy intake had the lowest levels of circulating IGF-1 (geometric mean [95% CI]: 120 [38,378] µg/L). Conclusions IGF-1 serum levels are significantly lower among women with the CC genotype for IGF-1-rs1520220. High soy isoflavone intake may interact with carrying CC genotype for IGF-1-rs1520220 to lower women's serum IGF-1 levels more. PMID:25285521

  20. MeCP2 silencing of LncRNA H19 controls hepatic stellate cell proliferation by targeting IGF1R

    International Nuclear Information System (INIS)

    Yang, Jing-Jing; Liu, Li-Ping; Tao, Hui; Hu, Wei; Shi, Peng; Deng, Zi-Yu; Li, Jun

    2016-01-01

    Highlights: • H19 plays a key role in HSCs proliferation and fibrosis. • MeCP2/H19 axis involvement in HSCs activation and fibrosis. • MeCP2 negative controls H19 expression in activated HSCs. • Identification of IGF1R as new target of H19 in HSC. - Abstract: Methyl-CpG-binding protein 2 (MeCP2) plays a key role in liver fibrosis. However, the potential mechanism of MeCP2 in liver fibrosis remains unclear. Early reports suggest that LncRNA H19 is important epigenetic regulator with critical roles in cell proliferation, but its role in hepatic fibrosis remains elusive. Sprague-Dawley rats liver fibrosis was generated by 12-weeks treatment with CCl 4 intraperitoneal injection. HSC-T6 cells were used in vitro study. The expression levels of MeCP2, H19, IGF1R, α-SMA, and Col1A1 were estimated by Western blotting, qRT-PCR and Immunohistochemistry. HSC-T6 cells were transfected with MeCP2-siRNA, pEGF-C1-MeCP2, pEX-3-H19, and H19-siRNA. Finally, cell proliferation ability was assessed by the MTT assay. Here, we found that H19 was significantly down-regulated in HSCs and fibrosis tissues, and an opposite pattern is observed for MeCP2 and IGF1R. Silencing of MeCP2 blocked HSCs proliferation. Knockdown of MeCP2 elevated H19 expression in activated HSCs, and over-expression of MeCP2 inhibited H19 expression in activated HSCs. Moreover, we investigated the effect of H19 on IGF1R expression. Overexpression of H19 in HSCs repressed the expression of IGF1R, and an opposite pattern is observed for H19 silenced. In addition, we reported that overexpression of H19 inhibited the TGF-β1-induced proliferation of HSCs. Furthermore, MeCP2 negative regulation of H19 by targeting the protein IGF1R. Taken together, these results demonstrated that MeCP2 silencing of H19 can alter the IGF1R overexpression, thus contributing to HSCs proliferation. These data could suggest the development of combination therapies that target the MeCP2.

  1. IGF-1 Has Plaque-Stabilizing Effects in Atherosclerosis by Altering Vascular Smooth Muscle Cell Phenotype

    Science.gov (United States)

    von der Thüsen, Jan H.; Borensztajn, Keren S.; Moimas, Silvia; van Heiningen, Sandra; Teeling, Peter; van Berkel, Theo J.C.; Biessen, Erik A.L.

    2011-01-01

    Insulin-like growth factor-1 (IGF-1) signaling is important for the maintenance of plaque stability in atherosclerosis due to its effects on vascular smooth muscle cell (vSMC) phenotype. To investigate this hypothesis, we studied the effects of the highly inflammatory milieu of the atherosclerotic plaque on IGF-1 signaling and stability-related phenotypic parameters of murine vSMCs in vitro, and the effects of IGF-1 supplementation on plaque phenotype in an atherosclerotic mouse model. M1-polarized, macrophage-conditioned medium inhibited IGF-1 signaling by ablating IGF-1 and increasing IGF-binding protein 3, increased vSMC apoptosis, and decreased proliferation. Expression of α-actin and col3a1 genes was strongly attenuated by macrophage-conditioned medium, whereas expression of matrix-degrading enzymes was increased. Importantly, all of these effects could be corrected by supplementation with IGF-1. In vivo, treatment with the stable IGF-1 analog Long R3 IGF-1 in apolipoprotein E knockout mice reduced stenosis and core size, and doubled cap/core ratio in early atherosclerosis. In advanced plaques, Long R3 IGF-1 increased the vSMC content of the plaque by more than twofold and significantly reduced the rate of intraplaque hemorrhage. We believe that IGF-1 in atherosclerotic plaques may have a role in preventing plaque instability, not only by modulating smooth muscle cell turnover, but also by altering smooth muscle cell phenotype. PMID:21281823

  2. IGF-1R tyrosine kinase inhibitors and Vitamin K1 enhance the antitumor effects of Regorafenib in HCC cell lines.

    Science.gov (United States)

    Refolo, Maria Grazia; D'Alessandro, Rosalba; Lippolis, Catia; Carella, Nicola; Cavallini, Aldo; Messa, Caterina; Carr, Brian Irving

    2017-11-28

    The recent RESORCE trial showed that treatment with Regorafenib after Sorafenib failure provided a significant improvement in overall survival in HCC patients. Preclinical and clinical trial data showed that Regorafenib is a more potent drug than Sorafenib. In this study we aimed at improving Regorafenib actions and at reducing its toxicity, by targeting parallel pathways or by combination with Vitamins K (VKs). We investigated the effects of Regorafenib administrated at low concentrations and in combination with either VK1 and/or with GSK1838705A or OSI-906, two IGF1-R inhibitors, on HCC cell growth and motility. Our results showed that both IGF1-R inhibitors potentiated the antiproliferative and pro-apoptotic effects of Regorafenib and/or VK1 in HCC cell lines. Moreover we provide evidence that the combined treatment with IG1-R antagonists and Regorafenib (and/or VK1) also caused a significant reduction and depolymerization of actin resulting in synergistic inhibition exerted on cell migration. Thus, simultaneous blocking of MAPK and PI3K/Akt cascades with IGF1-R inhibitors plus Regorafenib could represent a more potent approach for HCC treatment.

  3. IGF-1, oxidative stress, and atheroprotection

    Science.gov (United States)

    Higashi, Yusuke; Sukhanov, Sergiy; Anwar, Asif; Shai, Shaw-Yung; Delafontaine, Patrice

    2009-01-01

    Atherosclerosis is a chronic inflammatory disease in which early endothelial dysfunction and subintimal modified lipoprotein deposition progress to complex, advanced lesions that are predisposed to erosion, rupture and thrombosis. Oxidative stress plays a critical role not only in initial lesion formation but also in lesion progression and destabilization. While growth factors are thought to promote vascular smooth muscle cell proliferation and migration, thereby increasing neointima, recent animal studies indicate that IGF-1 exerts pleiotropic anti-oxidant effects along with anti-inflammatory effects that together reduce atherosclerotic burden. This review discusses the effects of IGF-1 in vascular injury and atherosclerosis models, emphasizing the relationship between oxidative stress and potential atheroprotective actions of IGF-1. PMID:20071192

  4. The Beneficial Impact of Antidepressant Drugs on Prenatal Stress-Evoked Malfunction of the Insulin-Like Growth Factor-1 (IGF-1) Protein Family in the Olfactory Bulbs of Adult Rats.

    Science.gov (United States)

    Trojan, Ewa; Głombik, Katarzyna; Ślusarczyk, Joanna; Budziszewska, Bogusława; Kubera, Marta; Roman, Adam; Lasoń, Władysław; Basta-Kaim, Agnieszka

    2016-02-01

    Insulin-like growth factor-1 (IGF-1) promotes the growth, differentiation, and survival of both neurons and glial cells, and it is believed to exert antidepressant-like activity. Thus, disturbances in the IGF-1 system could be responsible for the course of depression. To date, there have been no papers showing the impact of chronic antidepressant treatment on the IGF-1 network in the olfactory bulb (OB) in an animal model of depression. Prenatal stress was used as model of depression. Twenty-four 3-month-old male offspring of control and stressed mothers were subjected to behavioral testing (forced swim test). The mRNA expression of IGF-1 and IGF-1 receptor (IGF-1R) and the protein level of IGF-1 and its phosphorylation, as well as the concentrations of IGF-binding proteins (IGFBP-2, -4, -3, and -6), were measured in OBs before and after chronic imipramine, fluoxetine, or tianeptine administration. Adult rats exposed prenatally to stressful stimuli displayed not only depression-like behavior but also decreased IGF-1 expression, dysregulation in the IGFBP network, and diminished mRNA expression, as well as IGF-1R phosphorylation, in the OB. The administration of antidepressants normalized most of the changes in the IGF-1 system of the OB evoked by prenatal stress. These results suggested a beneficial effect of chronic antidepressant drug treatment in the alleviation of IGF-1 family malfunction in OBs in an animal model of depression.

  5. Disruption of IGF-1R signaling increases TRAIL-induced apoptosis: A new potential therapy for the treatment of melanoma

    Energy Technology Data Exchange (ETDEWEB)

    Karasic, Thomas B.; Hei, Tom K. [Center for Radiological Research, Department of Radiation Oncology, College of Physicians and Surgeons, Columbia University, New York, NY 10032 (United States); Ivanov, Vladimir N., E-mail: vni3@columbia.edu [Center for Radiological Research, Department of Radiation Oncology, College of Physicians and Surgeons, Columbia University, New York, NY 10032 (United States)

    2010-07-15

    Resistance of cancer cells to apoptosis is dependent on a balance of multiple genetic and epigenetic mechanisms, which up-regulate efficacy of the surviving growth factor-receptor signaling pathways and suppress death-receptor signaling pathways. The Insulin-like Growth Factor-1 Receptor (IGF-1R) signaling pathway is highly active in metastatic melanoma cells by mediating downstream activation of PI3K-AKT and MAPK pathways and controlling general cell survival and proliferation. In the present study, we used human melanoma lines with established genotypes that represented different phases of cancer development: radial-growth-phase WM35, vertical-growth-phase WM793, metastatic LU1205 and WM9 [1]. All these lines have normal NRAS. WM35, WM793, LU1205 and WM9 cells have mutated BRAF (V600E). WM35 and WM9 cells express normal PTEN, while in WM793 cells PTEN expression is down-regulated; finally, in LU1205 cells PTEN is inactivated by mutation. Cyclolignan picropodophyllin (PPP), a specific inhibitor of IGF-1R kinase activity, strongly down-regulated the basal levels of AKT activity in WM9 and in WM793 cells, modestly does so in LU1205, but has no effect on AKT activity in the early stage WM35 cells that are deficient in IGF-1R. In addition, PPP partially down-regulated the basal levels of active ERK1/2 in all lines used, highlighting the role of an alternative, non-BRAF pathway in MAPK activation. The final result of PPP treatment was an induction of apoptosis in WM793, WM9 and LU1205 melanoma cells. On the other hand, dose-dependent inhibition of IGF-1R kinase activity by PPP at a relatively narrow dose range (near 500 nM) has different effects on melanoma cells versus normal cells, inducing apoptosis in cancer cells and G2/M arrest of fibroblasts. To further enhance the pro-apoptotic effects of PPP on melanoma cells, we used a combined treatment of TNF-Related Apoptosis-Inducing Ligand (TRAIL) and PPP. This combination substantially increased death by apoptosis for

  6. Growth hormone mediates pubertal skeletal development independent of hepatic IGF-1 production.

    Science.gov (United States)

    Courtland, Hayden-William; Sun, Hui; Beth-On, Mordechay; Wu, Yingjie; Elis, Sebastien; Rosen, Clifford J; Yakar, Shoshana

    2011-04-01

    Deficiencies in either growth hormone (GH) or insulin-like growth factor 1 (IGF-1) are associated with reductions in bone size during growth in humans and animal models. Liver-specific IGF-1-deficient (LID) mice, which have 75% reductions in serum IGF-1, were created previously to separate the effects of endocrine (serum) IGF-1 from autocrine/paracrine IGF-1. However, LID mice also have two- to threefold increases in GH, and this may contribute to the observed pubertal skeletal phenotype. To clarify the role of GH in skeletal development under conditions of significantly reduced serum IGF-1 levels (but normal tissue IGF-1 levels), we studied the skeletal response of male LID and control mice to GH inhibition by pegvisomant from 4 to 8 weeks of age. Treatment of LID mice with pegvisomant resulted in significant reductions in body weight, femur length (Le), and femur total area (Tt.Ar), as well as further reductions in serum IGF-1 levels by 8 weeks of age, compared with the mean values of vehicle-treated LID mice. Reductions in both Tt.Ar and Le were proportional after treatment with pegvisomant. On the other hand, the relative amount of cortical tissue formed (RCA) in LID mice treated with pegvisomant was significantly less than that in both vehicle-treated LID and control mice, indicating that antagonizing GH action, either directly (through GH receptor signaling inhibition) or indirectly (through further reductions in serum/tissue IGF-1 levels), results in disproportionate reductions in the amount of cortical bone formed. This resulted in bones with significantly reduced mechanical properties (femoral whole-bone stiffness and work to failure were markedly decreased), suggesting that compensatory increases of GH in states of IGF-1 deficiency (LID mice) act to protect against a severe inhibition of bone modeling during growth, which otherwise would result in bones that are too weak for normal and/or extreme loading conditions. Copyright © 2011 American Society for

  7. Insulin-Like Growth Factor 1 (IGF-1) in Parkinson's Disease: Potential as Trait-, Progression- and Prediction Marker and Confounding Factors

    Science.gov (United States)

    Binder, Gerhard; Weber, Karin; Apel, Anja; Roeben, Benjamin; Deuschle, Christian; Maechtel, Mirjam; Heger, Tanja; Nussbaum, Susanne; Gasser, Thomas; Maetzler, Walter; Berg, Daniela

    2016-01-01

    Introduction Biomarkers indicating trait, progression and prediction of pathology and symptoms in Parkinson's disease (PD) often lack specificity or reliability. Investigating biomarker variance between individuals and over time and the effect of confounding factors is essential for the evaluation of biomarkers in PD, such as insulin-like growth factor 1 (IGF-1). Materials and Methods IGF-1 serum levels were investigated in up to 8 biannual visits in 37 PD patients and 22 healthy controls (HC) in the longitudinal MODEP study. IGF-1 baseline levels and annual changes in IGF-1 were compared between PD patients and HC while accounting for baseline disease duration (19 early stage: ≤3.5 years; 18 moderate stage: >4 years), age, sex, body mass index (BMI) and common medical factors putatively modulating IGF-1. In addition, associations of baseline IGF-1 with annual changes of motor, cognitive and depressive symptoms and medication dose were investigated. Results PD patients in moderate (130±26 ng/mL; p = .004), but not early stages (115±19, p>.1), showed significantly increased baseline IGF-1 levels compared with HC (106±24 ng/mL; p = .017). Age had a significant negative correlation with IGF-1 levels in HC (r = -.47, p = .028) and no correlation in PD patients (r = -.06, p>.1). BMI was negatively correlated in the overall group (r = -.28, p = .034). The annual changes in IGF-1 did not differ significantly between groups and were not correlated with disease duration. Baseline IGF-1 levels were not associated with annual changes of clinical parameters. Discussion Elevated IGF-1 in serum might differentiate between patients in moderate PD stages and HC. However, the value of serum IGF-1 as a trait-, progression- and prediction marker in PD is limited as IGF-1 showed large inter- and intraindividual variability and may be modulated by several confounders. PMID:26967642

  8. Serum IGF1 and insulin levels in girls with normal and precocious puberty

    DEFF Research Database (Denmark)

    Sørensen, Kaspar; Aksglaede, Lise; Petersen, Jørgen Holm

    2012-01-01

    IGF1 plays an important role in growth and metabolism during puberty. IGF1 levels are increased in girls with central precocious puberty (CPP). However, the relationship with insulin before and during gonadal suppression is unknown. In addition, the influence of the exon 3-deleted GH receptor gene...

  9. The Association between IGF-1 Polymorphisms, IGF-1 Serum Levels, and Cognitive Functions in Healthy Adults: The Amsterdam Growth and Health Longitudinal Study

    NARCIS (Netherlands)

    Licht, C.M.M.; van Turenhout, L.C.; Deijen, J.B.; Koppes, L.L.J.; van Mechelen, W.; Twisk, J.W.R.; Drent, M.L.

    2014-01-01

    Several studies have demonstrated an association between polymorphisms in the insulin-like growth factor-1 (IGF-1) gene and IGF-1 serum levels. IGF-1 levels have been associated with cognitive functioning in older persons and growth hormone deficient patients. The present study investigates whether

  10. The association between IGF-1 polymorphisms, IGF-1 serum levels, and cognitive functions in healthy adults: The amsterdam growth and health longitudinal study

    NARCIS (Netherlands)

    Licht, C.M.M.; Turenhout, L.C. van; Deijen, J.B.; Koppes, L.L.J.; Mechelen, W. van; Twisk, J.W.R.; Drent, M.L.

    2014-01-01

    Several studies have demonstrated an association between polymorphisms in the insulin-like growth factor-1 (IGF-1) gene and IGF-1 serum levels. IGF-1 levels have been associated with cognitive functioning in older persons and growth hormone deficient patients. The present study investigates whether

  11. The association between IGF-1 polymorphisms, IGF-1 serum levels, and cognitive functions in healthy adults: the Amsterdam Growth and Health longitudinal study.

    NARCIS (Netherlands)

    Licht, C.M.M.; Turenhout, L.C. van; Deijen, J.B.; Koppes, L.L.J.; Mechelen, W. van; Twisk, J.W.R.; Drent, M.L.

    2014-01-01

    Several studies have demonstrated an association between polymorphisms in the insulin-like growth factor-1 (IGF-1) gene and IGF-1 serum levels. IGF-1 levels have been associated with cognitive functioning in older persons and growth hormone deficient patients. The present study investigates whether

  12. Preeclampsia is associated with hypermethylation of IGF-1 promoter mediated by DNMT1.

    Science.gov (United States)

    Ma, Min; Zhou, Qiong-Jie; Xiong, Yu; Li, Bin; Li, Xiao-Tian

    2018-01-01

    Previous studies have demonstrated a dynamic epigenetic regulation of genes expression in placenta trophoblasts and a dynamic imbalance of DNA methylation and hydroxymethylation. Reduced IGF-1 has been observed in preeclampsia. This study was to investigate the interactive roles between IGF-1 and the global DNA methylation/hydroxymethylation, and the status of DNA methylation/hydroxymethylation and associated enzymes such as DNMTs and TETs in peeeclamptic placentas and hypoxic trophoblasts. It was found that IGF-1 was decreased in preeclamptic placentas and hypoxic trophoblasts when compared to the control group using immunohistochemisty, western blot, qRT-PCR and ELISA. Pyrophosphate sequencing showed IGF-1 promoter was significantly hypermethylated in preeclamptic placentas, which was responsible for reduced IGF-1 expression. Preeclamptic placentas and hypoxic trophoblasts were hypermethylated and hypohydroxymethylated accompanied by remarkably higher 5mC, DNMT1 and DNMT3b, and lower DNMT3a, 5hmC, TET1, TET2 and TET3 detected by immunohistochemisty, western blot, qRT-PCR and ELISA. Pearson's correlation confirmed a statistically significant negative correlation between IGF-1 and DNMT1. Furthermore, both treatment with 5-Aza-dc and DNMT1-siRNA significantly increased the expression of IGF-1 in HTR8 cells, indicating the potential mechanism of DNMT1-mediated DNA methylation in IGF-1 regulation. However, IGF-1 didn't change DNA methylation or hydroxymethylation. These findings suggest that preeclampsia is associated with hypermethylation of IGF-1 promoter mediated by DNMT1 and provide new insights into the diagnosis and treatment of preeclampsia.

  13. Central insulin-like growth factor-1 (IGF-1) restores whole-body insulin action in a model of age-related insulin resistance and IGF-1 decline.

    Science.gov (United States)

    Huffman, Derek M; Farias Quipildor, Gabriela; Mao, Kai; Zhang, Xueying; Wan, Junxiang; Apontes, Pasha; Cohen, Pinchas; Barzilai, Nir

    2016-02-01

    Low insulin-like growth factor-1 (IGF-1) signaling is associated with improved longevity, but is paradoxically linked with several age-related diseases in humans. Insulin-like growth factor-1 has proven to be particularly beneficial to the brain, where it confers protection against features of neuronal and cognitive decline. While aging is characterized by central insulin resistance in the face of hyperinsulinemia, the somatotropic axis markedly declines in older humans. Thus, we hypothesized that increasing IGF-1 in the brain may prove to be a novel therapeutic alternative to overcome central insulin resistance and restore whole-body insulin action in aging. Utilizing hyperinsulinemic-euglycemic clamps, we show that old insulin-resistant rats with age-related declines in IGF-1 level demonstrate markedly improved whole-body insulin action, when treated with central IGF-1, as compared to central vehicle or insulin (P IGF-1, but not insulin, suppressed hepatic glucose production and increased glucose disposal rates in aging rats (P IGF-1 action in the brain and periphery provides a 'balance' between its beneficial and detrimental actions. Therefore, we propose that strategies aimed at 'tipping the balance' of IGF-1 action centrally are the optimal approach to achieve healthy aging and longevity in humans. © 2015 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

  14. IGF-1 levels, complex formation, and IGF bioactivity in growth hormone-treated children with Prader-Willi syndrome

    NARCIS (Netherlands)

    Bakker, N. E.; Van Doorn, J.; Renes, J. S.; Donker, G. H.; Hokken-Koelega, A. C S

    2015-01-01

    Context: Children with Prader-Willi syndrome (PWS) attain high-serum immunoreactive IGF-1 levels during a standard-dose GH treatment, which leads to concern, but lowering the dose deteriorates their body composition. Objective: The objective of the study was to evaluate serum IGF-1, IGF binding

  15. HSF1 phosphorylation by ERK/GSK3 suppresses RNF126 to sustain IGF-IIR expression for hypertension-induced cardiomyocyte hypertrophy.

    Science.gov (United States)

    Huang, Chih-Yang; Lee, Fa-Lun; Peng, Shu-Fen; Lin, Kuan-Ho; Chen, Ray-Jade; Ho, Tsung-Jung; Tsai, Fu-Jen; Padma, Vijaya V; Kuo, Wei-Wen; Huang, Chih-Yang

    2018-02-01

    Hypertension-induced cardiac hypertrophy and apoptosis are major characteristics of early-stage heart failure (HF). Inhibition of extracellular signal-regulated kinases (ERK) efficaciously suppressed angiotensin II (ANG II)-induced cardiomyocyte hypertrophy and apoptosis by blocking insulin-like growth factor II receptor (IGF-IIR) signaling. However, the detailed mechanism by which ANG II induces ERK-mediated IGF-IIR signaling remains elusive. Here, we found that ANG II activated ERK to upregulate IGF-IIR expression via the angiotensin II type I receptor (AT 1 R). ERK activation subsequently phosphorylates HSF1 at serine 307, leading to a secondary phosphorylation by glycogen synthase kinase III (GSK3) at serine 303. Moreover, we found that ANG II mediated ERK/GSK3-induced IGF-IIR protein stability by downregulating the E3 ubiquitin ligase of IGF-IIR RING finger protein CXXVI (RNF126). The expression of RNF126 decreased following ANG II-induced HSF1 S303 phosphorylation, resulting in IGF-IIR protein stability and increased cardiomyocyte injury. Inhibition of GSK3 significantly alleviated ANG II-induced cardiac hypertrophy in vivo and in vitro. Taken together, these results suggest that HSF1 phosphorylation stabilizes IGF-IIR protein stability by downregulating RNF126 during cardiac hypertrophy. ANG II activates ERK/GSK3 to phosphorylate HSF1, resulting in RNF126 degradation, which stabilizes IGF-IIR protein expression and eventually results in cardiac hypertrophy. HSF1 could be a valuable therapeutic target for cardiac diseases among hypertensive patients. © 2017 Wiley Periodicals, Inc.

  16. Low Levels of IGF-1 Contribute to Alveolar Macrophage Dysfunction in Cystic Fibrosis1

    Science.gov (United States)

    Bessich, Jamie L.; Nymon, Amanda B.; Moulton, Lisa A; Dorman, Dana; Ashare, Alix

    2013-01-01

    Alveolar macrophages are major contributors to lung innate immunity. Although alveolar macrophages from CFTR−/− mice have impaired function, no study has investigated primary alveolar macrophages in adults with cystic fibrosis (CF). CF patients have low levels of insulin-like growth factor 1 (IGF-1), and our prior studies demonstrate a relationship between IGF-1 and macrophage function. We hypothesize that reduced IGF-1 in CF leads to impaired alveolar macrophage function and chronic infections. Serum and bronchoalveolar lavage (BAL) samples were obtained from 8 CF subjects and 8 healthy subjects. Macrophages were isolated from BAL fluid. We measured the ability of alveolar macrophages to kill Pseudomonas aeruginosa. Subsequently, macrophages were incubated with IGF-1 prior to inoculation with bacteria to determine the effect of IGF-1 on bacterial killing. We found a significant decrease in bacterial killing by CF alveolar macrophages compared to controls. CF subjects had lower serum and BAL IGF-1 levels compared to healthy controls. Exposure to IGF-1 enhanced alveolar macrophage macrophages in both groups. Finally, exposing healthy alveolar macrophages to CF BAL fluid decreased bacterial killing, and this was reversed by the addition of IGF-1, while IGF-1 blockade worsened bacterial killing. Our studies demonstrate that alveolar macrophage function is impaired in patients with CF. Reductions in IGF-1 levels in CF contribute to the impaired alveolar macrophage function. Exposure to IGF-1 ex vivo, results in improved function of CF alveolar macrophages. Further studies are needed to determine whether alveolar macrophage function can be enhanced in vivo with IGF-1 treatment. PMID:23698746

  17. Effect of GH/IGF-1 on Bone Metabolism and Osteoporsosis

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    Vittorio Locatelli

    2014-01-01

    Full Text Available Background. Growth hormone (GH and insulin-like growth factor (IGF-1 are fundamental in skeletal growth during puberty and bone health throughout life. GH increases tissue formation by acting directly and indirectly on target cells; IGF-1 is a critical mediator of bone growth. Clinical studies reporting the use of GH and IGF-1 in osteoporosis and fracture healing are outlined. Methods. A Pubmed search revealed 39 clinical studies reporting the effects of GH and IGF-1 administration on bone metabolism in osteopenic and osteoporotic human subjects and on bone healing in operated patients with normal GH secretion. Eighteen clinical studies considered the effect with GH treatment, fourteen studies reported the clinical effects with IGF-1 administration, and seven related to the GH/IGF-1 effect on bone healing. Results. Both GH and IGF-1 administration significantly increased bone resorption and bone formation in the most studies. GH/IGF-1 administration in patients with hip or tibial fractures resulted in increased bone healing, rapid clinical improvements. Some conflicting results were evidenced. Conclusions. GH and IGF-1 therapy has a significant anabolic effect. GH administration for the treatment of osteoporosis and bone fractures may greatly improve clinical outcome. GH interacts with sex steroids in the anabolic process. GH resistance process is considered.

  18. Effect of GH/IGF-1 on Bone Metabolism and Osteoporsosis

    Science.gov (United States)

    Locatelli, Vittorio; Bianchi, Vittorio E.

    2014-01-01

    Background. Growth hormone (GH) and insulin-like growth factor (IGF-1) are fundamental in skeletal growth during puberty and bone health throughout life. GH increases tissue formation by acting directly and indirectly on target cells; IGF-1 is a critical mediator of bone growth. Clinical studies reporting the use of GH and IGF-1 in osteoporosis and fracture healing are outlined. Methods. A Pubmed search revealed 39 clinical studies reporting the effects of GH and IGF-1 administration on bone metabolism in osteopenic and osteoporotic human subjects and on bone healing in operated patients with normal GH secretion. Eighteen clinical studies considered the effect with GH treatment, fourteen studies reported the clinical effects with IGF-1 administration, and seven related to the GH/IGF-1 effect on bone healing. Results. Both GH and IGF-1 administration significantly increased bone resorption and bone formation in the most studies. GH/IGF-1 administration in patients with hip or tibial fractures resulted in increased bone healing, rapid clinical improvements. Some conflicting results were evidenced. Conclusions. GH and IGF-1 therapy has a significant anabolic effect. GH administration for the treatment of osteoporosis and bone fractures may greatly improve clinical outcome. GH interacts with sex steroids in the anabolic process. GH resistance process is considered. PMID:25147565

  19. Overexpression of decorin promoted angiogenesis in diabetic cardiomyopathy via IGF1R-AKT-VEGF signaling.

    Science.gov (United States)

    Lai, Jinsheng; Chen, Fuqiong; Chen, Jing; Ruan, Guoran; He, Mengying; Chen, Chen; Tang, Jiarong; Wang, Dao Wen

    2017-03-14

    Microcirculatory dysfunction is believed to play an important role in diabetic cardiomyopathy. The small leucine-rich proteoglycan decorin is generally considered a pro-angiogenic factor. Here, we investigate whether overexpression of decorin ameliorates diabetic cardiomyopathy and its effects on angiogenesis in vivo and in vitro. Diabetes was induced through intraperitoneal injection with streptozotocin combined with a high-fat diet, and decorin was overexpressed via recombinant adeno-associated virus in Wistar rats. Six months later, cardiac function was determined using an echocardiography and cardiac catheter system. The results showed that cardiac function was decreased in diabetic rats and restored by overexpression of decorin. In addition, overexpression of decorin upregulated the expression of VEGF and attenuated the reduction in the cardiac capillary density. In the in vitro study, high glucose induced apoptosis and inhibited the capabilities of tube formation, migration and proliferation, which were all ameliorated by decorin overexpression. Meanwhile, decorin overexpression increased the expression of VEGF and IGF1R, as well as the phosphorylation level of AKT and AP-1. Nonetheless, all of these effects were abolished by pretreatment with the IGF1R antibody or AKT inhibitor. In conclusion, overexpression of decorin ameliorated diabetic cardiomyopathy and promoted angiogenesis through the IGF1R-AKT-VEGF signaling pathway in vivo and in vitro.

  20. Elevated IGFBP3 levels in diabetic tears: a negative regulator of IGF-1 signaling in the corneal epithelium.

    Science.gov (United States)

    Wu, Yu-Chieh; Buckner, Benjamin R; Zhu, Meifang; Cavanagh, H Dwight; Robertson, Danielle M

    2012-04-01

    To determine the ratio of IGFBP3:IGF-1 in normal and diabetic human tears, and in telomerase-immortalized human corneal epithelial cells (hTCEpi) cultured under elevated glucose conditions and to correlate these changes with total and phosphorylated levels of IGF-1R. Tear samples were collected noninvasively from diabetic subjects and non-diabetic controls; corneal sensitivity was assessed using a Cochet-Bonnet Aesthesiometer. Conditioned media were collected following culture of hTCEpi cells in normal (5 mM) and elevated (25 mM) glucose conditions; mannitol was used as an osmotic control. IGFBP3, IGF-1, and phosphorylated IGF-1R levels were assessed by ELISA. IGFBP3 and IGF-1R mRNA were assessed by real-time polymerase chain reaction (PCR). Total and phosphorylated IGF-1R expression in whole cell lysates was assessed by western blot. There was a 2.8-fold increase in IGFBP3 in diabetic tears compared to non-diabetic controls (P=0.006); IGF-1 levels were not significantly altered. No difference in corneal sensitivity was detected between groups. The concentration of IGFBP3 in tears was independent of IGF-1. Consistent with human tear measurements in vivo, IGFBP3 secretion was increased 2.2 fold (Ptears compared to normal controls blocked phosphorylation of the IGF-1R by IGF-1 (Ptears may attenuate IGF-1R signaling in the diabetic cornea. A long-term increase in IGFBP3 may contribute to epithelial compromise and the pathogenesis of ocular surface complications reported in diabetes. Copyright © 2012 Elsevier Inc. All rights reserved.

  1. INSULIN-LIKE GROWTH FACTOR (IGF-1 IN CNS AND CEREBROVASCULAR AGING

    Directory of Open Access Journals (Sweden)

    William E Sonntag

    2013-07-01

    Full Text Available Insulin-like growth factor-1 (IGF-1 is an important anabolic hormone that decreases with age. In the past two decades extensive research has determined that the reduction in IGF-1 is an important component of the age-related decline in cognitive function in multiple species including humans. Deficiency in circulating IGF-1 results in impairment in processing speed and deficiencies in both spatial and working memory. Replacement of IGF-1 or factors that increase IGF-1 to old animals and humans reverses many of these cognitive deficits. Despite the overwhelming evidence for IGF-1 as an important neurotrophic agent, the specific mechanisms through which IGF-1 acts have remained elusive. Recent evidence indicates that IGF-1 is both produced by and has important actions on the cerebrovasculature as well as neurons and glia. Nevertheless, the specific regulation and actions of brain- and vascular-derived IGF-1 is poorly understood. The diverse effects of IGF-1 discovered thus far reveal a complex endocrine and paracrine system essential for integrating many of the functions necessary for brain health. Identification of the mechanisms of IGF-1 actions will undoubtedly provide critical insight into regulation of brain function in general and the causes of cognitive decline with age.

  2. Overexpression of IGF-I receptor in HeLa cells enhances in vivo radioresponse

    International Nuclear Information System (INIS)

    Kaneko, Haruna; Yu, Dong; Miura, Masahiko

    2007-01-01

    Insulin-like growth factor I receptor (IGF-IR) is a transmembrane receptor tyrosine kinase whose activation strongly promotes cell growth and survival. We previously reported that IGF-IR activity confers intrinsic radioresistance in mouse embryo fibroblasts in vitro. However, it is still unclear whether tumor cells overexpressing IGF-IR exhibit radioresistance in vivo. For this purpose, we established HeLa cells that overexpress IGF-IR (HeLa-R), subcutaneously transplanted these cells into nude mice, and examined radioresponse in the resulting solid tumors. HeLa-R cells exhibited typical in vitro phenotypes generally observed in IGF-IR-overexpressing cells, as well as significant intrinsic radioresistance in vitro compared with parent cells. As expected, the transplanted HeLa-R tumors grew at a remarkably higher rate than parent tumors. Histological analysis revealed that HeLa-R tumors expressed more VEGF and had a higher density of tumor vessels. Unexpectedly, a marked growth delay was observed in HeLa-R tumors following 10 Gy of X-irradiation. Immunostaining of HeLa-R tumors for the hypoxia marker pimonidazole revealed a significantly lower level of hypoxic cells. Moreover, clamp hypoxia significantly increased radioresistance in HeLa-R tumors. Tumor microenvironments in vivo generated by the IGF-IR expression thus could be a major factor in determining the tumor radioresponse in vivo

  3. Autophagy resolves early retinal inflammation in Igf1-deficient mice

    Directory of Open Access Journals (Sweden)

    Ana I. Arroba

    2016-09-01

    Full Text Available Insulin-like growth factor-1 (IGF-1 is a growth factor with differentiating, anti-apoptotic and metabolic functions in the periphery, and anti-inflammatory properties in the nervous system. Mice that have mutations in the Igf1 gene, rendering the gene product inactive (Igf1−/−, present with age-related visual loss accompanied by structural alterations in the first synapses of the retinal pathway. Recent advances have revealed a crucial role of autophagy in immunity and inflammation. Keeping in mind this close relationship, we aimed to decipher these processes in the context of the defects that occur during ageing in the retina of Igf1−/− mice. Tnfa and Il1b mRNAs, and phosphorylation of JNK and p38 MAPK were elevated in the retinas of 6- and 12-month old Igf1−/− mice compared to those in age-matched Igf1+/+ controls. In 6-month-old Igf1−/− retinas, increased mRNA levels of the autophagy mediators Becn1, Atg9, Atg5 and Atg4, decreased p62 (also known as SQSTM1 protein expression together with an increased LC3-II:LC3-I ratio reflected active autophagic flux. However, in retinas from 12-month-old Igf1−/− mice, Nlrp3 mRNA, processing of the IL1β pro-form and immunostaining of active caspase-1 were elevated compared to those in age-matched Igf1+/+ controls, suggesting activation of the inflammasome. This effect concurred with accumulation of autophagosomes and decreased autophagic flux in the retina. Microglia localization and status of activation in the retinas of 12-month-old Igf1+/+ and Igf1−/− mice, analyzed by immunostaining of Cd11b and Iba-1, showed a specific distribution pattern in the outer plexiform layer (OPL, inner plexiform layer (IPL and inner nuclear layer (INL, and revealed an increased number of activated microglia cells in the retina of 12-month-old blind Igf1−/− mice. Moreover, reactive gliosis was exclusively detected in the retinas from 12-month-old blind Igf1−/− mice. In conclusion, this study

  4. Cyclic-glycine-proline accelerates mammary involution by promoting apoptosis and inhibiting IGF-1 function.

    Science.gov (United States)

    Singh-Mallah, Gagandeep; McMahon, Christopher D; Guan, Jian; Singh, Kuljeet

    2017-12-01

    In rodents, post-lactational involution of mammary glands is characterized by the loss of mammary epithelial cells via apoptosis, which is associated with a decline in the expression of insulin-like growth factor-1 (IGF-1). Overexpression of IGF-1 delays involution by inhibiting apoptosis of epithelial cells and preserving the remaining secretory alveoli. Cyclic-glycine-proline (cGP), a metabolite of IGF-1, normalizes IGF-1 function under pathological conditions by regulating the bioavailability of IGF-1. The present study investigated the effect of cGP on the physiological decline in IGF-1 function during post-lactational mammary involution. Rat dams were gavaged with either cGP (3 mg/kg) or saline once per day from post-natal d8-22. Before collecting tissue on post-natal d23, a pair of mammary glands were sealed on d20 (72 hr-engorgement, thus representative of late-involution) and d22 (24 hr-engorgement, thus representative of mid-involution), while the remaining glands were allowed to involute naturally (early-involution). During early-involution, cGP accelerated the loss of mammary cells through apoptosis, resulting in an earlier clearance of intact secretory alveoli compared with the control group. This coincided with an earlier up-regulation of the cell survival factors, Bcl-xl and IGF-1R, in the early-involution cGP glands compared with the control glands. During late-involution, cGP reduced the bioactivity of IGF-1, which was evident through decreased phosphorylation of IGF-1R in the regressed alveoli. Maternal administration of cGP did not alter milk production and composition during early-, peak-, or late-stage of lactation. These data show that cGP accelerates post-lactational involution by promoting apoptosis and the physiological decline in IGF-1 function. © 2017 Wiley Periodicals, Inc.

  5. Doxorubicin plus the IGF-1R antibody cixutumumab in soft tissue sarcoma: a phase I study using the TITE-CRM model.

    Science.gov (United States)

    Chugh, R; Griffith, K A; Davis, E J; Thomas, D G; Zavala, J D; Metko, G; Brockstein, B; Undevia, S D; Stadler, W M; Schuetze, S M

    2015-07-01

    Insulin-like growth factor receptor (IGF-1R) has been studied as an oncologic target in soft tissue sarcoma (STS), but its role in sarcoma biology is unclear. Anti-IGF-1R antibody cixutumumab demonstrated acceptable toxicity but limited activity as a single agent in STS. We carried out a dose-escalation study of cixutumumab with doxorubicin to evaluate safety and dosing of the combination. Eligible patients with advanced STS were treated with cixutumumab intravenously on days 1/8/15 at one of three dose levels (A: 1 mg/kg, B: 3 mg/kg, C: 6 mg/kg) with doxorubicin at 75 mg/m(2) as a 48 h infusion on day 1 of a 21 day cycle. After six cycles of the combination, patients could receive cixutumumab alone. The Time-to-Event Continual Reassessment Method was used to estimate the probability of dose-limiting toxicity (DLT) and to assign patients to the dose with an estimated probability of DLT≤20%. Between September 2008 and January 2012, 30 patients with advanced STS received a median of six cycles of therapy (range <1-22). Two DLTs were observed, grade 3 mucositis (dose level B) and grade 4 hyperglycemia (dose level C). Grade 2 and 3 reduced left ventricular ejection fraction was seen in three and two patients, respectively. Five partial responses were observed, and estimated progression-free survival was 5.3 months (95% confidence interval 3.0-6.3) in 26 response-assessable patients. Immunohistochemical staining of 11 available tumor samples for IGF-1R and phospho-IGF-1R was not significantly different among responders and non-responders, and serum analysis of select single-nucleotide polymorphisms did not predict for cardiotoxicity. The maximum tolerated dose was doxorubicin 75 mg/m(2) on day 1 and cixitumumab 6 mg/kg on days 1/8/15 of a 21 day cycle. Cardiac toxicity was observed and should be monitored in subsequent studies, which should be considered in STS only if a predictive biomarker of benefit to anti-IGF-1R therapy is identified. Clinical

  6. IGF-1 deficiency impairs cerebral myogenic autoregulation in hypertensive mice.

    Science.gov (United States)

    Toth, Peter; Tucsek, Zsuzsanna; Tarantini, Stefano; Sosnowska, Danuta; Gautam, Tripti; Mitschelen, Matthew; Koller, Akos; Sonntag, William E; Csiszar, Anna; Ungvari, Zoltan

    2014-12-01

    Aging impairs autoregulatory protection in the brain, exacerbating hypertension-induced cerebromicrovascular injury, neuroinflammation, and development of vascular cognitive impairment. Despite the importance of the age-related decline in circulating insulin-like growth factor-1 (IGF-1) levels in cerebrovascular aging, the effects of IGF-1 deficiency on functional adaptation of cerebral arteries to high blood pressure remain elusive. To determine whether IGF-1 deficiency impairs autoregulatory protection, hypertension was induced in control and IGF-1-deficient mice (Igf1(f/f)+TBG-iCre-AAV8) by chronic infusion of angiotensin-II. In hypertensive control mice, cerebral blood flow (CBF) autoregulation was extended to higher pressure values and the pressure-induced tone of middle cerebral arteries (MCAs) was increased. In hypertensive IGF-1-deficient mice, autoregulation was markedly disrupted, and MCAs did not show adaptive increases in myogenic tone. In control mice, the mechanism of adaptation to hypertension involved upregulation of TRPC channels in MCAs and this mechanism was impaired in hypertensive IGF-1-deficient mice. Likely downstream consequences of cerebrovascular autoregulatory dysfunction in hypertensive IGF-1-deficient mice included exacerbated disruption of the blood-brain barrier and neuroinflammation (microglia activation and upregulation of proinflammatory cytokines and chemokines), which were associated with impaired hippocampal cognitive function. Collectively, IGF-1 deficiency impairs autoregulatory protection in the brain of hypertensive mice, potentially exacerbating cerebromicrovascular injury and neuroinflammation mimicking the aging phenotype.

  7. IGF-1R and ErbB3/HER3 contribute to enhanced proliferation and carcinogenesis in trastuzumab-resistant ovarian cancer model

    International Nuclear Information System (INIS)

    Jia, Yanhan; Zhang, Yan; Qiao, Chunxia; Liu, Guijun; Zhao, Qing; Zhou, Tingting; Chen, Guojiang; Li, Yali; Feng, Jiannan; Li, Yan; Zhang, Qiuping; Peng, Hui

    2013-01-01

    Highlights: •We established trastuzumab-resistant cell line SKOV3/T. •SKOV3/T enhances proliferation and in vivo carcinogenesis. •IGF-1R and HER3 genes were up-regulated in SKOV3/T based on microarray analysis. •Targeting IGF-1R and/or HER3 inhibited the proliferation of SKOV3/T. •Therapies targeting IGF-1R and HER3 might be effective in ovarian cancer. -- Abstract: Trastuzumab (Herceptin®) has demonstrated clinical potential in several types of HER2-overexpressing human cancers. However, primary and acquired resistance occurs in many HER2-positive patients with regimens. To investigate the possible mechanism of acquired therapeutic resistance to trastuzumab, we have developed a preclinical model of human ovarian cancer cells, SKOV3/T, with the distinctive feature of stronger carcinogenesis. The differences in gene expression between parental and the resistant cells were explored by microarray analysis, of which IGF-1R and HER3 were detected to be key molecules in action. Their correctness was validated by follow-up experiments of RT-PCR, shRNA-mediated knockdown, downstream signal activation, cell cycle distribution and survival. These results suggest that IGF-1R and HER3 differentially regulate trastuzumab resistance and could be promising targets for trastuzumab therapy in ovarian cancer

  8. IGF-1R and ErbB3/HER3 contribute to enhanced proliferation and carcinogenesis in trastuzumab-resistant ovarian cancer model

    Energy Technology Data Exchange (ETDEWEB)

    Jia, Yanhan [Department of Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei 430071 (China); Department of Immunology, Institute of Basic Medical Sciences, Beijing 100850 (China); Zhang, Yan [Department of Gynaecology and Obstetrics, PLA General Hospital, Beijing 100853 (China); Qiao, Chunxia; Liu, Guijun [Department of Immunology, Institute of Basic Medical Sciences, Beijing 100850 (China); Zhao, Qing [Department of Immunology, Institute of Basic Medical Sciences, Beijing 100850 (China); Department of Gynaecology and Obstetrics, PLA General Hospital, Beijing 100853 (China); Zhou, Tingting; Chen, Guojiang [Department of Immunology, Institute of Basic Medical Sciences, Beijing 100850 (China); Li, Yali [Department of Gynaecology and Obstetrics, PLA General Hospital, Beijing 100853 (China); Feng, Jiannan; Li, Yan [Department of Immunology, Institute of Basic Medical Sciences, Beijing 100850 (China); Zhang, Qiuping, E-mail: qpzhang@whu.edu.cn [Department of Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei 430071 (China); Peng, Hui, E-mail: p_h2002@hotmail.com [Department of Immunology, Institute of Basic Medical Sciences, Beijing 100850 (China); Cardiovascular Drug Research Center, Institute of Health and Environmental Medicine, Beijing 100850 (China)

    2013-07-12

    Highlights: •We established trastuzumab-resistant cell line SKOV3/T. •SKOV3/T enhances proliferation and in vivo carcinogenesis. •IGF-1R and HER3 genes were up-regulated in SKOV3/T based on microarray analysis. •Targeting IGF-1R and/or HER3 inhibited the proliferation of SKOV3/T. •Therapies targeting IGF-1R and HER3 might be effective in ovarian cancer. -- Abstract: Trastuzumab (Herceptin®) has demonstrated clinical potential in several types of HER2-overexpressing human cancers. However, primary and acquired resistance occurs in many HER2-positive patients with regimens. To investigate the possible mechanism of acquired therapeutic resistance to trastuzumab, we have developed a preclinical model of human ovarian cancer cells, SKOV3/T, with the distinctive feature of stronger carcinogenesis. The differences in gene expression between parental and the resistant cells were explored by microarray analysis, of which IGF-1R and HER3 were detected to be key molecules in action. Their correctness was validated by follow-up experiments of RT-PCR, shRNA-mediated knockdown, downstream signal activation, cell cycle distribution and survival. These results suggest that IGF-1R and HER3 differentially regulate trastuzumab resistance and could be promising targets for trastuzumab therapy in ovarian cancer.

  9. IGF-1R Promotes Symmetric Self-Renewal and Migration of Alkaline Phosphatase+ Germ Stem Cells through HIF-2α-OCT4/CXCR4 Loop under Hypoxia

    Directory of Open Access Journals (Sweden)

    Yung-Che Kuo

    2018-02-01

    Full Text Available Summary: Hypoxia cooperates with endocrine signaling to maintain the symmetric self-renewal proliferation and migration of embryonic germline stem cells (GSCs. However, the lack of an appropriate in vitro cell model has dramatically hindered the understanding of the mechanism underlying this cooperation. Here, using a serum-free system, we demonstrated that hypoxia significantly induced the GSC mesenchymal transition, increased the expression levels of the pluripotent transcription factor OCT4 and migration-associated proteins (SDF-1, CXCR4, IGF-1, and IGF-1R, and activated the cellular expression and translocalization of the CXCR4-downstream proteins ARP3/pFAK. The underlying mechanism involved significant IGF-1/IGF-1R activation of OCT4/CXCR4 expression through HIF-2α regulation. Picropodophyllin-induced inhibition of IGF-1R phosphorylation significantly suppressed hypoxia-induced SDF-1/CXCR4 expression and cell migration. Furthermore, transactivation between IGF-1R and CXCR4 was involved. In summary, we demonstrated that niche hypoxia synergistically cooperates with its associated IGF-1R signaling to regulate the symmetric division (self-renewal proliferation and cell migration of alkaline phosphatase-positive GSCs through HIF-2α-OCT4/CXCR4 during embryogenesis. : In this article, Huang and colleagues demonstrate that niche hypoxia promotes symmetric self-renewal proliferation and migration of PGC-like CD49f+AP+GSCs through IGF-IR regulation. Using a serum-free culture system, the crosstalk between IGF-1R and CXCR4 signaling was discovered. This work demonstrated that embryonic hypoxia synergistically cooperated with IGF-1R signaling to regulate the symmetric self-renewal and migration of PGC-like GSCs through a HIF-2α–OCT4/CXCR4 loop. Keywords: hypoxia, niche, germline stem cells, self-renewal, migration, IGF-1R, HIF-2α, OCT4, SDF-1, CXCR4

  10. IMPACT STUDY: MK-0646 (DALOTUZUMAB, INSULIN GROWTH FACTOR 1 RECEPTOR (IGF-1R ANTIBODY COMBINED WITH PEMETREXED AND CISPLATIN IN STAGE IV METASTATIC NON-SQUAMOUS LUNG CANCER

    Directory of Open Access Journals (Sweden)

    Chao H Huang

    2016-01-01

    Full Text Available Background: Insulin-like growth factor 1 receptor (IGF-1R regulates cell growth, proliferation and apoptosis. Adenocarcinoma and never-smokers have a higher expression of IGF-1R, which is associated with worse overall survival. Dalotuzumab-MK0646 (D is a humanized monoclonal antibody that targets IGF-1R. Pemetrexed (P has higher activity in non-squamous lung cancer (NSQL. We initiated a randomized phase II trial to test the combination of P and Cisplatin (C +/- D in NSQL.Methods: Eligibility criteria: untreated NSQL stage IIIB or IV, ECOG 0 or 1, measurable disease, adequate renal, hepatic and hematologic function, and no other intercurrent illness. P at 500mg/m2 and C at 75mg/m2 IV were given every 3 weeks. D was given at 10mg/kg IV weekly on days 1, 8 and 15 of every 3-week cycle in the experimental group. The patients had a radiographic assessment after every 2 cycles and were treated for a maximum of 6 cycles if there was a response or stable disease. The primary objective of the study was to compare the clinical response rates of PC vs PC+D. Results: From 1/2009 to 2/2011, the study accrued 26 subjects: 16 male and 10 female, with a median age of 59; 14 were treated with PC and 12 were treated with PC+D. We observed 2 partial responses (PR, 7 stable disease (SD, 3 progressive disease (PD, and 2 were not evaluable (NE in the PC arm. In comparison, for the PC+D arm there were: 3 PR, 4 SD, 4 PD and 1 NE. The hematologic toxicity was similar in both groups. There higher incidence of hyperglycemia the experimental group; 4 cases with grade 3 and 1 case with grade 4. Conclusion: PC+D had a similar response rate compared to PC, with a higher rate of hyperglycemia. Identification of responders using predictive markers would be key to continuing the study of D in NSQL.

  11. The relationship between maternal insulin-like growth factors 1 and 2 (IGF-1, IGF-2) and IGFBP-3 to gestational age and preterm delivery.

    LENUS (Irish Health Repository)

    Cooley, Sharon M

    2012-02-01

    AIMS: To investigate the relationship between levels of insulin-like growth factors 1 and 2 (IGF-1, IGF-2), and insulin-like growth factor binding protein 3 (IGFBP-3) in antenatal maternal serum and gestational age at delivery. METHODS: Prospective cohort study of 1650 low-risk Caucasian women in a London University teaching hospital. Maternal IGF-1, IGF-2 and IGFBP-3 were measured in maternal blood at booking and analyzed with respect to gestational age at delivery. RESULTS: There was no significant association between maternal IGF-1 or IGF-2 and preterm birth (PTB). A significant reduction in mean IGFBP-3 levels was noted with delivery <32 completed weeks (P=0.02). CONCLUSION: Maternal mean IGFBP-3 levels are significantly reduced in cases complicated by delivery <32 completed weeks.

  12. BRCA1 is expressed in uterine serous carcinoma (USC) and controls insulin-like growth factor I receptor (IGF-IR) gene expression in USC cell lines.

    Science.gov (United States)

    Amichay, Keren; Kidron, Debora; Attias-Geva, Zohar; Schayek, Hagit; Sarfstein, Rive; Fishman, Ami; Werner, Haim; Bruchim, Ilan

    2012-06-01

    The insulin-like growth factor I receptor (IGF-IR) and BRCA1 affect cell growth and apoptosis. Little information is available about BRCA1 activity on the IGF signaling pathway. This study evaluated the effect of BRCA1 on IGF-IR expression. BRCA1 and IGF-IR immunohistochemistry on archival tissues (35 uterine serous carcinomas [USCs] and 17 metastases) were performed. USPC1 and USPC2 cell lines were transiently cotransfected with an IGF-IR promoter construct driving a luciferase reporter gene and a BRCA1 expression plasmid. Endogenous IGF-IR levels were evaluated by Western immunoblotting. We found high BRCA1 and IGF-IR protein expression in primary and metastatic USC tumors. All samples were immunostained for BRCA1-71% strongly stained; and 33/35 (94%) were stained positive for IGF-IR-2 (6%) strongly stained. No difference in BRCA1 and IGF-IR staining intensity was noted between BRCA1/2 mutation carriers and noncarriers. Metastatic tumors stained more intensely for BRCA1 than did the primary tumor site (P = 0.041) and with borderline significance for IGF-IR (P = 0.069). BRCA1 and IGF-IR staining did not correlate to survival. BRCA1 expression led to 35% and 54% reduction in IGF-IR promoter activity in the USPC1 and USCP2 cell lines, respectively. Western immunoblotting showed a decline in phosphorylated IGF-IR and phosphorylated AKT in both transiently and stably transfected cells. BRCA1 and IGF-IR are highly expressed in USC tumors. BRCA1 suppresses IGF-IR gene expression and activity. These findings suggest a possible biological link between the BRCA1 and the IGF-I signaling pathways in USC. The clinical implications of this association need to be explored.

  13. Insulin-like growth factor 1 (IGF-1 enhances the protein expression of CFTR.

    Directory of Open Access Journals (Sweden)

    Ha Won Lee

    Full Text Available Low levels of insulin-like growth factor 1 (IGF-1 have been observed in the serum of cystic fibrosis (CF patients. However, the effects of low serum IGF-1 on the cystic fibrosis transmembrane conductance regulator (CFTR, whose defective function is the primary cause of cystic fibrosis, have not been studied. Here, we show in human cells that IGF-1 increases the steady-state levels of mature wildtype CFTR in a CFTR-associated ligand (CAL- and TC10-dependent manner; moreover, IGF-1 increases CFTR-mediated chloride transport. Using an acceptor photobleaching fluorescence resonance energy transfer (FRET assay, we have confirmed the binding of CAL and CFTR in the Golgi. We also show that CAL overexpression inhibits forskolin-induced increases in the cell-surface expression of CFTR. We found that IGF-1 activates TC10, and active TC10 alters the functional association between CAL and CFTR. Furthermore, IGF-1 and active TC10 can reverse the CAL-mediated reduction in the cell-surface expression of CFTR. IGF-1 does not increase the expression of ΔF508 CFTR, whose processing is arrested in the ER. This finding is consistent with our observation that IGF-1 alters the functional interaction of CAL and CFTR in the Golgi. However, when ΔF508 CFTR is rescued with low temperature or the corrector VRT-325 and proceeds to the Golgi, IGF-1 can increase the expression of the rescued ΔF508 CFTR. Our data support a model indicating that CAL-CFTR binding in the Golgi inhibits CFTR trafficking to the cell surface, leading CFTR to the degradation pathway instead. IGF-1-activated TC10 changes the interaction of CFTR and CAL, allowing CFTR to progress to the plasma membrane. These findings offer a potential strategy using a combinational treatment of IGF-1 and correctors to increase the post-Golgi expression of CFTR in cystic fibrosis patients bearing the ΔF508 mutation.

  14. Activation of IGF-1 and insulin signaling pathways ameliorate mitochondrial function and energy metabolism in Huntington's Disease human lymphoblasts.

    Science.gov (United States)

    Naia, Luana; Ferreira, I Luísa; Cunha-Oliveira, Teresa; Duarte, Ana I; Ribeiro, Márcio; Rosenstock, Tatiana R; Laço, Mário N; Ribeiro, Maria J; Oliveira, Catarina R; Saudou, Frédéric; Humbert, Sandrine; Rego, A Cristina

    2015-02-01

    Huntington's disease (HD) is an inherited neurodegenerative disease caused by a polyglutamine repeat expansion in the huntingtin protein. Mitochondrial dysfunction associated with energy failure plays an important role in this untreated pathology. In the present work, we used lymphoblasts obtained from HD patients or unaffected parentally related individuals to study the protective role of insulin-like growth factor 1 (IGF-1) versus insulin (at low nM) on signaling and metabolic and mitochondrial functions. Deregulation of intracellular signaling pathways linked to activation of insulin and IGF-1 receptors (IR,IGF-1R), Akt, and ERK was largely restored by IGF-1 and, at a less extent, by insulin in HD human lymphoblasts. Importantly, both neurotrophic factors stimulated huntingtin phosphorylation at Ser421 in HD cells. IGF-1 and insulin also rescued energy levels in HD peripheral cells, as evaluated by increased ATP and phosphocreatine, and decreased lactate levels. Moreover, IGF-1 effectively ameliorated O2 consumption and mitochondrial membrane potential (Δψm) in HD lymphoblasts, which occurred concomitantly with increased levels of cytochrome c. Indeed, constitutive phosphorylation of huntingtin was able to restore the Δψm in lymphoblasts expressing an abnormal expansion of polyglutamines. HD lymphoblasts further exhibited increased intracellular Ca(2+) levels before and after exposure to hydrogen peroxide (H2O2), and decreased mitochondrial Ca(2+) accumulation, being the later recovered by IGF-1 and insulin in HD lymphoblasts pre-exposed to H2O2. In summary, the data support an important role for IR/IGF-1R mediated activation of signaling pathways and improved mitochondrial and metabolic function in HD human lymphoblasts.

  15. Relationships Between IGF-1, IGF-Binding Proteins and Diet in African American and Caucasian Men

    National Research Council Canada - National Science Library

    Agurs-Collins, Tanya

    2003-01-01

    .... The proposed study will help to explain the increased risk of prostate cancer for African American men and the role of specific nutrients in influencing IGF-1 and IGF-binding protein concentrations...

  16. Relationships Between IGF-1, IGF-Binding Proteins and Diet in African American and Caucasian Men

    National Research Council Canada - National Science Library

    Agura-Collins, Tanya

    2001-01-01

    .... The proposed study will help to explain the increased risk of prostate cancer for African American men and the role of specific nutrients in influencing IGF-1 and IGF-binding protein concentrations...

  17. Relationships Between IGF-1, IGF-Binding Proteins and Diet in African American and Caucasian Men

    National Research Council Canada - National Science Library

    Agurs-Collins, Tanya

    2002-01-01

    .... The proposed study will help to explain the increased risk of prostate cancer for African American men and the role of specific nutrients in influencing IGF-1 and IGF-binding protein concentrations...

  18. Endothelin-1-induced focal cerebral ischemia in the growth hormone/IGF-1 deficient Lewis Dwarf rat.

    Science.gov (United States)

    Yan, Han; Mitschelen, Matthew; Toth, Peter; Ashpole, Nicole M; Farley, Julie A; Hodges, Erik L; Warrington, Junie P; Han, Song; Fung, Kar-Ming; Csiszar, Anna; Ungvari, Zoltan; Sonntag, William E

    2014-11-01

    Aging is a major risk factor for cerebrovascular disease. Growth hormone (GH) and its anabolic mediator, insulin-like growth factor (IGF)-1, decrease with advancing age and this decline has been shown to promote vascular dysfunction. In addition, lower GH/IGF-1 levels are associated with higher stroke mortality in humans. These results suggest that decreased GH/IGF-1 level is an important factor in increased risk of cerebrovascular diseases. This study was designed to assess whether GH/IGF-1-deficiency influences the outcome of cerebral ischemia. We found that endothelin-1-induced middle cerebral artery occlusion resulted in a modest but nonsignificant decrease in cerebral infarct size in GH/IGF-1 deficient dw/dw rats compared with control heterozygous littermates and dw/dw rats with early-life GH treatment. Expression of endothelin receptors and endothelin-1-induced constriction of the middle cerebral arteries were similar in the three experimental groups. Interestingly, dw/dw rats exhibited reduced brain edema and less astrocytic infiltration compared with their heterozygous littermates and this effect was reversed by GH-treatment. Because reactive astrocytes are critical for the regulation of poststroke inflammatory processes, maintenance of the blood-brain barrier and neural repair, further studies are warranted to determine the long-term functional consequences of decreased astrocytic activation in GH/IGF-1 deficient animals after cerebral ischemia. Published by Oxford University Press on behalf of the Gerontological Society of America 2014.

  19. Increased linear bone growth by GH in the absence of SOCS2 is independent of IGF-1.

    Science.gov (United States)

    Dobie, Ross; Ahmed, Syed F; Staines, Katherine A; Pass, Chloe; Jasim, Seema; MacRae, Vicky E; Farquharson, Colin

    2015-11-01

    Growth hormone (GH) signaling is essential for postnatal linear bone growth, but the relative importance of GHs actions on the liver and/or growth plate cartilage remains unclear. The importance of liver derived insulin like-growth factor-1 (IGF-1) for endochondral growth has recently been challenged. Here, we investigate linear growth in Suppressor of Cytokine Signaling-2 (SOCS2) knockout mice, which have enhanced growth despite normal systemic GH/IGF-1 levels. Wild-type embryonic ex vivo metatarsals failed to exhibit increased linear growth in response to GH, but displayed increased Socs2 transcript levels (P growth over a 12 day period. Despite this increase, IGF-1 transcript and protein levels were not increased in response to GH. In accordance with these data, IGF-1 levels were unchanged in GH-challenged postnatal Socs2(-/-) conditioned medium despite metatarsals showing enhanced linear growth. Growth-plate Igf1 mRNA levels were not elevated in juvenile Socs2(-/-) mice. GH did however elevate IGF-binding protein 3 levels in conditioned medium from GH challenged metatarsals and this was more apparent in Socs2(-/-) metatarsals. GH did not enhance the growth of Socs2(-/-) metatarsals when the IGF receptor was inhibited, suggesting that IGF receptor mediated mechanisms are required. IGF-2 may be responsible as IGF-2 promoted metatarsal growth and Igf2 expression was elevated in Socs2(-/-) (but not WT) metatarsals in response to GH. These studies emphasise the critical importance of SOCS2 in regulating GHs ability to promote bone growth. Also, GH appears to act directly on the metatarsals of Socs2(-/-) mice, promoting growth via a mechanism that is independent of IGF-1. © 2014 The Authors. Journal of Cellular Physiology Published by Wiley Periodicals, Inc.

  20. IGF-II is up-regulated and myofibres are hypertrophied in regenerating soleus of mice lacking FGF6

    International Nuclear Information System (INIS)

    Armand, Anne-Sophie; Lecolle, Sylvie; Launay, Thierry; Pariset, Claude; Fiore, Frederic; Della Gaspera, Bruno; Birnbaum, Daniel; Chanoine, Christophe; Charbonnier, Frederic

    2004-01-01

    Important functions in myogenesis have been proposed for FGF6, a member of the fibroblast growth factor family accumulating almost exclusively in the myogenic lineage. However, the use of FGF6(-/-) mutant mice gave contradictory results and the role of FGF6 during myogenesis remains largely unclear. Using FGF6(-/-) mice, we first analysed the morphology of the regenerated soleus following cardiotoxin injection and showed hypertrophied myofibres in soleus of the mutant mice as compared to wild-type mice. Secondly, to examine the function of the IGF family in the hypertrophy process, we used semiquantitative and real-time RT-PCR assays and Western blots to monitor the expression of the insulin-like growth factors (IGF-I and IGF-II), their receptors [type I IGF receptor (IGF1R) and IGF-II receptor (IGF2R)], and of a binding protein IGFBP-5 in regenerating soleus muscles of FGF6(-/-) knockout mice vs. wild-type mice. In the mutant, both IGF-II and IGF2R, but not IGF-I and IGF1R, were strongly up-regulated, whereas IGFBP5 was down-regulated, strongly suggesting that, in the absence of FGF6, the mechanisms leading to myofibre hypertrophy were mediated specifically by an IGF-II/IGF2R signalling pathway distinct from the classic mechanism involving IGF-I and IGF1R previously described for skeletal muscle hypertrophy. The potential regulating role of IGFBP5 on IGF-II expression is also discussed. This report shows for the first time a specific role for FGF6 in the regulation of myofibre size during a process of in vivo myogenesis

  1. The role of the IGF axis in IGFBP-1 and IGF-I induced renal enlargement in Snell dwarf mice

    NARCIS (Netherlands)

    M. van Kleffens (Marjolein); D.J. Lindenbergh-Kortleve (Dicky); J.G. Koster; J.W. van Neck (Han); A. Flyvbjerg (Allan); R. Rasch; S.L.S. Drop (Stenvert); S.C. van Buul-Offers

    2001-01-01

    textabstractInsulin-like growth factor (IGF) binding protein-1 (IGFBP-1) is generally believed to inhibit IGF action in the circulation. In contrast, IGFBP-1 has been reported to interact with cell surfaces and enhance IGF-I action locally in some tissues. Renal IGFBP-1 levels are

  2. Adipose Tissue-Derived Stem Cell Secreted IGF-1 Protects Myoblasts from the Negative Effect of Myostatin

    Directory of Open Access Journals (Sweden)

    Sebastian Gehmert

    2014-01-01

    Full Text Available Myostatin, a TGF-β family member, is associated with inhibition of muscle growth and differentiation and might interact with the IGF-1 signaling pathway. Since IGF-1 is secreted at a bioactive level by adipose tissue-derived mesenchymal stem cells (ASCs, these cells (ASCs provide a therapeutic option for Duchenne Muscular Dystrophy (DMD. But the protective effect of stem cell secreted IGF-1 on myoblast under high level of myostatin remains unclear. In the present study murine myoblasts were exposed to myostatin under presence of ASCs conditioned medium and investigated for proliferation and apoptosis. The protective effect of IGF-1 was further examined by using IGF-1 neutralizing and receptor antibodies as well as gene silencing RNAi technology. MyoD expression was detected to identify impact of IGF-1 on myoblasts differentiation when exposed to myostatin. IGF-1 was accountable for 43.6% of the antiapoptotic impact and 48.8% for the proliferative effect of ASCs conditioned medium. Furthermore, IGF-1 restored mRNA and protein MyoD expression of myoblasts under risk. Beside fusion and transdifferentiation the beneficial effect of ASCs is mediated by paracrine secreted cytokines, particularly IGF-1. The present study underlines the potential of ASCs as a therapeutic option for Duchenne muscular dystrophy and other dystrophic muscle diseases.

  3. Association between Insulin Like Growth Factor-1 (IGF-1) gene ...

    African Journals Online (AJOL)

    The insulin-like growth factor-1 (IGF1) is a key regulator of muscle development and metabolism in birds and other vertebrate. Our objective was to determine the association between IGF1 gene polymorphism and carcass traits in FUNAAB Alpha chicken. Genomic DNA was extracted from the blood of 50 normal feathered ...

  4. Receptors for insulin-like growth factor II (IGF-II) in the rat kidney glomerulus

    International Nuclear Information System (INIS)

    Haskell, J.F.; Pillion, D.J.; Meezan, E.

    1986-01-01

    Renal glomeruli were isolated by a technique involving renal perfusion with a solution containing magnetic iron oxide particles, followed by homogenization, sieving and isolation over a strong magnet. Isolated glomeruli were treated with 1% Triton X-100 to solubilize plasma membrane components while insoluble basement membrane components were removed by centrifugation. [ 125 I]Insulin-like growth factor-II (IGF-II) binding to this preparation was competitively inhibited by increasing amounts of unlabelled IGF-II, with 50% inhibition of binding observed at an IGF-II concentration of 1 ng/ml. [ 125 I]IGF-II was covalently cross-linked to its receptor with disuccinimidyl suberate in two tissues known to contain IGF-II receptors, the rat chondrosarcoma chondrocyte and the rat kidney tubule, as well as in rat renal glomeruli. In all three cases, a specific high-molecular weight (Mr = 255,000) band could be identified on autoradiograms of dodecyl sulfate polyacrylamide gels. These results indicate that the rat glomerulus contains a high-affinity receptor for IGF-II. This finding is consistent with the hypothesis that IGF-II plays a role in glomerular growth and differentiation

  5. Serum Levels Of Free And Total Insulin-Like Growth Factor (IGF)-1 And IGF Binding Protein-3 In Normal And Growth Hormone Deficient Children

    International Nuclear Information System (INIS)

    Shousha, M.A.; Soliman, S.E.T.; Hafez, M.H.

    2006-01-01

    Serum levels of total insulin-like growth factor-1 (IGF-1) and IGF-binding protein-3 (IGFBP-3) reflect the endogenous GH secretion in healthy children, which makes them good diagnostic markers for screening growth hormone deficiency (GHD) in short children, although some controversy still exists. Only a minor fraction of the total IGF-1 circulates in its free form, which is believed to be the biologically active form. Serum levels of free IGF-1, total IGF-I and IGFBP-3 were measured in 144 healthy children (72 boys and 72 girls, aged from 0 to 16 years) and in 12 pre-pubertal GH deficient (GHD) children to study the correlation between the age and free IGF-1, total IGF-1 and IGFBP-3 levels. In healthy subjects (both sexes), serum free IGF-1, total IGF-1 and IGFBP-3 levels were low in infancy, increasing during puberty and declining thereafter. Free IGF-1 in serum occupied about 0.97-1.45 % of the total IGF-1 values, and the ratios of free IGF-1 to total IGF-1 were significantly increased in the pubertal age groups than in the pre-pubertal age groups. Serum levels of free IGF-1 showed significant positive correlation with those of total IGF-I and IGFBP-3. Serum free IGF-1, total IGF-1 and IGFBP-3 levels in patients with GHD were decreased significantly with increasing the degree of hypopituitarism. These observations suggest that the increase in serum free IGF-1 level during puberty was caused by a dramatic increase in total IGF-1 rather than IGFBP-3. Also, high levels of these hormones may play an important role in pubertal growth spurt and may become a useful tool for diagnosing GHD and predicting growth response to long term GH therapy

  6. Serum levels of free and total insulin-link growth factor (IGF)-1 and (IGF) binding protein-3 in normal and growth hormone deficient children

    International Nuclear Information System (INIS)

    Shousha, M.A.; Soliman, S.E.T.; Hafez, H.M.

    2008-01-01

    Serum levels of total insulin-like growth factor- 1 (IGF-1) and IGF-binding protein-3 (IGFBP-3) reflect endogenous GH secretion in healthy children, which makes them good diagnostic markers for screening GH deficiency (GHD) in short children, although some controversy still exists. Only a minor fraction of the total IGF-1 circulates in its free form, which is believed to be the biologically active form. Serum levels of free IGF-1, total IGF-I and IGFBP-3 were measured in 144 healthy children (72 boys and 72 girls, aged from 0 to 16 years) and in 12 prepubertal GH. deficient (GHD) children to study correlation between the age and free IGF-1, total IGF-1 and IGFBP-3 levels. In healthy subjects (both sexes), serum free IGF-1, total IGF-1 and IGFBP-3 levels were low in infancy, increasing during puberty and declining thereafter. Free IGF-1 in serum occupied about 0.97. 1.45 % of the total IGF-1 values, and the ratios of free IGF-1 to total IGF-1 were significantly increased in the pubertal age groups than in the prepubertal age groups. Serum levels of free IGF-1 showed significant positive correlation with those of total IGF-I and IGFBP-3. Serum free IGF-1, total IGF-1 and IGFBP-3 levels in patients with GHD decreased significantly with increasing degree of hypopituitarism. These observations suggest that the increase in serum free IGF-1 level during puberty was caused by a dramatic increase in total IGF-1 rather than IGFBP-3. Also, high levels of these hormones may play an important role in pubertal growth spurt and may become a useful tool for diagnosing GHD and predicting growth response to long term GH therapy

  7. Inhibition of IGF-1 receptor kinase blocks the differentiation into cardiomyocyte-like cells of BMSCs induced by IGF-1.

    Science.gov (United States)

    Gong, Haibin; Wang, Xiuli; Wang, Lei; Liu, Ying; Wang, Jie; Lv, Qian; Pang, Hui; Zhang, Qinglin; Wang, Zhenquan

    2017-07-01

    Bone marrow mesenchymal stem cells (BMSCs) have the potential to transdifferentiate into cardiomyocyte‑like cells (CLCs) if an appropriate cardiac environment is provided. Insulin‑like growth factor‑1 (IGF‑1) plays an important role in the cell migration, survival and differentiation of BMSCs. However, the effect of IGF‑1 on the cellular differentiation remains unclear. In the present study, BMSCs were isolated from rat femurs and tibias and the cells were purified at passage 6 (P6). IGF‑1 and IGF‑1 receptor (IGF‑1R) kinase inhibitor I‑OMe AG538 were added to detect if IGF‑1 could induce BMSCs to transdifferentiate into CLCs and if I‑OMe AG538 could inhibit IGF‑1‑mediated receptor activation and downstream signaling. Immunostaining demonstrated that all P6 BMSCs express CD29 and CD44 but not CD45. BMSCs induced by 15 ng/ml IGF‑1 revealed positivity for cardiac troponin‑T and cardiac troponin‑I. The optimal induction time was 14 days but the expression of these proteins were incompletely inhibited by 300 nmol/l I‑OMe AG538 and completely inhibited by 10 µmol/l I‑OMe AG538. Western blotting showed that the level of IGF‑1R autophosphorylation and the expression of cTnT and cTnI were higher when BMSCs were induced for 14 days. I‑OMe AG538 selectively inhibited IGF‑1‑mediated growth and signal transduction and the inhibitory effect of I‑OMe AG538 were not reverted in the presence of exogenous IGF‑1. In addition, when a time course analysis of the effects of I‑OMe AG538 on mitogen‑activated protein kinase kinase and phosphatidylinositol 3‑kinase signaling were done, we observed a transient inhibitory effect on Erk1/2 and Akt phosphorylation, in keeping with the inhibitory effects on cell growth. Taken together, these data indicate that I‑OMe AG538 could inhibit IGF-1-induced CLCs in BMSCs and this effect is time- and concentration-dependent.

  8. A dynamic ribosomal biogenesis response is not required for IGF-1-mediated hypertrophy of human primary myotubes.

    Science.gov (United States)

    Crossland, Hannah; Timmons, James A; Atherton, Philip J

    2017-12-01

    Increased ribosomal DNA transcription has been proposed to limit muscle protein synthesis, making ribosome biogenesis central to skeletal muscle hypertrophy. We examined the relationship between ribosomal RNA (rRNA) production and IGF-1-mediated myotube hypertrophy in vitro Primary skeletal myotubes were treated with IGF-1 (50 ng/ml) with or without 0.5 µM CX-5461 (CX), an inhibitor of RNA polymerase I. Myotube diameter, total protein, and RNA and DNA levels were measured along with markers of RNA polymerase I regulatory factors and regulators of protein synthesis. CX treatment reduced 45S pre-rRNA expression (-64 ± 5% vs. IGF-1; P IGF-1; P IGF-1-treated myotubes. IGF-1-mediated increases in myotube diameter (1.27 ± 0.09-fold, P IGF-1 treatment did not prevent early increases in AKT (+203 ± 39% vs. CX; P IGF-1, myotube diameter and protein accretion were sustained. Thus, while ribosome biogenesis represents a potential site for the regulation of skeletal muscle protein synthesis and muscle mass, it does not appear to be a prerequisite for IGF-1-induced myotube hypertrophy in vitro. -Crossland, H., Timmons, J. A., Atherton, P. J. A dynamic ribosomal biogenesis response is not required for IGF-1-mediated hypertrophy of human primary myotubes. © The Author(s).

  9. The cAMP Response Element Binding protein (CREB) is activated by Insulin-like Growth Factor-1 (IGF-1) and regulates myostatin gene expression in skeletal myoblast

    International Nuclear Information System (INIS)

    Zuloaga, R.; Fuentes, E.N.; Molina, A.; Valdés, J.A.

    2013-01-01

    Highlights: •IGF-1 induces the activation of CREB via IGF-1R/PI3K/PLC signaling pathway. •Calcium dependent signaling pathways regulate myostatin gene expression. •IGF-1 regulates myostatin gene expression via CREB transcription in skeletal myoblast. -- Abstract: Myostatin, a member of the Transforming Growth Factor beta (TGF-β) superfamily, plays an important role as a negative regulator of skeletal muscle growth and differentiation. We have previously reported that IGF-1 induces a transient myostatin mRNA expression, through the activation of the Nuclear Factor of Activated T cells (NFAT) in an IP 3 /calcium-dependent manner. Here we examined the activation of CREB transcription factor as downstream targets of IGF-1 during myoblast differentiation and its role as a regulator of myostatin gene expression. In cultured skeletal myoblast, IGF-1 induced the phosphorylation and transcriptional activation of CREB via IGF-1 Receptor/Phosphatidylinositol 3-Kinase (PI3K)/Phospholipase C gamma (PLC γ), signaling pathways. Also, IGF-1 induced calcium-dependent molecules such as Calmodulin Kinase II (CaMK II), Extracellular signal-regulated Kinases (ERK), Protein Kinase C (PKC). Additionally, we examined myostatin mRNA levels and myostatin promoter activity in differentiated myoblasts stimulated with IGF-1. We found a significant increase in mRNA contents of myostatin and its reporter activity after treatment with IGF-1. The expression of myostatin in differentiated myoblast was downregulated by the transfection of siRNA–CREB and by pharmacological inhibitors of the signaling pathways involved in CREB activation. By using pharmacological and genetic approaches together these data demonstrate that IGF-1 regulates the myostatin gene expression via CREB transcription factor during muscle cell differentiation

  10. The cAMP Response Element Binding protein (CREB) is activated by Insulin-like Growth Factor-1 (IGF-1) and regulates myostatin gene expression in skeletal myoblast

    Energy Technology Data Exchange (ETDEWEB)

    Zuloaga, R. [Facultad de Ciencias Biológicas, Universidad Andres Bello, Santiago (Chile); Fuentes, E.N.; Molina, A. [Facultad de Ciencias Biológicas, Universidad Andres Bello, Santiago (Chile); Interdisciplinary Center for Aquaculture Research (INCAR), Víctor Lamas 1290, PO Box 160-C, Concepción (Chile); Valdés, J.A., E-mail: jvaldes@unab.cl [Facultad de Ciencias Biológicas, Universidad Andres Bello, Santiago (Chile); Interdisciplinary Center for Aquaculture Research (INCAR), Víctor Lamas 1290, PO Box 160-C, Concepción (Chile)

    2013-10-18

    Highlights: •IGF-1 induces the activation of CREB via IGF-1R/PI3K/PLC signaling pathway. •Calcium dependent signaling pathways regulate myostatin gene expression. •IGF-1 regulates myostatin gene expression via CREB transcription in skeletal myoblast. -- Abstract: Myostatin, a member of the Transforming Growth Factor beta (TGF-β) superfamily, plays an important role as a negative regulator of skeletal muscle growth and differentiation. We have previously reported that IGF-1 induces a transient myostatin mRNA expression, through the activation of the Nuclear Factor of Activated T cells (NFAT) in an IP{sub 3}/calcium-dependent manner. Here we examined the activation of CREB transcription factor as downstream targets of IGF-1 during myoblast differentiation and its role as a regulator of myostatin gene expression. In cultured skeletal myoblast, IGF-1 induced the phosphorylation and transcriptional activation of CREB via IGF-1 Receptor/Phosphatidylinositol 3-Kinase (PI3K)/Phospholipase C gamma (PLC γ), signaling pathways. Also, IGF-1 induced calcium-dependent molecules such as Calmodulin Kinase II (CaMK II), Extracellular signal-regulated Kinases (ERK), Protein Kinase C (PKC). Additionally, we examined myostatin mRNA levels and myostatin promoter activity in differentiated myoblasts stimulated with IGF-1. We found a significant increase in mRNA contents of myostatin and its reporter activity after treatment with IGF-1. The expression of myostatin in differentiated myoblast was downregulated by the transfection of siRNA–CREB and by pharmacological inhibitors of the signaling pathways involved in CREB activation. By using pharmacological and genetic approaches together these data demonstrate that IGF-1 regulates the myostatin gene expression via CREB transcription factor during muscle cell differentiation.

  11. Early IGF-1 primes visual cortex maturation and accelerates developmental switch between NKCC1 and KCC2 chloride transporters in enriched animals.

    Science.gov (United States)

    Baroncelli, Laura; Cenni, Maria Cristina; Melani, Riccardo; Deidda, Gabriele; Landi, Silvia; Narducci, Roberta; Cancedda, Laura; Maffei, Lamberto; Berardi, Nicoletta

    2017-02-01

    Environmental enrichment (EE) has a remarkable impact on brain development. Continuous exposure to EE from birth determines a significant acceleration of visual system maturation both at retinal and cortical levels. A pre-weaning enriched experience is sufficient to trigger the accelerated maturation of the visual system, suggesting that factors affected by EE during the first days of life might prime visual circuits towards a faster development. The search for such factors is crucial not only to gain a better understanding of the molecular hierarchy of brain development but also to identify molecular pathways amenable to be targeted to correct atypical brain developmental trajectories. Here, we showed that IGF-1 levels are increased in the visual cortex of EE rats as early as P6 and this is a crucial event for setting in motion the developmental program induced by EE. Early intracerebroventricular (i.c.v.) infusion of IGF-1 in standard rats was sufficient to mimic the action of EE on visual acuity development, whereas blocking IGF-1 signaling by i.c.v. injections of the IGF-1 receptor antagonist JB1 prevented the deployment of EE effects. Early IGF-1 decreased the ratio between the expression of NKCC1 and KCC2 cation/chloride transporters, and the reversal potential for GABA A R-driven Cl - currents (E Cl ) was shifted toward more negative potentials, indicating that IGF-1 is a crucial factor in accelerating the maturation of GABAergic neurotransmission and promoting the developmental switch of GABA polarity from excitation to inhibition. In addition, early IGF-1 promoted a later occurring increase in its own expression, suggesting a priming effect of early IGF-1 in driving post-weaning cortical maturation. Copyright © 2016 Elsevier Ltd. All rights reserved.

  12. c-kitpos GATA-4 high rat cardiac stem cells foster adult cardiomyocyte survival through IGF-1 paracrine signalling.

    Directory of Open Access Journals (Sweden)

    Nanako Kawaguchi

    2010-12-01

    Full Text Available Resident c-kit positive (c-kitpos cardiac stem cells (CSCs could be considered the most appropriate cell type for myocardial regeneration therapies. However, much is still unknown regarding their biological properties and potential.We produced clones of high and low expressing GATA-4 CSCs from long-term bulk-cultured c-kitpos CSCs isolated from adult rat hearts. When c-kitpos GATA-4 high expressing clonal CSCs (cCSCs were co-cultured with adult rat ventricular cardiomyocytes, we observed increased survival and contractility of the cardiomyocytes, compared to cardiomyocytes cultured alone, co-cultured with fibroblasts or c-kitpos GATA-4 low expressing cCSCs. When analysed by ELISA, the concentration of IGF-1 was significantly increased in the c-kitpos GATA-4 high cCSC/cardiomyocyte co-cultures and there was a significant correlation between IGF-1 concentration and cardiomyocyte survival. We showed the activation of the IGF-1 receptor and its downstream molecular targets in cardiomyocytes co-cultured with c-kitpos GATA-4 high cCSCs but not in cardiomyocytes that were cultured alone, co-cultured with fibroblasts or c-kitpos GATA-4 low cCSCs. Addition of a blocking antibody specific to the IGF-1 receptor inhibited the survival of cardiomyocytes and prevented the activation of its signalling in cardiomyocytes in the c-kitpos GATA-4 high cCSC/cardiomyocyte co-culture system. IGF-1 supplementation or IGF-1 high conditioned medium taken from the co-culture of c-kitpos GATA-4 high cCSCs plus cardiomyocytes did extend the survival and contractility of cardiomyocytes cultured alone and cardiomyocytes co-cultured with c-kitpos GATA-4 low cCSCs.c-kitpos GATA-4 high cCSCs exert a paracrine survival effect on cardiomyocytes through induction of the IGF-1R and signalling pathway.

  13. Circulating levels of IGF-1 directly regulate bone growth and density

    Science.gov (United States)

    Yakar, Shoshana; Rosen, Clifford J.; Beamer, Wesley G.; Ackert-Bicknell, Cheryl L.; Wu, Yiping; Liu, Jun-Li; Ooi, Guck T.; Setser, Jennifer; Frystyk, Jan; Boisclair, Yves R.; LeRoith, Derek

    2002-01-01

    IGF-1 is a growth-promoting polypeptide that is essential for normal growth and development. In serum, the majority of the IGFs exist in a 150-kDa complex including the IGF molecule, IGF binding protein 3 (IGFBP-3), and the acid labile subunit (ALS). This complex prolongs the half-life of serum IGFs and facilitates their endocrine actions. Liver IGF-1–deficient (LID) mice and ALS knockout (ALSKO) mice exhibited relatively normal growth and development, despite having 75% and 65% reductions in serum IGF-1 levels, respectively. Double gene disrupted mice were generated by crossing LID+ALSKO mice. These mice exhibited further reductions in serum IGF-1 levels and a significant reduction in linear growth. The proximal growth plates of the tibiae of LID+ALSKO mice were smaller in total height as well as in the height of the proliferative and hypertrophic zones of chondrocytes. There was also a 10% decrease in bone mineral density and a greater than 35% decrease in periosteal circumference and cortical thickness in these mice. IGF-1 treatment for 4 weeks restored the total height of the proximal growth plate of the tibia. Thus, the double gene disruption LID+ALSKO mouse model demonstrates that a threshold concentration of circulating IGF-1 is necessary for normal bone growth and suggests that IGF-1, IGFBP-3, and ALS play a prominent role in the pathophysiology of osteoporosis. PMID:12235108

  14. The association between peripheral total IGF-1, IGFBP-3, and IGF-1/IGFBP-3 and functional and cognitive outcomes in the Mayo Clinic Study of Aging.

    Science.gov (United States)

    Wennberg, Alexandra M V; Hagen, Clinton E; Machulda, Mary M; Hollman, John H; Roberts, Rosebud O; Knopman, David S; Petersen, Ronald C; Mielke, Michelle M

    2018-06-01

    Levels of insulin-like growth factor (IGF)-1, IGF-binding protein (IGFBP)-3, and their ratio in the blood may be useful for monitoring those at risk of cognitive and functional decline. However, the association between IGF measures and functional and cognitive outcomes has been mixed, and the associations may vary by sex. The present study investigated the cross-sectional, sex-specific associations between serum measures total IGF-1, IGFBP-3, and the IGF-1/IGFBP-3 ratio, gait speed, and cognition in 1320 cognitively unimpaired participants aged 50-95 years enrolled in the Mayo Clinic Study of Aging. We used multivariable linear regression models to determine the association between IGF measures and gait speed or cognitive test performance by sex. IGF measures were not associated with cognitive or functional performance among men. Among women, higher levels of log total IGF-1 and IGFBP-3 were associated with better performance in attention, visuospatial, and global cognitive domains, independent of the gait speed. These findings suggest that among women, IGF measures are associated with cognition, and these associations are independent of function. Copyright © 2018 Elsevier Inc. All rights reserved.

  15. Estimated Prestroke Peak VO2 Is Related to Circulating IGF-1 Levels During Acute Stroke.

    Science.gov (United States)

    Mattlage, Anna E; Rippee, Michael A; Abraham, Michael G; Sandt, Janice; Billinger, Sandra A

    2017-01-01

    Background Insulin-like growth factor-1 (IGF-1) is neuroprotective after stroke and is regulated by insulin-like binding protein-3 (IGFBP-3). In healthy individuals, exercise and improved aerobic fitness (peak oxygen uptake; peak VO 2 ) increases IGF-1 in circulation. Understanding the relationship between estimated prestroke aerobic fitness and IGF-1 and IGFBP-3 after stroke may provide insight into the benefits of exercise and aerobic fitness on stroke recovery. Objective The purpose of this study was to determine the relationship of IGF-1 and IGFBP-3 to estimated prestroke peak VO 2 in individuals with acute stroke. We hypothesized that (1) estimated prestroke peak VO 2 would be related to IGF-1 and IGFBP-3 and (2) individuals with higher than median IGF-1 levels will have higher estimated prestroke peak VO 2 compared to those with lower than median levels. Methods Fifteen individuals with acute stroke had blood sampled within 72 hours of hospital admission. Prestroke peak VO 2 was estimated using a nonexercise prediction equation. IGF-1 and IGFBP-3 levels were quantified using enzyme-linked immunoassay. Results Estimated prestroke peak VO 2 was significantly related to circulating IGF-1 levels (r = .60; P = .02) but not IGFBP-3. Individuals with higher than median IGF-1 (117.9 ng/mL) had significantly better estimated aerobic fitness (32.4 ± 6.9 mL kg -1 min -1 ) than those with lower than median IGF-1 (20.7 ± 7.8 mL kg -1 min -1 ; P = .03). Conclusions Improving aerobic fitness prior to stroke may be beneficial by increasing baseline IGF-1 levels. These results set the groundwork for future clinical trials to determine whether high IGF-1 and aerobic fitness are beneficial to stroke recovery by providing neuroprotection and improving function. © The Author(s) 2016.

  16. miR-130b-3p Modulates Epithelial-Mesenchymal Crosstalk in Lung Fibrosis by Targeting IGF-1.

    Science.gov (United States)

    Li, Shuhong; Geng, Jing; Xu, Xuefeng; Huang, Xiaoxi; Leng, Dong; Jiang, Dingyuan; Liang, Jiurong; Wang, Chen; Jiang, Dianhua; Dai, Huaping

    2016-01-01

    Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and usually lethal fibrotic lung disease with largely unknown etiology and pathogenesis. Evidence suggests microRNAs (miRNA) contribute to pathogenesis of IPF. In this study, we sought to identify miRNA expression signatures and determine the role of miR-130b-3p in lung fibrosis. The miRNA expression profile of the lungs from patients with IPF and normal donors was determined by Affymetrix microarray, and transcriptome with Affymetrix array. The functions and signal pathways as well as miRNA-mRNA networks were established by bioinformatics analysis. Luciferase assays and ELISA were used to confirm the miRNA target gene. The effect of miRNA-transfected epithelium on fibroblast activities was assessed using a co-culture system. The fibroblast activities were determined by qRT-PCR, western blotting, Transwell and BrdU assays. Seven miRNAs were significantly decreased in IPF lungs, with miR-130b-3p being the highest in the miRNA-mRNA network. Insulin-like growth factor (IGF-1) was a target gene of miR-130b-3p in the epithelium. miR-130b-3p inhibition in the epithelium induced collagen I expression and enhanced the proliferation and migration ability of fibroblast in co-culture systems, which mimicked the functions of exogenous IGF-1 on fibroblasts. Neutralizing IGF-1 with an antibody significantly reduced the modulatory effects of miR-130b-3p inhibitor-transfected epithelium on the activation of fibroblasts. Our results show that miR-130b-3p was downregulated in IPF lungs. miR-130b-3p downregulation contributed to the activation of fibroblasts and the dysregulated epithelial-mesenchymal crosstalk by promoting IGF-1 secretion from lung epithelium, suggesting a key regulatory role for this miRNA in preventing lung fibrosis.

  17. IGF-1 protects cardiac myocytes from hyperosmotic stress-induced apoptosis via CREB

    International Nuclear Information System (INIS)

    Maldonado, Carola; Cea, Paola; Adasme, Tatiana; Collao, Andres; Diaz-Araya, Guillermo; Chiong, Mario; Lavandero, Sergio

    2005-01-01

    Hyperosmotic stress stimulates a rapid and pronounced apoptosis in cardiac myocytes which is attenuated by insulin-like growth factor-1 (IGF-1). Because in these cells IGF-1 induces intracellular Ca 2+ increase, we assessed whether the cyclic AMP response element-binding protein (CREB) is activated by IGF-1 through Ca 2+ -dependent signalling pathways. In cultured cardiac myocytes, IGF-1 induced phosphorylation (6.5 ± 1.0-fold at 5 min), nuclear translocation (30 min post-stimulus) and DNA binding activity of CREB. IGF-1-induced CREB phosphorylation was mediated by MEK1/ERK, PI3-K, p38-MAPK, as well as Ca 2+ /calmodulin kinase and calcineurin. Exposure of cardiac myocytes to hyperosmotic stress (sorbitol 600 mOsm) decreased IGF-1-induced CREB activation Moreover, overexpression of a dominant negative CREB abolished the anti-apoptotic effects of IGF-1. Our results suggest that IGF-1 activates CREB through a complex signalling pathway, and this transcription factor plays an important role in the anti-apoptotic action of IGF-1 in cultured cardiac myocytes

  18. Exercise and obesity in fibromyalgia: beneficial roles of IGF-1 and resistin?

    Science.gov (United States)

    Bjersing, Jan L; Erlandsson, Malin; Bokarewa, Maria I; Mannerkorpi, Kaisa

    2013-02-27

    Severe fatigue is a major health problem in fibromyalgia (FM). Obesity is common in FM, but the influence of adipokines and growth factors is not clear. The aim was to examine effects of exercise on fatigue, in lean, overweight and obese FM patients. In a longitudinal study, 48 FM patients (median 52 years) exercised for 15 weeks. Nine patients were lean (body mass index, BMI 18.5 to 24.9), 26 overweight (BMI 25 to 29.9) and 13 obese. Fatigue was rated on a 0 to 100 mm scale (fibromyalgia impact questionnaire [FIQ] fatigue) and multidimensional fatigue inventory (MFI-20) general fatigue (MFIGF). Higher levels in FIQ fatigue and MFIGF indicate greater degree of fatigue. Free and total IGF-1, neuropeptides, adipokines were determined in serum and cerebrospinal fluid (CSF). Baseline FIQ fatigue correlated negatively with serum leptin (r=-0.345; P=0.016) and nerve growth factor (NGF; r=-0.412; P=0.037). In lean patients, baseline MFIGF associated negatively with serum resistin (r=-0.694; P=0.038). FIQ Fatigue associated negatively with CSF resistin (r=-0.365; P=0.073). Similarly, FIQ fatigue (r=-0.444; P=0.026) and MFIGF correlated negatively with CSF adiponectin (r=-0.508; P=0.01). In lean patients, FIQ fatigue (P=0.046) decreased after 15 weeks. After 30 weeks, MFIGF decreased significantly in lean (MFIGF: P=0.017), overweight (MFIGF: P=0.001), and obese patients (MFIGF: P=0.016). After 15 weeks, total IGF-1 increased in lean (P=0.043) patients. ∆Total IGF-1 differed significantly between lean and obese patients (P=0.010). ∆Total IGF-1 related negatively with ∆MFIGF after 15 weeks (r=-0.329; P=0.050). After 30 weeks, ∆FIQ fatigue negatively correlated with ∆NGF (r=-0.463; P=0.034) and positively with ∆neuropeptide Y (NPY) (r=0.469; P=0.032). Resistin increased after 30 weeks (P=0.034). ∆MFIGF correlated negatively with ∆resistin (r=-0.346; P=0.031), being strongest in obese patients (r=-0.815; P=0.007). In obese patients, ∆FIQ fatigue after 30 weeks

  19. Identification of thioredoxin-interacting protein (TXNIP) as a downstream target for IGF1 action.

    Science.gov (United States)

    Nagaraj, Karthik; Lapkina-Gendler, Lena; Sarfstein, Rive; Gurwitz, David; Pasmanik-Chor, Metsada; Laron, Zvi; Yakar, Shoshana; Werner, Haim

    2018-01-30

    Laron syndrome (LS), or primary growth hormone (GH) insensitivity, is the best-characterized entity among the congenital insulin-like growth factor 1 (IGF1) deficiencies. Life-long exposure to minute endogenous IGF1 levels is linked to low stature as well as a number of endocrine and metabolic abnormalities. While elevated IGF1 is correlated with increased cancer incidence, epidemiological studies revealed that patients with LS do not develop tumors. The mechanisms associated with cancer protection in LS are yet to be discovered. Recent genomic analyses identified a series of metabolic genes that are overrepresented in patients with LS. Given the augmented expression of these genes in a low IGF1 milieu, we hypothesized that they may constitute targets for IGF1 action. Thioredoxin-interacting protein (TXNIP) plays a critical role in cellular redox control by thioredoxin. TXNIP serves as a glucose and oxidative stress sensor, being commonly silenced by genetic or epigenetic events in cancer cells. Consistent with its enhanced expression in LS, we provide evidence that TXNIP gene expression is negatively regulated by IGF1. These results were corroborated in animal studies. In addition, we show that oxidative and glucose stresses led to marked increases in TXNIP expression. Supplementation of IGF1 attenuated TXNIP levels, suggesting that IGF1 exerts its antiapoptotic effect via inhibition of TXNIP Augmented TXNIP expression in LS may account for cancer protection in this condition. Finally, TXNIP levels could be potentially useful in the clinic as a predictive or diagnostic biomarker for IGF1R-targeted therapies.

  20. Binding of IGF I and IGF I-stimulated phosphorylation in canine renal basolateral membranes

    International Nuclear Information System (INIS)

    Hammerman, M.R.; Gavin, J.R. III.

    1986-01-01

    To characterize the interaction of the renal proximal tubular cell with insulin like growth factor I (IGF I), we measured binding of 125 I-IGF I to proximal tubular basolateral membranes from dog kidney and induced IGF I-stimulated phosphorylation of basolateral membranes. Specific binding of 125 I-IGF I to basolateral membranes was observed that was half-maximal at between 10(-9) and 10(-8) M IGF I. 125 I-IGF I was affinity cross-linked to a 135,000 Mr protein in basolateral membranes that was distinct from the alpha-subunit of the insulin receptor and from the IGF II receptor. IGF I-stimulated phosphorylation of a 92,000 Mr protein was effected in detergent-solubilized membranes incubated with 100 microM [gamma- 32 P]ATP. The 32 P-labeled protein was distinct from the beta-subunit of the insulin receptor, the 32 P phosphorylation of which was stimulated by insulin. We conclude that specific receptors for IGF I are present in the basolateral membrane of the renal proximal tubular cell. Physiological actions of IGF I at this nephron site may occur through the binding of this peptide circulating in plasma, to specific basolateral membrane receptors, followed by IGF I stimulated phosphorylation

  1. Effect of i.p. insulin administration onIGF1 and IGFBP1 in type1 diabetes

    NARCIS (Netherlands)

    van Dijk, P R; Logtenberg, S J J; Groenier, K H; Kleefstra, N; Bilo, H J G; Arnqvist, H J

    2014-01-01

    In type 1 diabetes mellitus (T1DM), low concentrations of IGF1 and high concentrations of IGF-binding protein 1 (IGFBP1) have been reported. It has been suggested that these abnormalities in the GH-IGF1 axis are due to low insulin concentrations in the portal vein. We hypothesized that the i.p.

  2. Native and Complexed IGF-1: Biodistribution and Pharmacokinetics in Infantile Neuronal Ceroid Lipofuscinosis

    Directory of Open Access Journals (Sweden)

    Tuulia Huhtala

    2012-01-01

    Full Text Available Infantile neuronal ceroid lipofuscinosis (INCL is a severe neurodegenerative disorder of childhood characterized by selective death of cortical neurons. Insulin-like growth factor 1 (IGF-1 is important in embryonic development and is considered as a potential therapeutic agent for several disorders of peripheral and central nervous systems. In circulation IGF-1 is mainly bound to its carrier protein IGFBP-3. As a therapeutic agent IGF-1 has shown to be more active as free than complexed form. However, this may cause side effects during the prolonged treatment. In addition to IGFBP-3 the bioavailability of IGF-1 can be modulated by using mesoporous silicon nanoparticles (NPs which are optimal carriers for sustained release of unstable peptide hormones like IGF-1. In this study we compared biodistribution, pharmacokinetics, and bioavailability of radiolabeled free IGF-1, IGF-1/IGFBP-3, and IGF-1/NP complexes in a Cln1-/- knockout mouse model. IGF-1/NP was mainly accumulated in liver and spleen in all studied time points, whereas minor and more constant amounts were measured in other organs compared to free IGF-1 or IGF-1/IGFBP-3. Also concentration of IGF-1/NP in blood was relatively high and stable during studied time points suggesting continuous release of IGF-1 from the particles.

  3. Serum insulin-like growth factor-1 (IGF-1) during CF pulmonary exacerbation: trends and biomarker correlations.

    Science.gov (United States)

    Gifford, A H; Nymon, A B; Ashare, A

    2014-04-01

    Cystic fibrosis (CF) is characterized by low circulating levels of insulin-like growth factor-1 (IGF-1), a hormone produced by the liver that governs anabolism and influences immune cell function. Because treatment of CF pulmonary exacerbation (CFPE) often improves body weight and lung function, we questioned whether serum IGF-1 trends were emblematic of these responses. Initially, we compared serum levels between healthy adults with CF and controls of similar age. We then measured serum IGF-1 throughout the CFPE cycle. We also investigated correlations among IGF-1 and other serum biomarkers during CFPE. Anthopometric, spirometric, and demographic data were collected. Serum IGF-1 concentrations were measured by ELISA. CF subjects in their usual state of health had lower serum IGF-1 levels than controls. Serum IGF-1 concentrations fell significantly from baseline at the beginning of CFPE. Treatment with intravenous antibiotics was associated with significant improvement in serum IGF-1 levels, body mass index (BMI), and percent-predicted forced expiratory volume in 1 sec (FEV1 %). At early and late CFPE, serum IGF-1 was directly correlated with FEV1 %, serum iron, hemoglobin concentration, and transferrin saturation (TSAT) and indirectly correlated with alpha-1-antitrypsin. This study not only supports the paradigm that CF is characterized by IGF-1 deficiency but also that trends in lung function, nutritional status, and serum IGF-1 are related. Improvements in all three parameters after antibiotics for CFPE likely highlight the connection between lung function and nutritional status in CF. Close correlations among IGF-1 and iron-related hematologic parameters suggest that IGF-1 may participate in CF iron homeostasis, another process that is known to be influenced by CFPE. © 2013 Wiley Periodicals, Inc.

  4. IGF-1R Promotes Symmetric Self-Renewal and Migration of Alkaline Phosphatase+ Germ Stem Cells through HIF-2α-OCT4/CXCR4 Loop under Hypoxia.

    Science.gov (United States)

    Kuo, Yung-Che; Au, Heng-Kien; Hsu, Jue-Liang; Wang, Hsiao-Feng; Lee, Chiung-Ju; Peng, Syue-Wei; Lai, Ssu-Chuan; Wu, Yu-Chih; Ho, Hong-Nerng; Huang, Yen-Hua

    2018-02-13

    Hypoxia cooperates with endocrine signaling to maintain the symmetric self-renewal proliferation and migration of embryonic germline stem cells (GSCs). However, the lack of an appropriate in vitro cell model has dramatically hindered the understanding of the mechanism underlying this cooperation. Here, using a serum-free system, we demonstrated that hypoxia significantly induced the GSC mesenchymal transition, increased the expression levels of the pluripotent transcription factor OCT4 and migration-associated proteins (SDF-1, CXCR4, IGF-1, and IGF-1R), and activated the cellular expression and translocalization of the CXCR4-downstream proteins ARP3/pFAK. The underlying mechanism involved significant IGF-1/IGF-1R activation of OCT4/CXCR4 expression through HIF-2α regulation. Picropodophyllin-induced inhibition of IGF-1R phosphorylation significantly suppressed hypoxia-induced SDF-1/CXCR4 expression and cell migration. Furthermore, transactivation between IGF-1R and CXCR4 was involved. In summary, we demonstrated that niche hypoxia synergistically cooperates with its associated IGF-1R signaling to regulate the symmetric division (self-renewal proliferation) and cell migration of alkaline phosphatase-positive GSCs through HIF-2α-OCT4/CXCR4 during embryogenesis. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  5. Insulin/IGF-driven cancer cell-stroma crosstalk as a novel therapeutic target in pancreatic cancer.

    Science.gov (United States)

    Mutgan, Ayse Ceren; Besikcioglu, H Erdinc; Wang, Shenghan; Friess, Helmut; Ceyhan, Güralp O; Demir, Ihsan Ekin

    2018-02-23

    Pancreatic ductal adenocarcinoma (PDAC) is unrivalled the deadliest gastrointestinal cancer in the western world. There is substantial evidence implying that insulin and insulin-like growth factor (IGF) signaling axis prompt PDAC into an advanced stage by enhancing tumor growth, metastasis and by driving therapy resistance. Numerous efforts have been made to block Insulin/IGF signaling pathway in cancer therapy. However, therapies that target the IGF1 receptor (IGF-1R) and IGF subtypes (IGF-1 and IGF-2) have been repeatedly unsuccessful. This failure may not only be due to the complexity and homology that is shared by Insulin and IGF receptors, but also due to the complex stroma-cancer interactions in the pancreas. Shedding light on the interactions between the endocrine/exocrine pancreas and the stroma in PDAC is likely to steer us toward the development of novel treatments. In this review, we highlight the stroma-derived IGF signaling and IGF-binding proteins as potential novel therapeutic targets in PDAC.

  6. Changes of Cerebral and/or Peripheral Adenosine A₁ Receptor and IGF-I Concentrations under Extended Sleep Duration in Rats.

    Science.gov (United States)

    Chennaoui, Mounir; Arnal, Pierrick J; Dorey, Rodolphe; Sauvet, Fabien; Ciret, Sylvain; Gallopin, Thierry; Leger, Damien; Drogou, Catherine; Gomez-Merino, Danielle

    2017-11-17

    Extended sleep improves sustained attention and reduces sleep pressure in humans. Downregulation of adenosine A₁ receptor (A₁R) and modulation of the neurotrophic factor insulin growth factor-1 (IGF-I) in brain structures controlling attentional capacities could be involved. In the frontal cortex and hippocampus of rats, we measured adenosine A₁R and IGF-I protein concentrations after photoperiod-induced sleep extension. Two groups of twelve rats were adapted over 14 days to a habitual (CON) 12:12 light-dark (LD) schedule and an extended (EXT) 16:8 LD schedule. IGF-I content was also measured in plasma, liver, and skeletal muscle. In EXT, compared to CON rats, A₁R content in the frontal cortex was significantly lower ( p IGF-I content was higher ( p IGF-I content in plasma and muscle was higher ( p IGF-I levels. This photoperiod induced an anabolic profile with increased weight gain and circulating and muscular IGF-I levels. An extension of sleep duration might favor cerebral and peripheral anabolism, which may help attentional and physical capacities.

  7. Clinical and functional characterization of a patient carrying a compound heterozygous pericentrin mutation and a heterozygous IGF1 receptor mutation.

    Directory of Open Access Journals (Sweden)

    Eva Müller

    Full Text Available Intrauterine and postnatal longitudinal growth is controlled by a strong genetic component that regulates a complex network of endocrine factors integrating them with cellular proliferation, differentiation and apoptotic processes in target tissues, particularly the growth centers of the long bones. Here we report on a patient born small for gestational age (SGA with severe, proportionate postnatal growth retardation, discreet signs of skeletal dysplasia, microcephaly and moyamoya disease. Initial genetic evaluation revealed a novel heterozygous IGF1R p.Leu1361Arg mutation affecting a highly conserved residue with the insulin-like growth factor type 1 receptor suggestive for a disturbance within the somatotropic axis. However, because the mutation did not co-segregate with the phenotype and functional characterization did not reveal an obvious impairment of the ligand depending major IGF1R signaling capabilities a second-site mutation was assumed. Mutational screening of components of the somatotropic axis, constituents of the IGF signaling system and factors involved in cellular proliferation, which are described or suggested to provoke syndromic dwarfism phenotypes, was performed. Two compound heterozygous PCNT mutations (p.[Arg585X];[Glu1774X] were identified leading to the specification of the diagnosis to MOPD II. These investigations underline the need for careful assessment of all available information to derive a firm diagnosis from a sequence aberration.

  8. Clinical and functional characterization of a patient carrying a compound heterozygous pericentrin mutation and a heterozygous IGF1 receptor mutation.

    Science.gov (United States)

    Müller, Eva; Dunstheimer, Desiree; Klammt, Jürgen; Friebe, Daniela; Kiess, Wieland; Kratzsch, Jürgen; Kruis, Tassilo; Laue, Sandy; Pfäffle, Roland; Wallborn, Tillmann; Heidemann, Peter H

    2012-01-01

    Intrauterine and postnatal longitudinal growth is controlled by a strong genetic component that regulates a complex network of endocrine factors integrating them with cellular proliferation, differentiation and apoptotic processes in target tissues, particularly the growth centers of the long bones. Here we report on a patient born small for gestational age (SGA) with severe, proportionate postnatal growth retardation, discreet signs of skeletal dysplasia, microcephaly and moyamoya disease. Initial genetic evaluation revealed a novel heterozygous IGF1R p.Leu1361Arg mutation affecting a highly conserved residue with the insulin-like growth factor type 1 receptor suggestive for a disturbance within the somatotropic axis. However, because the mutation did not co-segregate with the phenotype and functional characterization did not reveal an obvious impairment of the ligand depending major IGF1R signaling capabilities a second-site mutation was assumed. Mutational screening of components of the somatotropic axis, constituents of the IGF signaling system and factors involved in cellular proliferation, which are described or suggested to provoke syndromic dwarfism phenotypes, was performed. Two compound heterozygous PCNT mutations (p.[Arg585X];[Glu1774X]) were identified leading to the specification of the diagnosis to MOPD II. These investigations underline the need for careful assessment of all available information to derive a firm diagnosis from a sequence aberration.

  9. Changes in circulating level of IGF-I and IGF-binding protein-1 from the first to second trimester as predictors of preeclampsia

    DEFF Research Database (Denmark)

    Vatten, Lars J; Nilsen, Tom I L; Juul, Anders

    2008-01-01

    To assess whether circulating IGF-I and IGF-binding protein-1 (IGFBP-1) in the first and second trimester are associated with subsequent risk of preterm and term preeclampsia.......To assess whether circulating IGF-I and IGF-binding protein-1 (IGFBP-1) in the first and second trimester are associated with subsequent risk of preterm and term preeclampsia....

  10. IGF-1 promotes the development and cytotoxic activity of human NK cells

    OpenAIRE

    Ni, Fang; Sun, Rui; Fu, Binqing; Wang, Fuyan; Guo, Chuang; Tian, Zhigang; Wei, Haiming

    2013-01-01

    Insulin-like growth factor 1 (IGF-1) is a critical regulator of many physiological functions, ranging from longevity to immunity. However, little is known about the role of IGF-1 in natural killer cell development and function. Here, we identify an essential role for IGF-1 in the positive regulation of human natural killer cell development and cytotoxicity. Specifically, we show that human natural killer cells have the ability to produce IGF-1 and that differential endogenous IGF-1 expression...

  11. IGF-1R/MDM2 relationship confers enhanced sensitivity to RITA in Ewing sarcoma cells.

    Science.gov (United States)

    Di Conza, Giusy; Buttarelli, Marianna; Monti, Olimpia; Pellegrino, Marsha; Mancini, Francesca; Pontecorvi, Alfredo; Scotlandi, Katia; Moretti, Fabiola

    2012-06-01

    Ewing sarcoma is one of the most frequent bone cancers in adolescence. Although multidisciplinary therapy has improved the survival rate for localized tumors, a critical step is the development of new drugs to improve the long-term outcome of recurrent and metastatic disease and to reduce side effects of conventional therapy. Here, we show that the small molecule reactivation of p53 and induction of tumor cell apoptosis (RITA, NSC652287) is highly effective in reducing growth and tumorigenic potential of Ewing sarcoma cell lines. These effects occur both in the presence of wt-p53 as well as of mutant or truncated forms of p53, or in its absence, suggesting the presence of additional targets in this tumor histotype. Further experiments provided evidence that RITA modulates an important oncogenic mark of these cell lines, insulin-like growth factor receptor 1 (IGF-1R). Particularly, RITA causes downregulation of IGF-1R protein levels. MDM2 degradative activity is involved in this phenomenon. Indeed, inhibition of MDM2 function by genetic or pharmacologic approaches reduces RITA sensitivity of Ewing sarcoma cell lines. Overall, these data suggest that in the cell context of Ewing sarcoma, RITA may adopt additional mechanism of action besides targeting p53, expanding its field of application. Noteworthy, these results envisage the promising utilization of RITA or its derivative as a potential treatment for Ewing sarcomas. ©2012 AACR

  12. Differences in IGF-axis protein expression and survival among multiethnic breast cancer patients

    International Nuclear Information System (INIS)

    Hernandez, Brenda Y; Wilkens, Lynne R; Le Marchand, Loïc; Horio, David; Chong, Clayton D; Loo, Lenora W M

    2015-01-01

    There is limited knowledge about the biological basis of racial/ethnic disparities in breast cancer outcomes. Aberrations in IGF signaling induced by obesity and other factors may contribute to these disparities. This study examines the expression profiles of the insulin-like growth factor (IGF)-axis proteins and the association with breast cancer survival across a multiethnic population. We examined the expression profiles of the IGF1, IGF1R, IGFBP2 (IGF-binding proteins), and IGFBP3 proteins in breast tumor tissue and their relationships with all-cause and breast cancer-specific survival up to 17 years postdiagnosis in a multiethnic series of 358 patients in Hawaii, USA. Native Hawaiians, Caucasians, and Japanese were compared. Covariates included demographic and clinical factors and ER/PR/HER2 (estrogen receptor/progesterone receptor/human epidermal growth factor receptor-2) status. In Native Hawaiian patients, IGFBP2 and IGFBP3 expression were each independently associated with overall and breast cancer mortality (IGFB2: HR mort = 10.96, 95% CI: 2.18–55.19 and HR mort = 35.75, 95% CI: 3.64–350.95, respectively; IGFBP3: HR mort = 5.16, 95% CI: 1.27–20.94 and HR mort = 8.60, 95% CI: 1.84–40.15, respectively). IGF1R expression was also positively associated with all-cause mortality in Native Hawaiians. No association of IGF-axis protein expression and survival was observed in Japanese or Caucasian patients. The interaction of race/ethnicity and IGFBP3 expression on mortality risk was significant. IGF-axis proteins may have variable influence on breast cancer progression across different racial/ethnic groups. Expression of binding proteins and receptors in breast tumors may influence survival in breast cancer patients by inducing aberrations in IGF signaling and/or through IGF-independent mechanisms. Additional studies to evaluate the role of the IGF-axis in breast cancer are critical to improve targeted breast cancer treatment strategies

  13. Insulin and insulin-like growth factor-I (IGF-I) receptor phosphorylation in µ-calpain knockout mice

    Science.gov (United States)

    Numerous cellular processes are controlled by insulin and IGF-I signaling pathways. Due to previous work in our laboratories, we hypothesized that insulin (IR) and type 1 IGF-I (IGF-IR) receptor signaling is decreased due to increased protein tyrosine phosphatase 1B (PTP1B) activity. C57BL/6J mice...

  14. Expanding the clinical spectrum of chromosome 15q26 terminal deletions associated with IGF-1 resistance.

    Science.gov (United States)

    O'Riordan, Aisling M; McGrath, Niamh; Sharif, Farhana; Murphy, Nuala P; Franklin, Orla; Lynch, Sally Ann; O'Grady, Michael J

    2017-01-01

    Haploinsufficiency of the insulin-like growth factor-1 receptor (IGF1R) gene on chromosome 15q26.3 is associated with impaired prenatal and postnatal growth, developmental delay, dysmorphic features and skeletal abnormalities. Terminal deletions of chromosome 15q26 arising more proximally may also be associated with congenital heart disease, epilepsy, diaphragmatic hernia and renal anomalies. We report three additional cases of 15q26 terminal deletions with novel features which may further expand the spectrum of this rarely reported contiguous gene syndrome. Phenotypic features including neonatal lymphedema, aplasia cutis congenita and aortic root dilatation have not been reported previously. Similarly, laboratory features of insulin-like growth factor 1 (IGF-1) resistance are described, including markedly elevated IGF-1 of up to +4.7 SDS. In one patient, the elevated IGF-1 declined over time and this coincided with a period of spontaneous growth acceleration. Deletions of 15q26 are a potential risk factor for aortic root dilatation, neonatal lymphedema and aplasia cutis in addition to causing growth restriction. What is Known: • Terminal deletions of chromosome 15q26 are associated with impaired prenatal and postnatal growth, developmental delay, dysmorphic features and skeletal abnormalities. What is New: • Neonatal lymphedema, aplasia cutis congenita and aortic root dilatation have not been previously described in 15q26 terminal deletions and may represent novel features. • IGF-1 levels may be increased up to 4.7 SDS.

  15. Dietary protein-induced hepatic IGF-1 secretion mediated by PPARγ activation.

    Science.gov (United States)

    Wan, Xiaojuan; Wang, Songbo; Xu, Jingren; Zhuang, Lu; Xing, Kongping; Zhang, Mengyuan; Zhu, Xiaotong; Wang, Lina; Gao, Ping; Xi, Qianyun; Sun, Jiajie; Zhang, Yongliang; Li, Tiejun; Shu, Gang; Jiang, Qingyan

    2017-01-01

    Dietary protein or amino acid (AA) is a crucial nutritional factor to regulate hepatic insulin-like growth factor-1 (IGF-1) expression and secretion. However, the underlying intracellular mechanism by which dietary protein or AA induces IGF-1 expression remains unknown. We compared the IGF-1 gene expression and plasma IGF-1 level of pigs fed with normal crude protein (CP, 20%) and low-protein levels (LP, 14%). RNA sequencing (RNA-seq) was performed to detect transcript expression in the liver in response to dietary protein. The results showed that serum concentrations and mRNA levels of IGF-1 in the liver were higher in the CP group than in the LP group. RNA-seq analysis identified a total of 1319 differentially expressed transcripts (667 upregulated and 652 downregulated), among which the terms "oxidative phosphorylation", "ribosome", "gap junction", "PPAR signaling pathway", and "focal adhesion" were enriched. In addition, the porcine primary hepatocyte and HepG2 cell models also demonstrated that the mRNA and protein levels of IGF-1 and PPARγ increased with the increasing AA concentration in the culture. The PPARγ activator troglitazone increased IGF-1 gene expression and secretion in a dose dependent manner. Furthermore, inhibition of PPARγ effectively reversed the effects of the high AA concentration on the mRNA expression of IGF-1 and IGFBP-1 in HepG2 cells. Moreover, the protein levels of IGF-1 and PPARγ, as well as the phosphorylation of mTOR, significantly increased in HepG2 cells under high AA concentrations. mTOR phosphorylation can be decreased by the mTOR antagonist, rapamycin. The immunoprecipitation results also showed that high AA concentrations significantly increased the interaction of mTOR and PPARγ. In summary, PPARγ plays an important role in the regulation of IGF-1 secretion and gene expression in response to dietary protein.

  16. Circadian clocks govern calorie restriction-mediated life span extension through BMAL1- and IGF-1-dependent mechanisms.

    Science.gov (United States)

    Patel, Sonal A; Chaudhari, Amol; Gupta, Richa; Velingkaar, Nikkhil; Kondratov, Roman V

    2016-04-01

    Calorie restriction (CR) increases longevity in many species by unknown mechanisms. The circadian clock was proposed as a potential mediator of CR. Deficiency of the core component of the circadian clock-transcriptional factor BMAL1 (brain and muscle ARNT [aryl hydrocarbon receptor nuclear translocator]-like protein 1)-results in accelerated aging. Here we investigated the role of BMAL1 in mechanisms of CR. The 30% CR diet increased the life span of wild-type (WT) mice by 20% compared to mice on anad libitum(AL) diet but failed to increase life span ofBmal1(-/-)mice. BMAL1 deficiency impaired CR-mediated changes in the plasma levels of IGF-1 and insulin. We detected a statistically significantly reduction of IGF-1 in CRvs.AL by 50 to 70% in WT mice at several daily time points tested, while inBmal1(-/-)the reduction was not significant. Insulin levels in WT were reduced by 5 to 9%, whileBmal1(-/-)induced it by 10 to 35% at all time points tested. CR up-regulated the daily average expression ofBmal1(by 150%) and its downstream target genesPeriods(by 470% forPer1and by 130% forPer2). We propose that BMAL1 is an important mediator of CR, and activation of BMAL1 might link CR mechanisms with biologic clocks.-Patel, S. A., Chaudhari, A., Gupta, R., Velingkaar, N., Kondratov, R. V. Circadian clocks govern calorie restriction-mediated life span extension through BMAL1- and IGF-1-dependent mechanisms. © FASEB.

  17. Sustained IGF-1 Secretion by Adipose-Derived Stem Cells Improves Infarcted Heart Function.

    Science.gov (United States)

    Bagno, Luiza L; Carvalho, Deivid; Mesquita, Fernanda; Louzada, Ruy A; Andrade, Bruno; Kasai-Brunswick, Taís H; Lago, Vivian M; Suhet, Grazielle; Cipitelli, Debora; Werneck-de-Castro, João Pedro; Campos-de-Carvalho, Antonio C

    2016-01-01

    The mechanism by which stem cell-based therapy improves heart function is still unknown, but paracrine mechanisms seem to be involved. Adipose-derived stem cells (ADSCs) secrete several factors, including insulin-like growth factor-1 (IGF-1), which may contribute to myocardial regeneration. Our aim was to investigate whether the overexpression of IGF-1 in ADSCs (IGF-1-ADSCs) improves treatment of chronically infarcted rat hearts. ADSCs were transduced with a lentiviral vector to induce IGF-1 overexpression. IGF-1-ADSCs transcribe100- to 200-fold more IGF-1 mRNA levels compared to nontransduced ADSCs. IGF-1 transduction did not alter ADSC immunophenotypic characteristics even under hypoxic conditions. However, IGF-1-ADSCs proliferate at higher rates and release greater amounts of growth factors such as IGF-1, vascular endothelial growth factor (VEGF), and hepatocyte growth factor (HGF) under normoxic and hypoxic conditions. Importantly, IGF-1 secreted by IGF-1-ADSCs is functional given that Akt-1 phosphorylation was remarkably induced in neonatal cardiomyocytes cocultured with IGF-1-ADSCs, and this increase was prevented with phosphatidylinositol 3-kinase (PI3K) inhibitor treatment. Next, we tested IGF-1-ADSCs in a rat myocardial infarction (MI) model. MI was performed by coronary ligation, and 4 weeks after MI, animals received intramyocardial injections of either ADSCs (n = 7), IGF-1-ADSCs (n = 7), or vehicle (n = 7) into the infarcted border zone. Left ventricular function was evaluated by echocardiography before and after 6 weeks of treatment, and left ventricular hemodynamics were assessed 7 weeks after cell injection. Notably, IGF-1-ADSCs improved left ventricular ejection fraction and cardiac contractility index, but did not reduce scar size when compared to the ADSC-treated group. In summary, transplantation of ADSCs transduced with IGF-1 is a superior therapeutic approach to treat MI compared to nontransduced ADSCs, suggesting that gene and cell

  18. Insulin, IGF-1, and GH Receptors Are Altered in an Adipose Tissue Depot-Specific Manner in Male Mice With Modified GH Action.

    Science.gov (United States)

    Hjortebjerg, Rikke; Berryman, Darlene E; Comisford, Ross; Frank, Stuart J; List, Edward O; Bjerre, Mette; Frystyk, Jan; Kopchick, John J

    2017-05-01

    Growth hormone (GH) is a determinant of glucose homeostasis and adipose tissue (AT) function. Using 7-month-old transgenic mice expressing the bovine growth hormone (bGH) gene and growth hormone receptor knockout (GHR-/-) mice, we examined whether changes in GH action affect glucose, insulin, and pyruvate tolerance and AT expression of proteins involved in the interrelated signaling pathways of GH, insulinlike growth factor 1 (IGF-1), and insulin. Furthermore, we searched for AT depot-specific differences in control mice. Glycated hemoglobin levels were reduced in bGH and GHR-/- mice, and bGH mice displayed impaired gluconeogenesis as judged by pyruvate tolerance testing. Serum IGF-1 was elevated by 90% in bGH mice, whereas IGF-1 and insulin were reduced by 97% and 61% in GHR-/- mice, respectively. Igf1 RNA was increased in subcutaneous, epididymal, retroperitoneal, and brown adipose tissue (BAT) depots in bGH mice (mean increase ± standard error of the mean in all five depots, 153% ± 27%) and decreased in all depots in GHR-/- mice (mean decrease, 62% ± 4%). IGF-1 receptor expression was decreased in all AT depots of bGH mice (mean decrease, 49% ± 6%) and increased in all AT depots of GHR-/- mice (mean increase, 94% ± 8%). Insulin receptor expression was reduced in retroperitoneal, mesenteric, and BAT depots in bGH mice (mean decrease in all depots, 56% ± 4%) and augmented in subcutaneous, retroperitoneal, mesenteric, and BAT depots in GHR-/- mice (mean increase: 51% ± 1%). Collectively, our findings indicate a role for GH in influencing hormone signaling in AT in a depot-dependent manner. Copyright © 2017 Endocrine Society.

  19. IDH1R132H Promotes Malignant Transformation of Benign Prostatic Epithelium by Dysregulating MicroRNAs: Involvement of IGF1R-AKT/STAT3 Signaling Pathway

    Directory of Open Access Journals (Sweden)

    Lili Zhang

    2018-02-01

    Full Text Available Risk stratification using molecular features could potentially help distinguish indolent from aggressive prostate cancer (PCa. Mutations in isocitrate dehydrogenase (IDH acquire an abnormal enzymatic activity, resulting in the production of 2-hydroxyglutarate and alterations in cellular metabolism, histone modification, and DNA methylation. Mutant IDH1 has been identified in various human malignancies, and IDH1R132H constituted the vast majority of mutational events of IDH1. Most recent studies suggested that IDH1 mutations define a methylator subtype in PCa. However, the function of IDH1R132H in PCa development and progression is largely unknown. In this study, we showed that the prevalence of IDH1R132H in Chinese PCa patients is 0.6% (2/336. Of note, IDH1R132H-mutant PCa patients lacked other canonical genomic lesions (e.g., ERG rearrangement, PTEN deletion that are common in most other PCa patients. The in vitro experiment suggested that IDH1R132H can promote proliferation of benign prostate epithelial cell RWPE-1 when under the situation of low cytokine. It could also promote migration capacity of RWPE-1 cells. Mechanistically, IDH1R132H was an important regulator of insulin-like growth factor 1receptor (IGF1R by downregulating a set of microRNAs (miR-141-3p, miR-7-5p, miR-223-3p. These microRNAs were repressed by the alteration of epigenetic modification to decrease the enrichment of active marker H3K4me3 or to increase repressive marker H3K27me3 at their promoters. Collectively, we proposed a novel model for an IDH1R132H-microRNAs-IGF1R regulatory axis, which might provide insight into the function of IDH1R132H in PCa development.

  20. Plasma IGF-1 and IGFBP-3 may be imprecise surrogates for breast concentrations: an analysis of healthy women

    Science.gov (United States)

    Llanos, Adana A.; Brasky, Theodore M.; Dumitrescu, Ramona G.; Marian, Catalin; Makambi, Kepher H.; Kallakury, Bhaskar V. S.; Spear, Scott L.; Perry, David J.; Convit, Rafael J.; Platek, Mary E.; Adams-Campbell, Lucile L.; Freudenheim, Jo L.; Shields, Peter G.

    2013-01-01

    We investigated insulin-like growth factor (IGF)-1 and IGF binding protein (IGFBP)-3 concentrations in histologically normal breast tissues and assessed their association with plasma concentrations, and breast cancer risk factors. IGF-1 and IGFBP-3 were assessed in plasma and breast tissues of 90 women with no history of any cancer and undergoing reduction mammoplasty. Pearson correlations and ANOVAs were used to describe plasma-breast associations and biomarker differences by breast cancer risk factors, respectively. Multivariable regression models were used to determine associations between risk factors, and breast IGF-1 and IGFBP-3. The mean age of the study sample was 37.3 years, 58 % were white, and generally these women were obese (mean BMI = 30.8 kg/m2). We observed no plasma-breast correlation for IGF-1, IGFBP-3, or IGF-1/IGFBP-3 (r = −0.08, r = 0.14, and r = 0.03, respectively; p-values >0.05). Through age- and BMI-adjusted analysis, BMI and years of oral contraceptive (OC) use were inversely associated with breast IGF-1 (p-values = 0.02 and 0.003, respectively) and age was associated with breast IGFBP-3 (p = 0.01), while breast IGF-1/IGFBP-3 was higher in blacks than whites (1.08 vs. 0.68, p = 0.04) and associated with age and BMI (p-values = 0.03 and 0.002, respectively). In multivariable-adjusted models, some breast cancer risk factors studied herein explained 24, 10, and 15 % of the variation in breast IGF-1, IGFBP-3, and IGF-1/IGFBP-3, respectively. While reasons for the lack of plasma-breast hormone correlations in these cancer-free women are unknown, several factors were shown to be associated with breast concentrations. The lack of correlation between blood and tissue IGF-1 and IGFBP-3 suggests that studies of breast cancer risk assessing blood IGF-1 and IGFBP-3 may have important limitations in understanding their role in breast carcinogenesis. PMID:23456194

  1. Up-Regulation of MicroRNA-190b Plays a Role for Decreased IGF-1 That Induces Insulin Resistance in Human Hepatocellular Carcinoma

    Science.gov (United States)

    Hung, Tzu-Min; Ho, Cheng-Maw; Liu, Yen-Chun; Lee, Jia-Ling; Liao, Yow-Rong; Wu, Yao-Ming; Ho, Ming-Chih; Chen, Chien-Hung; Lai, Hong-Shiee; Lee, Po-Huang

    2014-01-01

    Background & Aims Insulin-like growth factor, (IGF)-1, is produced mainly by the liver and plays important roles in promoting growth and regulating metabolism. Previous study reported that development of hepatocellular carcinoma (HCC) was accompanied by a significant reduction in serum IGF-1 levels. Here, we hypothesized that dysregulation of microRNAs (miRNA) in HCC can modulate IGF-1 expression post-transcriptionally. Methods The miRNAs expression profiles in a dataset of 29 HCC patients were examined using illumina BeadArray. Specific miRNA (miR)-190b, which was significantly up-regulated in HCC tumor tissues when compared with paired non-tumor tissues, was among those predicted to interact with 3′-untranslated region (UTR) of IGF-1. In order to explore the regulatory effects of miR-190b on IGF-1 expression, luciferase reporter assay, quantitative real-time PCR, western blotting and immunofluorecence analysis were performed in HCC cells. Results Overexpression of miR-190b in Huh7 cells attenuated the expression of IGF-1, whereas inhibition of miR-190b resulted in up-regulation of IGF-1. Restoration of IGF-1 expression reversed miR-190b-mediated impaired insulin signaling in Huh7 cells, supporting that IGF-1 was a direct and functional target of miR-190b. Additionally, low serum IGF-1 level was associated with insulin resistance and poor overall survival in HCC patients. Conclusions Increased expression of miR-190 may cause decreased IGF-1 in HCC development. Insulin resistance appears to be a part of the physiopathologic significance of decreased IGF-1 levels in HCC progression. This study provides a novel miRNA-mediated regulatory mechanism for controlling IGF-1 expression in HCC and elucidates the biological relevance of this interaction in HCC. PMID:24586785

  2. Role of androgen receptor on cyclic mechanical stretch-regulated proliferation of C2C12 myoblasts and its upstream signals: IGF-1-mediated PI3K/Akt and MAPKs pathways.

    Science.gov (United States)

    Ma, Yiming; Fu, Shaoting; Lu, Lin; Wang, Xiaohui

    2017-07-15

    To detect the effects of androgen receptor (AR) on cyclic mechanical stretch-modulated proliferation of C2C12 myoblasts and its pathways: roles of IGF-1, PI3K and MAPK. C2C12 were randomly divided into five groups: un-stretched control, six or 8 h of fifteen percent stretch, and six or 8 h of twenty percent stretch. Cyclic mechanical stretch of C2C12 were completed using a computer-controlled FlexCell Strain Unit. Cell proliferation and IGF-1 concentration in medium were detected by CCK8 and ELISA, respectively. Expressions of AR and IGF-1R, and expressions and activities of PI3K, p38 and ERK1/2 in stretched C2C12 cells were determined by Western blot. ①The proliferation of C2C12 cells, IGF-1 concentration in medium, expressions of AR and IGF-1R, and activities of PI3K, p38 and ERK1/2 were increased by 6 h of fifteen percent stretch, while decreased by twenty percent stretch for six or 8 h ②The fifteen percent stretch-increased proliferation of C2C12 cells was reversed by AR inhibitor, Flutamide. ③The increases of AR expression, activities of PI3K, p38 and ERK1/2 resulted from fifteen percent stretch were attenuated by IGF-1 neutralizing antibody, while twenty percent stretch-induced decreases of the above indicators were enhanced by recombinant IGF-1. ④Specific inhibitors of p38, ERK1/2 and PI3K all decreased the expression of AR in fifteen percent and twenty percent of stretched C2C12 cells. Cyclic mechanical stretch modulated the proliferation of C2C12 cells, which may be attributed to the alterations of AR via IGF-1-PI3K/Akt and IGF-1-MAPK (p38, ERK1/2) pathways in C2C12 cells. Copyright © 2017 Elsevier B.V. All rights reserved.

  3. The Role of Type I Insulin Like Growth Factor Receptor (IGF-IR) in Adult and Childhood Acute Lymphoblastic Leukemia

    International Nuclear Information System (INIS)

    KAMEL, M.M.; HAMMAM, A.A.; ELHOSEINY, Sh.M.; MOKHLES, A.; MOHSEN, E.

    2008-01-01

    Background: Type 1 insulin like growth factor receptor (IGF-IR) is over expressed in many tumors including hematological cancers. It is a critical signaling molecule for tumor cell proliferation and survival. Data suggest that IGF-IR antibodies can effectively and specifically inhibit cancer cell growth in vitro and in vivo. Blockage of IGF-IR expression could be a promising therapeutic approach for the management of cancer patients. Aim of Work: To characterize the expression pattern of IGF-IR gene in malignant lymphoblasts of children and adults suffering from ALL in relation to clinical features at diagnosis. Patients and Methods: The expression of IGF-IR was analyzed in 60 patients with ALL, 30 childhood ALL (16 newly diagnosed and 14 in complete remission) and 30 adulthood ALL (15 newly diagnosed and 15 in complete remission) together with 20 normal age and sex matched healthy controls using a Real-Time Quantitative Reverse- Transcriptase Polymerase Chain Reaction (RTQ-PCR) to assess the possible relation, association or correlation between IGF-IR expression and ALL clinical and laboratory features at diagnosis. Results: IGF-IR was expressed in all 60 patients with ALL; the expression levels of IGF-IR were significantly higher in newly diagnosed patients than in patients in complete remission (CR) and controls (p<0.001). There were no statistically significant differences in the expression of IGF-IR between patients with different clinical and laboratory features. Conclusion: IGF-1R seems to play a crucial role in patients with ALL since it is expressed in all ALL cases (adulthood and childhood). Therefore, new therapeutic agents targeting IGF-1R may provide a better chance for those patients

  4. Curcumin inhibits urothelial tumor development by suppressing IGF2 and IGF2-mediated PI3K/AKT/mTOR signaling pathway.

    Science.gov (United States)

    Tian, Binqiang; Zhao, Yingmei; Liang, Tao; Ye, Xuxiao; Li, Zuowei; Yan, Dongliang; Fu, Qiang; Li, Yonghui

    2017-08-01

    We have previously reported that curcumin inhibits urothelial tumor development in a rat bladder carcinogenesis model. In this study, we report that curcumin inhibits urothelial tumor development by suppressing IGF2 and IGF2-mediated PI3K/AKT/mTOR signaling pathway. Curcumin inhibits IGF2 expression at the transcriptional level and decreases the phosphorylation levels of IGF1R and IRS-1 in bladder cancer cells and N-methyl-N-nitrosourea (MNU)-induced urothelial tumor tissue. Ectopic expression of IGF2 and IGF1R, but not IGF1, in bladder cancer cells restored this process, suggesting that IGF2 is a target of curcumin. Moreover, introduction of constitutively active AKT1 abolished the inhibitory effect of curcumin on cell proliferation, migration, and restored the phosphorylation levels of 4E-BP1 and S6K1, suggesting that curcumin functions via suppressing IGF2-mediated AKT/mTOR signaling pathway. In summary, our results reveal that suppressing IGF2 and IGF2-mediated PI3K/AKT/mTOR signaling pathway is one of the mechanisms of action of curcumin. Our findings suggest a new therapeutic strategy against human bladder cancer caused by aberrant activation of IGF2, which are useful for translational application of curcumin.

  5. Insulin-like growth factor (IGF) binding protein from human decidua inhibits the binding and biological action of IGF-I in cultured choriocarcinoma cells

    International Nuclear Information System (INIS)

    Ritvos, O.; Ranta, T.; Jalkanen, J.; Suikkari, A.M.; Voutilainen, R.; Bohn, H.; Rutanen, E.M.

    1988-01-01

    The placenta expresses genes for insulin-like growth factors (IGFs) and possesses IGF-receptors, suggesting that placental growth is regulated by IGFs in an autocrine manner. We have previously shown that human decidua, but not placenta, synthesizes and secretes a 34 K IGF-binding protein (34 K IGF-BP) called placental protein 12. We now used human choriocarcinoma JEG-3 cell monolayer cultures and recombinant (Thr59)IGF-I as a model to study whether the decidual 34 K IGF-BP is able to modulate the receptor binding and biological activity of IGFs in trophoblasts. JEG-3 cells, which possess type I IGF receptors, were unable to produce IGF-BPs. Purified 34 K IGF-BP specifically bound [125I]iodo-(Thr59)IGF-I. Multiplication-stimulating activity had 2.5% the potency of (Thr59)IGF-I, and insulin had no effect on the binding of [125I] iodo-(Thr59)IGF-I. 34 K IGF-BP inhibited the binding of [125I] iodo-(Thr59)IGF-I to JEG-3 monolayers in a concentration-dependent manner by forming with the tracer a soluble complex that could not bind to the cell surface as demonstrated by competitive binding and cross-linking experiments. After incubating the cell monolayers with [125I]iodo-(Thr59)IGF-I in the presence of purified binding protein, followed by cross-linking, no affinity labeled bands were seen on autoradiography. In contrast, an intensely labeled band at 40 K was detected when the incubation medium was analyzed, suggesting that (Thr59)IGF-I and 34 K IGF-BP formed a complex in a 1:1 molar ratio. Also, 34 K IGF-BP inhibited both basal and IGF-I-stimulated uptake of alpha-[3H]aminoisobutyric acid in JEG-3 cells. RNA analysis revealed that IGF-II is expressed in JEG-3 cells

  6. HFpEF and HFrEF Display Different Phenotypes as Assessed by IGF-1 and IGFBP-1.

    Science.gov (United States)

    Faxén, Ulrika Ljung; Hage, Camilla; Benson, Lina; Zabarovskaja, Stanislava; Andreasson, Anna; Donal, Erwan; Daubert, Jean-Claude; Linde, Cecilia; Brismar, Kerstin; Lund, Lars H

    2017-04-01

    Anabolic drive is impaired in heart failure with reduced ejection fraction (HFrEF) but insufficiently studied in heart failure with preserved ejection fraction (HFpEF). Insulin-like growth factor 1 (IGF-1) mediates growth hormone effects and IGF binding protein 1 (IGFBP-1) regulates IGF-1 activity. We tested the hypothesis that HFpEF and HFrEF are similar with regard to IGF-1 and IGFBP-1. In patients with HFpEF (n = 79), HFrEF (n = 85), and controls (n = 136), we analyzed serum IGF-1 and IGFBP-1 concentrations, correlations, and associations with outcome. Age-standardized scores of IGF-1 were higher in HFpEF, median arbitrary units (interquartile range); 1.21 (0.57-1.96) vs HFrEF, 0.09 (-1.40-1.62), and controls, 0.22 (-0.47-0.96), P overall IGF-1 was associated with outcomes in HFrEF, hazard ratio per natural logarithmic increase in IGF-1 SD score 0.51 (95% confidence interval 0.32-0.82, P = .005), but not significantly in HFpEF. IGFBP-1 was not associated with outcomes in either HFpEF nor HFrEF. HFpEF and HFrEF phenotypes were similar with regard to increased IGFBP-1 concentrations but differed regarding IGF-1 levels and prognostic role. HFrEF and HFpEF may display different impairment in anabolic drive. Copyright © 2016 Elsevier Inc. All rights reserved.

  7. Regulation of human trophoblast GLUT1 glucose transporter by insulin-like growth factor I (IGF-I.

    Directory of Open Access Journals (Sweden)

    Marc U Baumann

    Full Text Available Glucose transport to the fetus across the placenta takes place via glucose transporters in the opposing faces of the barrier layer, the microvillous and basal membranes of the syncytiotrophoblast. While basal membrane content of the GLUT1 glucose transporter appears to be the rate-limiting step in transplacental transport, the factors regulating transporter expression and activity are largely unknown. In view of the many studies showing an association between IGF-I and fetal growth, we investigated the effects of IGF-I on placental glucose transport and GLUT1 transporter expression. Treatment of BeWo choriocarcinoma cells with IGF-I increased cellular GLUT1 protein. There was increased basolateral (but not microvillous uptake of glucose and increased transepithelial transport of glucose across the BeWo monolayer. Primary syncytial cells treated with IGF-I also demonstrated an increase in GLUT1 protein. Term placental explants treated with IGF-I showed an increase in syncytial basal membrane GLUT1 but microvillous membrane GLUT1 was not affected. The placental dual perfusion model was used to assess the effects of fetally perfused IGF-I on transplacental glucose transport and syncytial GLUT1 content. In control perfusions there was a decrease in transplacental glucose transport over the course of the perfusion, whereas in tissues perfused with IGF-I through the fetal circulation there was no change. Syncytial basal membranes from IGF-I perfused tissues showed an increase in GLUT1 content. These results demonstrate that IGF-I, whether acting via microvillous or basal membrane receptors, increases the basal membrane content of GLUT1 and up-regulates basal membrane transport of glucose, leading to increased transepithelial glucose transport. These observations provide a partial explanation for the mechanism by which IGF-I controls nutrient supply in the regulation of fetal growth.

  8. IGF-1 colocalizes with muscle satellite cells following acute exercise in humans.

    Science.gov (United States)

    Grubb, Amanda; Joanisse, Sophie; Moore, Daniel R; Bellamy, Leeann M; Mitchell, Cameron J; Phillips, Stuart M; Parise, Gianni

    2014-04-01

    Insulin-like growth factor-1 (IGF-1) regulates stem cell proliferation and differentiation in vitro. The aim of this study was to quantify the change in satellite cell (SC) specific IGF-1 colocalization following exercise. We observed a significant increase (p IGF-1 colocalization from baseline to 72 h after a bout of resistance exercise. This strongly supports a role for IGF-1 in human SC function following exercise.

  9. Role of RBP2-Induced ER and IGF1R-ErbB Signaling in Tamoxifen Resistance in Breast Cancer.

    Science.gov (United States)

    Choi, Hee-Joo; Joo, Hyeong-Seok; Won, Hee-Young; Min, Kyueng-Whan; Kim, Hyung-Yong; Son, Taekwon; Oh, Young-Ha; Lee, Jeong-Yeon; Kong, Gu

    2018-04-01

    Despite the benefit of endocrine therapy, acquired resistance during or after treatment still remains a major challenge in estrogen receptor (ER)-positive breast cancer. We investigated the potential role of histone demethylase retinoblastoma-binding protein 2 (RBP2) in endocrine therapy resistance of breast cancer. Survival of breast cancer patients according to RBP2 expression was analyzed in three different breast cancer cohorts including METABRIC (n = 1980) and KM plotter (n = 1764). RBP2-mediated tamoxifen resistance was confirmed by invitro sulforhodamine B (SRB) colorimetric, colony-forming assays, and invivo xenograft models (n = 8 per group). RNA-seq analysis and receptor tyrosine kinase assay were performed to identify the tamoxifen resistance mechanism by RBP2. All statistical tests were two-sided. RBP2 was associated with poor prognosis to tamoxifen therapy in ER-positive breast cancer (P = .04 in HYU cohort, P = .02 in KM plotter, P = .007 in METABRIC, log-rank test). Furthermore, RBP2 expression was elevated in patients with tamoxifen-resistant breast cancer (P = .04, chi-square test). Knockdown of RBP2 conferred tamoxifen sensitivity, whereas overexpression of RBP2 induced tamoxifen resistance invitro and invivo (MCF7 xenograft: tamoxifen-treated control, mean [SD] tumor volume = 70.8 [27.9] mm3, vs tamoxifen-treated RBP2, mean [SD] tumor volume = 387.9 [85.1] mm3, P < .001). Mechanistically, RBP2 cooperated with ER co-activators and corepressors and regulated several tamoxifen resistance-associated genes, including NRIP1, CCND1, and IGFBP4 and IGFBP5. Furthermore, epigenetic silencing of IGFBP4/5 by RBP2-ER-NRIP1-HDAC1 complex led to insulin-like growth factor-1 receptor (IGF1R) activation. RBP2 also increased IGF1R-ErbB crosstalk and subsequent PI3K-AKT activation via demethylase activity-independent ErbB protein stabilization. Combinational treatment with tamoxifen and PI3K inhibitor could overcome RBP2-mediated tamoxifen

  10. [Association between IGF system and PAPP-A in coronary atherosclerosis].

    Science.gov (United States)

    Fierro-Macías, Alfonso Eduardo; Floriano-Sánchez, Esaú; Mena-Burciaga, Victoria Michelle; Gutiérrez-Leonard, Hugo; Lara-Padilla, Eleazar; Abarca-Rojano, Edgar; Fierro-Almanzán, Alfonso Edmundo

    2016-01-01

    Atherosclerosis is a condition that involves multiple pathophysiological mechanisms and whose knowledge has not been fully elucidated. Often, scientific advances on the atherogenic pathophysiology generate that molecules not previously considered in the scene of this disease, were attributed actions on the onset or progression of it. A representative example is the study of a new mechanism involved in the atherogenic process, consisting of the association between the insulin-like growth factor (IGF) system and pregnancy-associated plasma protein-A (PAPP-A). Insulin-like growth factor system is a family of peptides that include 3 peptide hormones, 4 transmembrane receptors and 6 binding proteins. Insulin-like growth factor-1 (IGF-1) is the main ligand of the IGF system involved in coronary atherosclerosis. IGF-1 exerts its effects via activation of the IGF-1R receptor on vascular smooth muscle cells or macrophages. In vascular smooth muscle cells promotes migration and prevents apoptosis which increases plaque stability while in macrophages reduces reverse cholesterol transport leading to the formation of foam cells. Regulation of IGF-1 endothelial bioavailability is carried out by IGFBP proteases, mainly by PAPP-A. In this review, we address the mechanisms between IGF system and PAPP-A in atherosclerosis with emphasis on molecular effects on vascular smooth muscle cells and macrophages. Copyright © 2016 Instituto Nacional de Cardiología Ignacio Chávez. Published by Masson Doyma México S.A. All rights reserved.

  11. IGF-1: an endogenous link between traumatic brain injury and Alzheimer disease?

    Science.gov (United States)

    Zheng, Ping; Tong, Wusong

    2017-08-01

    There is a growing body of evidence that the insulin-like growth factor-1 (IGF-1) is dynamically involved in the regulation of body homeostasis and glucose regulation. Traumatic brain injury (TBI) is considered to be a risk factor for Alzheimer's disease (AD). As alterations of IGF-1 have been implicated in both TBI and AD and the IGF-1 signaling also mediates the neuronal excitability and synaptic plasticity in both diseases, we propose that IGF-1 may act as the endogenous connection between TBI and AD. Growing evidence suggests that dysfunction of this pathway contributes to the progressive loss of neurons in Alzheimer's disease (AD), one of the most frequent neurodegenerative disorders. These findings have led to numerous studies in preclinical models of neurodegenerative disorders targeting IGF-1 signaling with currently available antidiabetics. These studies have shown that exogenous administration of IGF-1 reverses signaling abnormalities and has neuroprotective effects. In the first part of this review, we discuss physiological functions of IGF-1 signaling pathway including its distribution within the brain and its relationship with TBI and AD. In the second part, we undertake a comprehensive overview of IGF-1 signaling in TBI and AD, respectively. We then detail targeted IGF-1 in preclinical models of neurodegeneration and the design of clinical trials that have used anti-diabetics for treating AD patients. We close with future considerations that treat relevant issues for successful translation of these encouraging preclinical results into clinical sessions.

  12. β-Catenin/POU5F1/SOX2 transcription factor complex mediates IGF-I receptor signaling and predicts poor prognosis in lung adenocarcinoma.

    Science.gov (United States)

    Xu, Chuan; Xie, Dan; Yu, Shi-Cang; Yang, Xiao-Jun; He, Li-Ru; Yang, Jing; Ping, Yi-Fang; Wang, Bin; Yang, Lang; Xu, Sen-Lin; Cui, Wei; Wang, Qing-Liang; Fu, Wen-Juan; Liu, Qing; Qian, Cheng; Cui, You-Hong; Rich, Jeremy N; Kung, Hsiang-Fu; Zhang, Xia; Bian, Xiu-Wu

    2013-05-15

    Cancer stem-like cells (CSLC) are crucial in tumor initiation and progression; however, the underlying mechanism for the self-renewal of cancer cells remains undefined. In the study, immunohistochemical analysis of specimens freshly excised from patients with lung adenocarcinoma showed that high expression of insulin-like growth factor I receptor (IGF-IR) in lung adenocarcinoma cells was positively correlated with the expressions of cancer stem cell markers CD133 and aldehyde dehydrogenase 1 family member A1 (ALDH1A1). IGF-IR activation enhanced POU class 5 homeobox 1 (POU5F1) expression on human lung adenocarcinoma stem-like cells (LACSLC) through PI3K/AKT/GSK3β/β-catenin cascade. POU5F1 could form a novel complex with β-catenin and SOX2 to bind Nanog promoter for transcription to maintain self-renewal of LACSLCs, which was dependent on the functional IGF-IR. Genetic and pharmacologic inhibition of IGF-IR abrogated LACSLC capabilities for self-renewal and tumorigenicity in vitro. In an in vivo xenograft tumor model, knockdown of either IGF-IR or POU5F1 impeded tumorigenic potentials of LACSLCs. By analyzing pathologic specimens excised from 200 patients with lung adenocarcinoma, we found that colocalization of highly expressed IGF-IR with β-catenin and POU5F1 predicted poor prognosis. Taken together, we show that IGF-IR-mediated POU5F1 expression to form a complex with β-catenin and SOX2 is crucial for the self-renewal and oncogenic potentials of LACSLCs, and the integrative clinical detection of the expressions of IGF-IR, β-catenin, and POU5F1 is indicatory for predicting prognosis in the patients of lung adenocarcinoma. ©2013 AACR.

  13. IGF1 stimulates greater muscle hypertrophy in the absence of myostatin in male mice.

    Science.gov (United States)

    Hennebry, Alexander; Oldham, Jenny; Shavlakadze, Tea; Grounds, Miranda D; Sheard, Philip; Fiorotto, Marta L; Falconer, Shelley; Smith, Heather K; Berry, Carole; Jeanplong, Ferenc; Bracegirdle, Jeremy; Matthews, Kenneth; Nicholas, Gina; Senna-Salerno, Mônica; Watson, Trevor; McMahon, Christopher D

    2017-08-01

    Insulin-like growth factors (IGFs) and myostatin have opposing roles in regulating the growth and size of skeletal muscle, with IGF1 stimulating, and myostatin inhibiting, growth. However, it remains unclear whether these proteins have mutually dependent, or independent, roles. To clarify this issue, we crossed myostatin null ( Mstn -/- ) mice with mice overexpressing Igf1 in skeletal muscle ( Igf1 + ) to generate six genotypes of male mice; wild type ( Mstn +/+ ), Mstn +/- , Mstn -/- , Mstn +/+ :Igf1 + , Mstn +/- :Igf1 + and Mstn -/- :Igf1 + Overexpression of Igf1 increased the mass of mixed fibre type muscles (e.g. Quadriceps femoris ) by 19% over Mstn +/+ , 33% over Mstn +/- and 49% over Mstn -/- ( P  Myostatin regulated the number, while IGF1 regulated the size of myofibres, and the deletion of Mstn and Igf1 + independently increased the proportion of fast type IIB myosin heavy chain isoforms in T. anterior (up to 10% each, P  myostatin is absent and IGF1 is in excess. Finally, we show that myostatin and IGF1 regulate skeletal muscle size, myofibre type and gonadal fat through distinct mechanisms that involve increasing the total abundance and phosphorylation status of AKT and rpS6. © 2017 Society for Endocrinology.

  14. Does the GH/IGF-1 axis contribute to skeletal sexual dimorphism? Evidence from mouse studies.

    Science.gov (United States)

    Liu, Zhongbo; Mohan, Subburaman; Yakar, Shoshana

    2016-04-01

    The contribution of the gonadotropic axis to skeletal sexual dimorphism (SSD) was clarified in recent years. Studies with animal models of estrogen receptor (ER) or androgen receptor (AR) null mice, as well as mice with bone cell-specific ablation of ER or AR, revealed that both hormones play major roles in skeletal acquisition, and that estrogen regulates skeletal accrual in both sexes. The growth hormone (GH) and its downstream effector, the insulin-like growth factor-1 (IGF-1) are also major determinants of peak bone mass during puberty and young adulthood, and play important roles in maintaining bone integrity during aging. A few studies in both humans and animal models suggest that in addition to the differences in sex steroid actions on bone, sex-specific effects of GH and IGF-1 play essential roles in SSD. However, the contributions of the somatotropic (GH/IGF-1) axis to SSD are controversial and data is difficult to interpret. GH/IGF-1 are pleotropic hormones that act in an endocrine and autocrine/paracrine fashion on multiple tissues, affecting body composition as well as metabolism. Thus, understanding the contribution of the somatotropic axis to SSD requires the use of mouse models that will differentiate between these two modes of action. Elucidation of the relative contribution of GH/IGF-1 axis to SSD is significant because GH is approved for the treatment of normal children with short stature and children with congenital growth disorders. Thus, if the GH/IGF-1 axis determines SSD, treatment with GH may be tailored according to sex. In the following review, we give an overview of the roles of sex steroids in determining SSD and how they may interact with the GH/IGF-1 axis in bone. We summarize several mouse models with impaired somatotropic axis and speculate on the possible contribution of that axis to SSD. Copyright © 2015 Elsevier Ltd. All rights reserved.

  15. IGF-1 levels may increase paradoxically with dopamine agonist treatment for prolactinomas.

    Science.gov (United States)

    Akirov, Amit; Greenman, Yona; Glaser, Benjamin; S'chigol, Irena; Mansiterski, Yossi; Eizenberg, Yoav; Shraga-Slutzky, Ilana; Shimon, Ilan

    2018-05-04

    Hyperprolactinemia is common in acromegaly and in these patients, insulin-like growth factor (IGF)-1 level may decrease with dopamine agonist. We report a series of patients with prolactinoma and a paradoxical increase of IGF-1 levels during cabergoline treatment. Clinical characteristics and response to treatment of patients with prolactinomas, in whom normal or slightly elevated baseline IGF-1 levels increased with cabergoline. The cohort consisted of ten prolactinoma patients (nine males, mean age 48 ± 14 years). Mean adenoma size was 23.8 ± 16.2 mm, with cavernous sinus invasion in eight. In five patients baseline IGF-1 levels were normal and in four levels were 1.2-1.5-fold the upper limit of the normal (ULN). One patient had IGF-1 measured shortly after initiating cabergoline and it was 1.4 × ULN. During cabergoline treatment (dose range 0.5-2 mg/week) PRL normalization was achieved in all and tumor shrinkage occurred in seven patients. The mean IGF-1 increase on cabergoline was 1.7 ± 0.4 × ULN. Cabergoline dose reduction or interruption was attempted in five patients and resulted in decreased IGF-1 levels in all, including normalization in two patients. Three patients were eventually diagnosed with acromegaly, one was referred for pituitary surgery followed by complete remission, another patient was switched to somatostatin analogue, and the third was treated by combination of somatostatin analogues with pegvisomant, with reduction of IGF-1 in all these patients. IGF-1 levels may increase to clinically significant levels during cabergoline treatment for PRL-adenoma. We suggest IGF-1 monitoring in all patients treated with dopamine agonists and not only in those presenting symptoms of acromegaly.

  16. The relationship between maternal insulin-like growth factors 1 and 2 (IGF-1, IGF-2) and IGFBP-3 to gestational age and preterm delivery.

    LENUS (Irish Health Repository)

    Cooley, Sharon M

    2010-05-01

    To investigate the relationship between levels of insulin-like growth factors 1 and 2 (IGF-1, IGF-2), and insulin-like growth factor binding protein 3 (IGFBP-3) in antenatal maternal serum and gestational age at delivery.

  17. IGF-1 contributes to the expansion of melanoma-initiating cells through an epithelial-mesenchymal transition process.

    Science.gov (United States)

    Le Coz, Vincent; Zhu, Chaobin; Devocelle, Aurore; Vazquez, Aimé; Boucheix, Claude; Azzi, Sandy; Gallerne, Cindy; Eid, Pierre; Lecourt, Séverine; Giron-Michel, Julien

    2016-12-13

    Melanoma is a particularly virulent human cancer, due to its resistance to conventional treatments and high frequency of metastasis. Melanomas contain a fraction of cells, the melanoma-initiating cells (MICs), responsible for tumor propagation and relapse. Identification of the molecular pathways supporting MICs is, therefore, vital for the development of targeted treatments. One factor produced by melanoma cells and their microenvironment, insulin-like growth factor-1 (IGF- 1), is linked to epithelial-mesenchymal transition (EMT) and stemness features in several cancers.We evaluated the effect of IGF-1 on the phenotype and chemoresistance of B16-F10 cells. IGF-1 inhibition in these cells prevented malignant cell proliferation, migration and invasion, and lung colony formation in immunodeficient mice. IGF-1 downregulation also markedly inhibited EMT, with low levels of ZEB1 and mesenchymal markers (N-cadherin, CD44, CD29, CD105) associated with high levels of E-cadherin and MITF, the major regulator of melanocyte differentiation. IGF-1 inhibition greatly reduced stemness features, including the expression of key stem markers (SOX2, Oct-3/4, CD24 and CD133), and the functional characteristics of MICs (melanosphere formation, aldehyde dehydrogenase activity, side population). These features were associated with a high degree of sensitivity to mitoxantrone treatment.In this study, we deciphered new connections between IGF-1 and stemness features and identified IGF-1 as instrumental for maintaining the MIC phenotype. The IGF1/IGF1-R nexus could be targeted for the development of more efficient anti-melanoma treatments. Blocking the IGF-1 pathway would improve the immune response, decrease the metastatic potential of tumor cells and sensitize melanoma cells to conventional treatments.

  18. Development and clinical evaluation of a novel immunoassay for the binary complex of IGF-I and IGF-binding protein-1 in human serum

    DEFF Research Database (Denmark)

    Frystyk, Jan; Højlund, Kurt; Rasmussen, Kirsten Nyborg

    2002-01-01

    Correlation studies have suggested that IGF-binding protein (IGFBP)-1 is a dynamic regulator of free IGF-I. To further study this, we developed a monoclonal immunofluorometric assay specific for the binary complex of IGF-I and IGFBP-1 in human serum. An IGFBP-1 antibody, which recognizes all...... phospho-forms of IGFBP-1, was used for coating. An europium-labeled IGF-I antibody served as tracer. Assay incubation was performed at conditions approaching those in vivo (i.e. pH 7.4, 37 C). The assay was highly specific: no signal was obtained unless both IGF-I and IGFBP-1 were present and neither...... IGFBP-2, -3, -4, nor IGF-II caused any cross-reaction. The linear standard curve covered 3 orders of magnitude, and within and in-between assay coefficients of variation were less than 5 and 15%, respectively. To study the dynamic relationship between free IGF-I and binary complex formation, seven...

  19. The GH/IGF-1 axis in ageing and longevity

    Science.gov (United States)

    List, Edward O.; Berryman, Darlene E.; Murrey, John W.

    2014-01-01

    Secretion of growth hormone (GH), and consequently that of insulin-like growth factor 1 (IGF-1), declines over time until only low levels can be detected in individuals aged ≥60 years. This phenomenon, which is known as the ‘somatopause’, has led to recombinant human GH being widely promoted and abused as an antiageing drug, despite lack of evidence of efficacy. By contrast, several mutations that decrease the tone of the GH/IGF-1 axis are associated with extended longevity in mice. In humans, corresponding or similar mutations have been identified, but whether these mutations alter longevity has yet to be established. The powerful effect of reduced GH activity on lifespan extension in mice has generated the hypothesis that pharmaceutically inhibiting, rather than increasing, GH action might delay ageing. Moreover, mice as well as humans with reduced activity of the GH/IGF-1 axis are protected from cancer and diabetes mellitus, two major ageing-related morbidities. Here, we review data on mouse strains with alterations in the GH/IGF-1 axis and their effects on lifespan. The outcome of corresponding or similar mutations in humans is described, as well as the potential mechanisms underlying increased longevity and the therapeutic benefits and risks of medical disruption of the GH/IGF-1 axis in humans. PMID:23591370

  20. Low Levels of IGF-1 Contribute to Alveolar Macrophage Dysfunction in Cystic Fibrosis1

    OpenAIRE

    Bessich, Jamie L.; Nymon, Amanda B.; Moulton, Lisa A; Dorman, Dana; Ashare, Alix

    2013-01-01

    Alveolar macrophages are major contributors to lung innate immunity. Although alveolar macrophages from CFTR−/− mice have impaired function, no study has investigated primary alveolar macrophages in adults with cystic fibrosis (CF). CF patients have low levels of insulin-like growth factor 1 (IGF-1), and our prior studies demonstrate a relationship between IGF-1 and macrophage function. We hypothesize that reduced IGF-1 in CF leads to impaired alveolar macrophage function and chronic infectio...

  1. IGF-1R and Leptin Expression Profile and the Effects of Metformin Treatment on Metabolic and Endocrine Parameters in PCOS Mice

    Directory of Open Access Journals (Sweden)

    Luis Eduardo Prado Correia

    2017-01-01

    Full Text Available We aim to assess the effects of metformin treatment on metabolic and endocrine parameters and genes expression related to the insulin-responsive pathway in polycystic ovary syndrome (PCOS. This study comprises twenty-eight obese mice divided into three metformin-treated groups for seven and twenty days and eight nonobese and nontreated ones. We found a significant decrease in glycemia after metformin treatment at days seven and twenty. However, we did not observe differences in body weight measurement. Histologically, after twenty days we observed follicular development with regression of androgenic effects. Levels of IGF-1R protein expression were low after twenty days of treatment, but LEP proteins showed an overexpression in the ovarian stroma. We assessed the IGF-1R and LEP mRNAs levels; data showed a significant overexpression of LEP after seven days of treatment, while the IGF-1R was downregulated. Metformin therapy seems to exert a beneficial effect on histological and anovulatory features, reducing follicular number and pyknosis formation, possibly involved in the reversion of androgenic stimulus. Expression of IGF-1 and LEPR indicates a relevant role in androgenic features reversion present in PCOS, hormonal equilibrium, body weight regulation, and glucose metabolism, therefore, under phenotype obesity and infertility regulation in this model.

  2. Development and clinical evaluation of a novel immunoassay for the binary complex of IGF-I and IGF-binding protein-1 in human serum

    DEFF Research Database (Denmark)

    Frystyk, Jan; Højlund, Kurt; Rasmussen, Kirsten Nyborg

    2002-01-01

    Correlation studies have suggested that IGF-binding protein (IGFBP)-1 is a dynamic regulator of free IGF-I. To further study this, we developed a monoclonal immunofluorometric assay specific for the binary complex of IGF-I and IGFBP-1 in human serum. An IGFBP-1 antibody, which recognizes all...... phospho-forms of IGFBP-1, was used for coating. An europium-labeled IGF-I antibody served as tracer. Assay incubation was performed at conditions approaching those in vivo (i.e. pH 7.4, 37 C). The assay was highly specific: no signal was obtained unless both IGF-I and IGFBP-1 were present and neither...

  3. Insulin-like growth factor-II (IGF II) receptor from rat brain is of lower apparent molecular weight than the IGF II receptor from rat liver

    International Nuclear Information System (INIS)

    McElduff, A.; Poronnik, P.; Baxter, R.C.

    1987-01-01

    The binding subunits of the insulin and insulin-like growth factor-I (IGF I) receptors from rat brain are of lower molecular weight than the corresponding receptor in rat liver, possibly due to variations in sialic acid content. We have compared the IGF II receptor from rat brain and rat liver. The brain receptor is of smaller apparent mol wt (about 10 K) on sodium dodecyl sulfate polyacrylamide gel electrophoresis. This size difference is independent of ligand binding as it persists in iodinated and specifically immunoprecipitated receptors. From studies of wheat germ agglutinin binding and the effect of neuraminidase on receptor mobility, we conclude that this difference is not simply due to variations in sialic acid content. Treatment with endoglycosidase F results in reduction in the molecular size of both liver and brain receptors and after this treatment the aglycoreceptors are of similar size. We conclude that in rat brain tissue the IGF II receptor like the binding subunits of the insulin and IGF I receptors is of lower molecular size than the corresponding receptors in rat liver. This difference is due to differences in N-linked glycosylation

  4. Regulation of hypoxia-inducible factor-1α (HIF-1α expression by interleukin-1β (IL-1 β, insulin-like growth factors I (IGF-I and II (IGF-II in human osteoarthritic chondrocytes

    Directory of Open Access Journals (Sweden)

    Angelica Rossi Sartori-Cintra

    2012-01-01

    Full Text Available OBJECTIVE: Hypoxia-inducible factor 1 alpha regulates genes related to cellular survival under hypoxia. This factor is present in osteroarthritic chondrocytes, and cytokines, such as interleukin-1 beta, participate in the pathogenesis of osteoarthritis, thereby increasing the activities of proteolytic enzymes, such as matrix metalloproteinases, and accelerating cartilage destruction. We hypothesize that Hypoxia Inducible Factor-1 alpha (HIF-1α can regulate cytokines (catabolic action and/or growth factors (anabolic action in osteoarthritis. The purpose of this study was to investigate the modulation of HIF-1α in human osteoarthritic chondrocytes by interleukin-1 beta (IL-1β and insulin-like growth factors I (IGF-I and II (IGF-II and to determine the involvement of the phosphatidylinositol-3kinase (PI-3K pathway in this process. METHODS: Human osteroarthritic chondrocytes were stimulated with IL-1β, IGF-I and IGF-II and LY294002, a specific inhibitor of PI-3K. Nuclear protein levels and gene expression were analyzed by western blot and quantitative reverse transcription-polymerase chain reaction analyses, respectively. RESULTS: HIF-1α expression was upregulated by IL-1β at the protein level but not at the gene level. IGF-I treatment resulted in increases in both the protein and mRNA levels of HIF-1α , whereas IGF-II had no effect on its expression. However, all of these stimuli exploited the PI-3K pathway. CONCLUSION: IL-1β upregulated the levels of HIF-1α protein post-transcriptionally, whereas IGF-I increased HIF-1α at the transcript level. In contrast, IGF-II did not affect the protein or gene expression levels of HIF-1α . Furthermore, all of the tested stimuli exploited the PI-3K pathway to some degree. Based on these findings, we are able to suggest that Hypoxia inducible Factor-1 exhibits protective activity in chondrocytes during osteoarthritis.

  5. NREM sleep architecture and relation to GH/IGF-1 axis in Laron syndrome.

    Science.gov (United States)

    Verrillo, Elisabetta; Bizzarri, Carla; Cappa, Marco; Bruni, Oliviero; Pavone, Martino; Cutrera, Renato

    2010-01-01

    Laron syndrome (LS), known as growth hormone (GH) receptor deficiency, is a rare form of inherited GH resistance. Sleep disorders were described as a common feature of adult LS patients, while no data are available in children. Bi-directional interactions between human sleep and the somatotropic system were previously described, mainly between slow wave sleep and the nocturnal GH surge. To analyze the sleep macro- and microstructure in LS and to evaluate the influence of substitutive insulin-like growth factor 1 (IGF-1) therapy on it. Two young LS females underwent polysomnography; the first study was performed during IGF-1 therapy, the second one after a 3-month wash-out period. In both patients, the sleep macrostructure showed that time in bed, sleep period time, total sleep time, sleep efficiency and rapid eye movement (REM) percentage were all increased during wash-out. The sleep microstructure (cyclic alternating pattern: CAP) showed significantly higher EEG slow oscillations (A1%) in NREM sleep, both during IGF-1 therapy and wash-out. Sleep macrostructure in LS children is slightly affected by substitutive IGF-1 therapy. Sleep microstructure shows an increase of A1%, probably related to abnormally high hypothalamic GHRH secretion, due to GH insensitivity. Copyright 2010 S. Karger AG, Basel.

  6. Salivary and serum insulin-like growth factor (IGF-1) assays in anorexic patients.

    Science.gov (United States)

    Paszynska, Elzbieta; Dmitrzak-Weglarz, Monika; Slopien, Agnieszka; Tyszkiewicz-Nwafor, Marta; Rajewski, Andrzej

    2016-12-01

    The purpose of this study was to measure the salivary and serum free IGF-1 concentration of patients with anorexia nervosa (AN) in comparison to an average population. A controlled clinical trial was designed for an age- and gender-matched group of 121 AN patients and 77 healthy individuals. A clinical examination was made and blood and salivary samples were taken during the acute stage of AN (BMI measuring free IGF-1 was used. Anorexic patients had significant reductions in salivary unstimulated flow rate (UFR), pH and free IGF-1 levels in their saliva and serum. Significant correlations between serum IGF-1 and BMI; salivary IGF-1 and UFR and pH were detected. Salivary and serum IGF-1 analyses appear to be a reliable biochemical indicator of malnutrition in AN patients. Measurement of salivary IGF-1 levels would allow new perspectives in monitoring AN in its early stages.

  7. Distribution and levels of [125I]IGF-I, [125I]IGF-II and [125I]insulin receptor binding sites in the hippocampus of aged memory-unimpaired and -impaired rats

    International Nuclear Information System (INIS)

    Quirion, R.; Rowe, W.; Kar, S.; Dore, S.

    1997-01-01

    The insulin-like growth factors (IGF-I and IGF-II) and insulin are localized within distinct brain regions and their respective functions are mediated by specific membrane receptors. High densities of binding sites for these growth factors are discretely and differentially distributed throughout the brain, with prominent levels localized to the hippocampal formation. IGFs and insulin, in addition to their growth promoting actions, are considered to play important roles in the development and maintenance of normal cell functions throughout life. We compared the anatomical distribution and levels of IGF and insulin receptors in young (five month) and aged (25 month) memory-impaired and memory-unimpaired male Long-Evans rats as determined in the Morris water maze task in order to determine if alterations in IGF and insulin activity may be related to the emergence of cognitive deficits in the aged memory-impaired rat. In the hippocampus, [ 125 I]IGF-I receptors are concentrated primarily in the dentate gyrus (DG) and the CA3 sub-field while high amounts of [ 125 I]IGF-II binding sites are localized to the pyramidal cell layer, and the granular cell layer of the DG. [ 125 I]insulin binding sites are mostly found in the molecular layer of the DG and the CA1 sub-field. No significant differences were found in [ 125 I]IGF-I, [ 125 I]IGF-II or [ 125 I]insulin binding levels in any regions or laminae of the hippocampus of young vs aged rats, and deficits in cognitive performance did not relate to altered levels of these receptors in aged memory-impaired vs aged memory-unimpaired rats. Other regions, including various cortical areas, were also examined and failed to reveal any significant differences between the three groups studied.It thus appears that IGF-I, IGF-II and insulin receptor sites are not markedly altered during the normal ageing process in the Long-Evans rat, in spite of significant learning deficits in a sub-group (memory-impaired) of aged animals. Hence

  8. Regulation of skeletal growth and mineral acquisition by the GH/IGF-1 axis: Lessons from mouse models.

    Science.gov (United States)

    Yakar, Shoshana; Isaksson, Olle

    2016-06-01

    The growth hormone (GH) and its downstream mediator, the insulin-like growth factor-1 (IGF-1), construct a pleotropic axis affecting growth, metabolism, and organ function. Serum levels of GH/IGF-1 rise during pubertal growth and associate with peak bone acquisition, while during aging their levels decline and associate with bone loss. The GH/IGF-1 axis was extensively studied in numerous biological systems including rodent models and cell cultures. Both hormones act in an endocrine and autocrine/paracrine fashion and understanding their distinct and overlapping contributions to skeletal acquisition is still a matter of debate. GH and IGF-1 exert their effects on osteogenic cells via binding to their cognate receptor, leading to activation of an array of genes that mediate cellular differentiation and function. Both hormones interact with other skeletal regulators, such as sex-steroids, thyroid hormone, and parathyroid hormone, to facilitate skeletal growth and metabolism. In this review we summarized several rodent models of the GH/IGF-1 axis and described key experiments that shed new light on the regulation of skeletal growth by the GH/IGF-1 axis. Copyright © 2015 Elsevier Ltd. All rights reserved.

  9. IGF-1 Alleviates High Fat Diet-Induced Myocardial Contractile Dysfunction: Role of Insulin Signaling and Mitochondrial Function

    Science.gov (United States)

    Zhang, Yingmei; Yuan, Ming; Bradley, Katherine M.; Dong, Feng; Anversa, Piero; Ren, Jun

    2012-01-01

    Obesity is often associated with reduced plasma IGF-1 levels, oxidative stress, mitochondrial damage and cardiac dysfunction. This study was designed to evaluate the impact of IGF-1 on high fat diet-induced oxidative, myocardial, geometric and mitochondrial responses. FVB and cardiomyocyte-specific IGF-1 overexpression transgenic mice were fed a low (10%) or high fat (45%) diet to induce obesity. High fat diet feeding led to glucose intolerance, elevated plasma levels of leptin, interleukin-6, insulin and triglyceride as well as reduced circulating IGF-1 levels. Echocardiography revealed reduced fractional shortening, increased end systolic and diastolic diameter, increased wall thickness, and cardiac hypertrophy in high fat-fed FVB mice. High fat diet promoted ROS generation, apoptosis, protein and mitochondrial damage, reduced ATP content, cardiomyocyte cross-sectional area, contractile and intracellular Ca2+ dysregulation, including depressed peak shortening and maximal velocity of shortening/relengthening, prolonged duration of relengthening, and dampened intracellular Ca2+ rise and clearance. Western blot analysis revealed disrupted phosphorylation of insulin receptor, post-receptor signaling molecules IRS-1 (tyrosine/serine phosphorylation), Akt, GSK3β, Foxo3a, mTOR, as well as downregulated expression of mitochondrial proteins PPARγ coactivator 1α (PGC1α) and UCP-2. Intriguingly, IGF-1 mitigated high fat diet feeding-induced alterations in ROS, protein and mitochondrial damage, ATP content, apoptosis, myocardial contraction, intracellular Ca2+ handling and insulin signaling, but not whole body glucose intolerance and cardiac hypertrophy. Exogenous IGF-1 treatment also alleviated high fat diet-induced cardiac dysfunction. Our data revealed that IGF-1 alleviates high fat diet-induced cardiac dysfunction despite persistent cardiac remodeling, possibly due to preserved cell survival, mitochondrial function and insulin signaling. PMID:22275536

  10. IGF-1 Protects Dopamine Neurons Against Oxidative Stress: Association with Changes in Phosphokinases

    Science.gov (United States)

    El Ayadi, Amina; Zigmond, Michael J.; Smith, Amanda D.

    2016-01-01

    Insulin-like growth factor-1 (IGF-1) is an endogenous peptide transported across the blood brain barrier that is protective in several brain injury models, including an acute animal model of Parkinson’s disease (PD). Motor deficits in PD are due largely to the progressive loss of nigrostriatal dopaminergic neurons. Thus, we examined the neuroprotective potential of IGF-1 in a progressive model of dopamine deficiency in which 6-hydroxydopamine (6-OHDA) is infused into the striatum. Rats received intrastriatal IGF-1 (5 or 50 μg) 6 hrs prior to infusion of 4 μg 6-OHDA into the same site and were sacrificed 1 or 4 wks later. Both concentrations of IGF-1 protected tyrosine hydroxylase (TH) immunoreactive terminals in striatum at 4 wks but not at 1 wk, indicating that IGF-induced restoration of the dopaminergic phenotype occurred over several weeks. TH-immunoreactive cell loss was only attenuated with 50 μg IGF-1. We then examined the effect of striatal IGF-1 on the Ras/ERK1/2 and PI3K/Akt pathways to ascertain if their activation correlated with IGF-1-induced protection. Striatal and nigral levels of phospho-ERK1/2 (pERK1/2) were maximal 6 hrs after IGF-1 infusion and, with the exception of an increase in nigral pERK2 at 48 hrs, returned to basal levels by 7 days. Phospho-Akt (Ser473) was elevated 6–24 hrs post-IGF-1 infusion in both striatum and substantia nigra concomitant with inhibition of pro-death GSK-3β, a downstream target of Akt. These results suggest that IGF-1 can protect the nigrostriatal pathway in a progressive PD model and that this protection is preceded by activation of key pro-survival signaling cascades PMID:26894890

  11. Importance of circulating IGF-1 for normal cardiac morphology, function and post infarction remodeling.

    Science.gov (United States)

    Scharin Täng, M; Redfors, B; Lindbom, M; Svensson, J; Ramunddal, T; Ohlsson, C; Shao, Y; Omerovic, E

    2012-12-01

    IGF-1 plays an important role in cardiovascular homeostasis, and plasma levels of IGF-1 correlate inversely with systolic function in heart failure. It is not known to what extent circulating IGF-1 secreted by the liver and local autocrine/paracrine IGF-1 expressed in the myocardium contribute to these beneficial effects on cardiac function and morphology. In the present study, we used a mouse model of liver-specific inducible deletion of the IGF-1 gene (LI-IGF-1 -/- mouse) in an attempt to evaluate the importance of circulating IGF-I on cardiac morphology and function under normal and pathological conditions, with an emphasis on its regulatory role in myocardial phosphocreatine metabolism. Echocardiography was performed in LI-IGF-1 -/- and control mice at rest and during dobutamine stress, both at baseline and post myocardial infarction (MI). High-energy phosphate metabolites were compared between LI-IGF-1 -/- and control mice at 4 weeks post MI. We found that LI-IGF-1 -/- mice had significantly greater left ventricular dimensions at baseline and showed a greater relative increase in cardiac dimensions, as well as deterioration of cardiac function, post MI. Myocardial creatine content was 17.9% lower in LI-IGF-1 -/- mice, whereas there was no detectable difference in high-energy nucleotides. These findings indicate an important role of circulating IGF-1 in preserving cardiac structure and function both in physiological settings and post MI. Copyright © 2012 Elsevier Ltd. All rights reserved.

  12. The transcription factor MEF2C mediates cardiomyocyte hypertrophy induced by IGF-1 signaling

    Energy Technology Data Exchange (ETDEWEB)

    Munoz, Juan Pablo; Collao, Andres; Chiong, Mario; Maldonado, Carola; Adasme, Tatiana; Carrasco, Loreto; Ocaranza, Paula; Bravo, Roberto; Gonzalez, Leticia; Diaz-Araya, Guillermo [Centro FONDAP Estudios Moleculares de la Celula, Facultad de Medicina, Universidad de Chile, Santiago 8380492 (Chile); Facultad de Ciencias Quimicas y Farmaceuticas, Facultad de Medicina, Universidad de Chile, Santiago 8380492 (Chile); Hidalgo, Cecilia [Centro FONDAP Estudios Moleculares de la Celula, Facultad de Medicina, Universidad de Chile, Santiago 8380492 (Chile); Instituto de Ciencias Biomedicas, Facultad de Medicina, Universidad de Chile, Santiago 8380492 (Chile); Lavandero, Sergio, E-mail: slavander@uchile.cl [Centro FONDAP Estudios Moleculares de la Celula, Facultad de Medicina, Universidad de Chile, Santiago 8380492 (Chile); Facultad de Ciencias Quimicas y Farmaceuticas, Facultad de Medicina, Universidad de Chile, Santiago 8380492 (Chile); Instituto de Ciencias Biomedicas, Facultad de Medicina, Universidad de Chile, Santiago 8380492 (Chile)

    2009-10-09

    Myocyte enhancer factor 2C (MEF2C) plays an important role in cardiovascular development and is a key transcription factor for cardiac hypertrophy. Here, we describe MEF2C regulation by insulin-like growth factor-1 (IGF-1) and its role in IGF-1-induced cardiac hypertrophy. We found that IGF-1 addition to cultured rat cardiomyocytes activated MEF2C, as evidenced by its increased nuclear localization and DNA binding activity. IGF-1 stimulated MEF2 dependent-gene transcription in a time-dependent manner, as indicated by increased MEF2 promoter-driven reporter gene activity; IGF-1 also induced p38-MAPK phosphorylation, while an inhibitor of p38-MAPK decreased both effects. Additionally, inhibitors of phosphatidylinositol 3-kinase and calcineurin prevented IGF-1-induced MEF2 transcriptional activity. Via MEF2C-dependent signaling, IGF-1 also stimulated transcription of atrial natriuretic factor and skeletal {alpha}-actin but not of fos-lux reporter genes. These novel data suggest that MEF2C activation by IGF-1 mediates the pro-hypertrophic effects of IGF-1 on cardiac gene expression.

  13. The transcription factor MEF2C mediates cardiomyocyte hypertrophy induced by IGF-1 signaling

    International Nuclear Information System (INIS)

    Munoz, Juan Pablo; Collao, Andres; Chiong, Mario; Maldonado, Carola; Adasme, Tatiana; Carrasco, Loreto; Ocaranza, Paula; Bravo, Roberto; Gonzalez, Leticia; Diaz-Araya, Guillermo; Hidalgo, Cecilia; Lavandero, Sergio

    2009-01-01

    Myocyte enhancer factor 2C (MEF2C) plays an important role in cardiovascular development and is a key transcription factor for cardiac hypertrophy. Here, we describe MEF2C regulation by insulin-like growth factor-1 (IGF-1) and its role in IGF-1-induced cardiac hypertrophy. We found that IGF-1 addition to cultured rat cardiomyocytes activated MEF2C, as evidenced by its increased nuclear localization and DNA binding activity. IGF-1 stimulated MEF2 dependent-gene transcription in a time-dependent manner, as indicated by increased MEF2 promoter-driven reporter gene activity; IGF-1 also induced p38-MAPK phosphorylation, while an inhibitor of p38-MAPK decreased both effects. Additionally, inhibitors of phosphatidylinositol 3-kinase and calcineurin prevented IGF-1-induced MEF2 transcriptional activity. Via MEF2C-dependent signaling, IGF-1 also stimulated transcription of atrial natriuretic factor and skeletal α-actin but not of fos-lux reporter genes. These novel data suggest that MEF2C activation by IGF-1 mediates the pro-hypertrophic effects of IGF-1 on cardiac gene expression.

  14. IGF-1, IGFBP-3 and ALS in adult patients with chronic kidney disease.

    Science.gov (United States)

    Lepenies, Julia; Wu, Zida; Stewart, Paul M; Strasburger, Christian J; Quinkler, Marcus

    2010-04-01

    Insulin-like growth factor I (IGF-1) is for the most part bound in a ternary complex with IGF-binding protein-3 (IGFBP-3) and acid-labile subunit (ALS). This ternary complex is a storage form of IGF-1 in blood and passes not through the renal glomerulus. Little information is available in regard to the components of the ternary complex in adult renal disease. To investigate levels of serum IGF-1, IGFBP-3 and ALS in relation to renal function and extent of proteinuria. We measured IGF-1, IGFBP-3 and ALS concentrations in 137 patients who were investigated due to proteinuria and/or haematuria and/or renal impairment. The patients received renal biopsies and the histological diagnosis was documented. Urinary albumin excretion and relevant clinical parameter were evaluated. IGF-1 showed a highly positive correlation to IGFBP-3 and ALS, and the latter to IGFBP-3. IGF-1, IGFBP-3 and ALS decreased with increasing age. IGF-1 and IGFBP-3 showed no significant change depending on the creatinine clearance. However, ALS decreased with decreasing renal function. In patients with heavy proteinuria ALS levels, but not IGF-1 and IGFBP-3 levels, decreased significantly. Patients with chronic ischaemic renal damage and diabetic glomerulopathy showed higher IGF-1 and IGFBP-3 levels compared to patients with thin glomerular basement membrane disease despite their older age. IGF-1 and IGFBP-3 levels seem to be independent of renal function and severity of proteinuria. However, ALS levels are altered in renal failure and nephrotic syndrome, which may be due to increased renal loss or diminished hepatic production or both. Copyright (c) 2009 Elsevier Ltd. All rights reserved.

  15. Evidence for the possible biological significance of the igf-1 gene alternative splicing in prostate cancer

    Directory of Open Access Journals (Sweden)

    Anastassios ePhilippou

    2013-03-01

    Full Text Available Insulin-like growth factor I (IGF-I has been implicated in the pathogenesis of prostate cancer (PCa, since it plays a key role in cell proliferation, differentiation and apoptosis. The IGF-I actions are mediated mainly via its binding to the type I IGF receptor (IGF-IR, however IGF-I signaling via insulin receptor (IR and hybrid IGF-I/IR is also evident. Different IGF-I mRNA splice variants, namely IGF-IEa, IGF-IEb and IGF-IEc, are expressed in human cells and tissues. These transcripts encode several IGF-I precursor proteins which contain the same bioactive product (mature IGF-I, however, they differ by the length of their signal peptides on the amino-terminal end and the structure of the extension peptides (E-peptides on the carboxy-terminal end. There is an increasing interest in the possible different role of the IGF-I transcripts and their respective non-(matureIGF-I products in the regulation of distinct biological activities. Moreover, there is strong evidence of a differential expression profile of the IGF-I splice variants in normal vs. PCa tissues and PCa cells, implying that the expression pattern of the various IGF-I transcripts and their respective protein products may possess different functions in cancer biology. Herein, the evidence that the IGF-IEc transcript regulates PCa growth via Ec-peptide specific and IGF-IR/IR-independent signaling is discussed.

  16. Sex, Sport, IGF-1 and the Community Effect in Height Hypothesis

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    Barry Bogin

    2015-05-01

    Full Text Available We test the hypothesis that differences in social status between groups of people within a population may induce variation in insulin-like growth factor-1(IGF-1 levels and, by extension, growth in height. This is called the community effect in height hypothesis. The relationship between IGF-1, assessed via finger-prick dried blood spot, and elite level sport competition outcomes were analysed for a sample of 116 undergraduate men and women. There was a statistically significant difference between winners and losers of a competition. Winners, as a group, had higher average pre-game and post-game IGF-1 levels than losers. We proposed this type of difference as a proxy for social dominance. We found no evidence that winners increased in IGF-1 levels over losers or that members of the same team were more similar in IGF-1 levels than they were to players from other teams. These findings provide limited support toward the community effect in height hypothesis. The findings are discussed in relation to the action of the growth hormone/IGF-1 axis as a transducer of multiple bio-social influences into a coherent signal which allows the growing human to adjust and adapt to local ecological conditions.

  17. Insulin-like Growth Factor 1 (IGF-1) as a marker of cognitive decline in normal ageing: A review.

    Science.gov (United States)

    Frater, Julanne; Lie, David; Bartlett, Perry; McGrath, John J

    2018-03-01

    Insulin-like Growth Factor 1 (IGF-1) and its signaling pathway play a primary role in normal growth and ageing, however serum IGF-1 is known to reduce with advancing age. Recent findings suggest IGF-1 is essential for neurogenesis in the adult brain, and this reduction of IGF-1 with ageing may contribute to age-related cognitive decline. Experimental studies have shown manipulation of the GH/GF-1 axis can slow rates of cognitive decline in animals, making IGF-1 a potential biomarker of cognition, and/or its signaling pathway a possible therapeutic target to prevent or slow age-related cognitive decline. A systematic literature review and qualitative narrative summary of current evidence for IGF-1 as a biomarker of cognitive decline in the ageing brain was undertaken. Results indicate IGF-1 concentrations do not confer additional diagnostic information for those with cognitive decline, and routine clinical measurement of IGF-1 is not currently justified. In cases of established cognitive impairment, it remains unclear whether increasing circulating or brain IGF-1 may reverse or slow down the rate of further decline. Advances in neuroimaging, genetics, neuroscience and the availability of large well characterized biobanks will facilitate research exploring the role of IGF-1 in both normal ageing and age-related cognitive decline. Copyright © 2017 Elsevier B.V. All rights reserved.

  18. Potency of full-length MGF to induce maximal activation of the IGF-I R Is similar to recombinant human IGF-I at high equimolar concentrations

    NARCIS (Netherlands)

    J.A.M.J.L. Janssen (Joseph); L.J. Hofland (Leo); C.J. Strasburger; E.S.R.D. Van Dungen (Elisabeth S.R. Den); M. Thevis (Mario)

    2016-01-01

    textabstractAims To compare full-length mechano growth factor (full-length MGF) with human recombinant insulin-like growth factor-I (IGF-I) and human recombinant insulin (HI) in their ability to activate the human IGF-I receptor (IGF-IR), the human insulin receptor (IR-A) and the human insulin

  19. Dwarfism in Mice Lacking Collagen-binding Integrins α2β1 and α11β1 Is Caused by Severely Diminished IGF-1 Levels*

    Science.gov (United States)

    Blumbach, Katrin; Niehoff, Anja; Belgardt, Bengt F.; Ehlen, Harald W. A.; Schmitz, Markus; Hallinger, Ralf; Schulz, Jan-Niklas; Brüning, Jens C.; Krieg, Thomas; Schubert, Markus; Gullberg, Donald; Eckes, Beate

    2012-01-01

    Mice with a combined deficiency in the α2β1 and α11β1 integrins lack the major receptors for collagen I. These mutants are born with inconspicuous differences in size but develop dwarfism within the first 4 weeks of life. Dwarfism correlates with shorter, less mineralized and functionally weaker bones that do not result from growth plate abnormalities or osteoblast dysfunction. Besides skeletal dwarfism, internal organs are correspondingly smaller, indicating proportional dwarfism and suggesting a systemic cause for the overall size reduction. In accordance with a critical role of insulin-like growth factor (IGF)-1 in growth control and bone mineralization, circulating IGF-1 levels in the sera of mice lacking either α2β1 or α11β1 or both integrins were sharply reduced by 39%, 64%, or 81% of normal levels, respectively. Low hepatic IGF-1 production resulted from diminished growth hormone-releasing hormone expression in the hypothalamus and, subsequently, reduced growth hormone expression in the pituitary glands of these mice. These findings point out a novel role of collagen-binding integrin receptors in the control of growth hormone/IGF-1-dependent biological activities. Thus, coupling hormone secretion to extracellular matrix signaling via integrins represents a novel concept in the control of endocrine homeostasis. PMID:22210772

  20. Dwarfism in mice lacking collagen-binding integrins α2β1 and α11β1 is caused by severely diminished IGF-1 levels.

    Science.gov (United States)

    Blumbach, Katrin; Niehoff, Anja; Belgardt, Bengt F; Ehlen, Harald W A; Schmitz, Markus; Hallinger, Ralf; Schulz, Jan-Niklas; Brüning, Jens C; Krieg, Thomas; Schubert, Markus; Gullberg, Donald; Eckes, Beate

    2012-02-24

    Mice with a combined deficiency in the α2β1 and α11β1 integrins lack the major receptors for collagen I. These mutants are born with inconspicuous differences in size but develop dwarfism within the first 4 weeks of life. Dwarfism correlates with shorter, less mineralized and functionally weaker bones that do not result from growth plate abnormalities or osteoblast dysfunction. Besides skeletal dwarfism, internal organs are correspondingly smaller, indicating proportional dwarfism and suggesting a systemic cause for the overall size reduction. In accordance with a critical role of insulin-like growth factor (IGF)-1 in growth control and bone mineralization, circulating IGF-1 levels in the sera of mice lacking either α2β1 or α11β1 or both integrins were sharply reduced by 39%, 64%, or 81% of normal levels, respectively. Low hepatic IGF-1 production resulted from diminished growth hormone-releasing hormone expression in the hypothalamus and, subsequently, reduced growth hormone expression in the pituitary glands of these mice. These findings point out a novel role of collagen-binding integrin receptors in the control of growth hormone/IGF-1-dependent biological activities. Thus, coupling hormone secretion to extracellular matrix signaling via integrins represents a novel concept in the control of endocrine homeostasis.

  1. Role of insulin-like growth factor-1 (IGF-1) in regulating cell cycle progression

    International Nuclear Information System (INIS)

    Ma, Qi-lin; Yang, Tian-lun; Yin, Ji-ye; Peng, Zhen-yu; Yu, Min; Liu, Zhao-qian; Chen, Fang-ping

    2009-01-01

    Aims: Insulin-like growth factor-1 (IGF-1) is a polypeptide protein hormone, similar in molecular structure to insulin, which plays an important role in cell migration, cell cycle progression, cell survival and proliferation. In this study, we investigated the possible mechanisms of IGF-1 mediated cell cycle redistribution and apoptosis of vascular endothelial cells. Method: Human umbilical vein endothelial cells (HUVECs) were pretreated with 0.1, 0.5, or 2.5 μg/mL of IGF-1 for 30 min before the addition of Ang II. Cell cycle redistribution and apoptosis were examined by flow cytometry. Expression of Ang II type 1 (AT 1 ) mRNA and cyclin E protein were determined by RT-PCR and Western blot, respectively. Results: Ang II (1 μmol/L) induced HUVECs arrested at G 0 /G 1 , enhanced the expression level of AT 1 mRNA in a time-dependent manner, reduced the enzymatic activity of nitric oxide synthase (NOS) and nitric oxide (NO) content as well as the expression level of cyclin E protein. However, IGF-1 enhanced NOS activity, NO content, and the expression level of cyclin E protein, and reduced the expression level of AT 1 mRNA. L-NAME significantly counteracted these effects of IGF-1. Conclusions: Our data suggests that IGF-1 can reverse vascular endothelial cells arrested at G 0 /G 1 and apoptosis induced by Ang II, which might be mediated via a NOS-NO signaling pathway and is likely associated with the expression levels of AT1 mRNA and cyclin E proteins.

  2. Novel nuclear localization and potential function of insulin-like growth factor-1 receptor/insulin receptor hybrid in corneal epithelial cells.

    Directory of Open Access Journals (Sweden)

    Yu-Chieh Wu

    Full Text Available BACKGROUND: Type I insulin-like growth factor receptor (IGF-1R and insulin receptor (INSR are highly homologous molecules, which can heterodimerize to form an IGF-1R/INSR hybrid (Hybrid-R. The presence and biological significance of the Hybrid-R in human corneal epithelium has not yet been established. In addition, while nuclear localization of IGF-1R was recently reported in cancer cells and human corneal epithelial cells, the function and profile of nuclear IGF-1R is unknown. In this study, we characterized the nuclear localization and function of the Hybrid-R and the role of IGF-1/IGF-1R and Hybrid-R signaling in the human corneal epithelium. METHODOLOGY/PRINCIPLE FINDINGS: IGF-1-mediated signaling and cell growth were examined in a human telomerized corneal epithelial (hTCEpi cell line using co-immunoprecipitation, immunoblotting and cell proliferation assays. The presence of Hybrid-R in hTCEpi and primary cultured human corneal epithelial cells was confirmed by immunofluorescence and reciprocal immunoprecipitation of whole cell lysates. We found that IGF-1 stimulated Akt and promoted cell growth through IGF-1R activation, which was independent of the Hybrid-R. The presence of Hybrid-R, but not IGF-1R/IGF-1R, was detected in nuclear extracts. Knockdown of INSR by small interfering RNA resulted in depletion of the INSR/INSR and preferential formation of Hybrid-R. Chromatin-immunoprecipitation sequencing assay with anti-IGF-1R or anti-INSR was subsequently performed to identify potential genomic targets responsible for critical homeostatic regulatory pathways. CONCLUSION/SIGNIFICANCE: In contrast to previous reports on nuclear localized IGF-1R, this is the first report identifying the nuclear localization of Hybrid-R in an epithelial cell line. The identification of a nuclear Hybrid-R and novel genomic targets suggests that IGF-1R traffics to the nucleus as an IGF-1R/INSR heterotetrameric complex to regulate corneal epithelial homeostatic

  3. Regulation of IGF-1 signaling by microRNAs

    Directory of Open Access Journals (Sweden)

    Hwa Jin eJung

    2015-01-01

    Full Text Available The insulin-like growth factor 1 (IGF-1 signaling pathway regulates critical biological processes including development, homeostasis, and aging. Dysregulation of this pathway has been implicated in a myriad of diseases such as cancers, neurodegenerative diseases, and metabolic disorders, making the IGF-1 signaling pathway a prime target to develop therapeutic and intervention strategies. Recently, small non-coding RNA molecules in ~22 nucleotide length, microRNAs (miRNAs, have emerged as a new regulator of biological processes in virtually all organ systems and increasing studies are linking altered miRNA function to disease mechanisms. A miRNA binds to 3’UTRs of multiple target genes and coordinately down-regulates their expression, thereby exerting a profound influence on gene regulatory networks. Here we review the components of the IGF-1 signaling pathway that are known targets of miRNA regulation, and highlight recent studies that suggest therapeutic potential of these miRNAs against various diseases.

  4. Gemcitabine-(5'-phosphoramidate)-[anti-IGF-1R]: molecular design, synthetic organic chemistry reactions, and antineoplastic cytotoxic potency in populations of pulmonary adenocarcinoma (A549).

    Science.gov (United States)

    Coyne, Cody P; Narayanan, Lakshmi

    2017-03-01

    One molecular-based approach that increases potency and reduces dose-limited sequela is the implementation of selective 'targeted' delivery strategies for conventional small molecular weight chemotherapeutic agents. Descriptions of the molecular design and organic chemistry reactions that are applicable for synthesis of covalent gemcitabine-monophosphate immunochemotherapeutics have to date not been reported. The covalent immunopharmaceutical, gemcitabine-(5'-phosphoramidate)-[anti-IGF-1R] was synthesized by reacting gemcitabine with a carbodiimide reagent to form a gemcitabine carbodiimide phosphate ester intermediate which was subsequently reacted with imidazole to create amine-reactive gemcitabine-(5'-phosphorylimidazolide) intermediate. Monoclonal anti-IGF-1R immunoglobulin was combined with gemcitabine-(5'-phosphorylimidazolide) resulting in the synthetic formation of gemcitabine-(5'-phosphoramidate)-[anti-IGF-1R]. The gemcitabine molar incorporation index for gemcitabine-(5'-phosphoramidate)-[anti-IGF-R1] was 2.67:1. Cytotoxicity Analysis - dramatic increases in antineoplastic cytotoxicity were observed at and between the gemcitabine-equivalent concentrations of 10 -9  M and 10 -7  M where lethal cancer cell death increased from 0.0% to a 93.1% maximum (100.% to 6.93% residual survival), respectively. Advantages of the organic chemistry reactions in the multistage synthesis scheme for gemcitabine-(5'-phosphoramidate)-[anti-IGF-1R] include their capacity to achieve high chemotherapeutic molar incorporation ratios; option of producing an amine-reactive chemotherapeutic intermediate that can be preserved for future synthesis applications; and non-dedicated organic chemistry reaction scheme that allows substitutions of either or both therapeutic moieties, and molecular delivery platforms. © 2016 The Authors Chemical Biology & Drug Design Published by John Wiley & Sons Ltd.

  5. IGF-1 and Chondroitinase ABC Augment Nerve Regeneration after Vascularized Composite Limb Allotransplantation.

    Directory of Open Access Journals (Sweden)

    Nataliya V Kostereva

    Full Text Available Impaired nerve regeneration and inadequate recovery of motor and sensory function following peripheral nerve repair remain the most significant hurdles to optimal functional and quality of life outcomes in vascularized tissue allotransplantation (VCA. Neurotherapeutics such as Insulin-like Growth Factor-1 (IGF-1 and chondroitinase ABC (CH have shown promise in augmenting or accelerating nerve regeneration in experimental models and may have potential in VCA. The aim of this study was to evaluate the efficacy of low dose IGF-1, CH or their combination (IGF-1+CH on nerve regeneration following VCA. We used an allogeneic rat hind limb VCA model maintained on low-dose FK506 (tacrolimus therapy to prevent rejection. Experimental animals received neurotherapeutics administered intra-operatively as multiple intraneural injections. The IGF-1 and IGF-1+CH groups received daily IGF-1 (intramuscular and intraneural injections. Histomorphometry and immunohistochemistry were used to evaluate outcomes at five weeks. Overall, compared to controls, all experimental groups showed improvements in nerve and muscle (gastrocnemius histomorphometry. The IGF-1 group demonstrated superior distal regeneration as confirmed by Schwann cell (SC immunohistochemistry as well as some degree of extrafascicular regeneration. IGF-1 and CH effectively promote nerve regeneration after VCA as confirmed by histomorphometric and immunohistochemical outcomes.

  6. Serum IGF-1 affects skeletal acquisition in a temporal and compartment-specific manner.

    Directory of Open Access Journals (Sweden)

    Hayden-William Courtland

    2011-03-01

    Full Text Available Insulin-like growth factor-1 (IGF-1 plays a critical role in the development of the growing skeleton by establishing both longitudinal and transverse bone accrual. IGF-1 has also been implicated in the maintenance of bone mass during late adulthood and aging, as decreases in serum IGF-1 levels appear to correlate with decreases in bone mineral density (BMD. Although informative, mouse models to date have been unable to separate the temporal effects of IGF-1 depletion on skeletal development. To address this problem, we performed a skeletal characterization of the inducible LID mouse (iLID, in which serum IGF-1 levels are depleted at selected ages. We found that depletion of serum IGF-1 in male iLID mice prior to adulthood (4 weeks decreased trabecular bone architecture and significantly reduced transverse cortical bone properties (Ct.Ar, Ct.Th by 16 weeks (adulthood. Likewise, depletion of serum IGF-1 in iLID males at 8 weeks of age, resulted in significantly reduced transverse cortical bone properties (Ct.Ar, Ct.Th by 32 weeks (late adulthood, but had no effect on trabecular bone architecture. In contrast, depletion of serum IGF-1 after peak bone acquisition (at 16 weeks resulted in enhancement of trabecular bone architecture, but no significant changes in cortical bone properties by 32 weeks as compared to controls. These results indicate that while serum IGF-1 is essential for bone accrual during the postnatal growth phase, depletion of IGF-1 after peak bone acquisition (16 weeks is compartment-specific and does not have a detrimental effect on cortical bone mass in the older adult mouse.

  7. C. elegans VANG-1 modulates life span via insulin/IGF-1-like signaling.

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    Sebastian J Honnen

    Full Text Available The planar cell polarity (PCP pathway is highly conserved from Drosophila to humans and a PCP-like pathway has recently been described in the nematode Caenorhabditis elegans. The developmental function of this pathway is to coordinate the orientation of cells or structures within the plane of an epithelium or to organize cell-cell intercalation required for correct morphogenesis. Here, we describe a novel role of VANG-1, the only C. elegans ortholog of the conserved PCP component Strabismus/Van Gogh. We show that two alleles of vang-1 and depletion of the protein by RNAi cause an increase of mean life span up to 40%. Consistent with the longevity phenotype vang-1 animals also show enhanced resistance to thermal- and oxidative stress and decreased lipofuscin accumulation. In addition, vang-1 mutants show defects like reduced brood size, decreased ovulation rate and prolonged reproductive span, which are also related to gerontogenes. The germline, but not the intestine or neurons, seems to be the primary site of vang-1 function. Life span extension in vang-1 mutants depends on the insulin/IGF-1-like receptor DAF-2 and DAF-16/FoxO transcription factor. RNAi against the phase II detoxification transcription factor SKN-1/Nrf2 also reduced vang-1 life span that might be explained by gradual inhibition of insulin/IGF-1-like signaling in vang-1. This is the first time that a key player of the PCP pathway is shown to be involved in the insulin/IGF-1-like signaling dependent modulation of life span in C. elegans.

  8. High fat-diet and saturated fatty acid palmitate inhibits IGF-1 function in chondrocytes.

    Science.gov (United States)

    Nazli, S A; Loeser, R F; Chubinskaya, S; Willey, J S; Yammani, R R

    2017-09-01

    Insulin-like growth factor-1 (IGF-1) promotes matrix synthesis and cell survival in cartilage. Chondrocytes from aged and osteoarthritic cartilage have a reduced response to IGF-1. The purpose of this study was to determine the effect of free fatty acids (FFA) present in a high-fat diet on IGF-1 function in cartilage and the role of endoplasmic reticulum (ER) stress. C57BL/6 male mice were maintained on either a high-fat (60% kcal from fat) or a low-fat (10% kcal from fat) diet for 4 months. Mice were then sacrificed; femoral head cartilage caps were collected and treated with IGF-1 to measure proteoglycan (PG) synthesis. Cultured human chondrocytes were treated with 500 μM FFA palmitate or oleate, followed by stimulation with (100 ng/ml) IGF-1 overnight to measure CHOP (a protein marker for ER stress) and PG synthesis. Human chondrocytes were pre-treated with palmitate or 1 mM 4-phenyl butyric acid (PBA) or 1 μM C-Jun N terminal Kinase (JNK) inhibitor, and IGF-1 function (PG synthesis and signaling) was measured. Cartilage explants from mice on the high fat-diet showed reduced IGF-1 mediated PG synthesis compared to a low-fat group. Treatment of human chondrocytes with palmitate induced expression of CHOP, activated JNK and inhibited IGF-1 function. PBA, a small molecule chemical chaperone that alleviates ER stress rescued IGF-1 function and a JNK inhibitor rescued IGF-1 signaling. Palmitate-induced ER stress inhibited IGF-1 function in chondrocytes/cartilage via activating the mitogen-activated protein (MAP) kinase JNK. This is the first study to demonstrate that ER stress is metabolic factor that regulates IGF-1 function in chondrocytes. Copyright © 2017 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

  9. SP600125 Induces Src and Type I IGF Receptor Phosphorylation Independent of JNK

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    Qingbin Kong

    2014-09-01

    Full Text Available c-Jun N-terminal kinases (JNK are members of the mitogen-activated protein kinase (MAPK family that have important roles in signal transduction. The small molecule SP600125 is widely used in biochemical studies as a JNK inhibitor. However, recent studies indicate that SP600125 may also act independent of JNK. Here, we report that SP600125 can induce Src, type I insulin-like growth factor receptor (IGF-IR, Akt and Erk1/2 phosphorylation. Notably, these effects are independent of its inhibition of JNK. Inhibition of Src abrogates the stimulation of IGF-IR, Akt and Erk1/2 phosphorylation. IGF-IR knockdown blunts the induction of both Akt and Erk1/2 phosphorylation by SP600125. Moreover, combination of SP600125 and the Src inhibitor saracatinib synergistically inhibits cell proliferation. We conclude that SP600125 can activate Src-IGF-IR-Akt/Erk1/2 signaling pathways independent of JNK.

  10. IGF1-Dependent Synaptic Plasticity of Mitral Cells in Olfactory Memory during Social Learning.

    Science.gov (United States)

    Liu, Zhihui; Chen, Zijun; Shang, Congping; Yan, Fei; Shi, Yingchao; Zhang, Jiajing; Qu, Baole; Han, Hailin; Wang, Yanying; Li, Dapeng; Südhof, Thomas C; Cao, Peng

    2017-07-05

    During social transmission of food preference (STFP), mice form long-term memory of food odors presented by a social partner. How does the brain associate a social context with odor signals to promote memory encoding? Here we show that odor exposure during STFP, but not unconditioned odor exposure, induces glomerulus-specific long-term potentiation (LTP) of synaptic strength selectively at the GABAergic component of dendrodendritic synapses of granule and mitral cells in the olfactory bulb. Conditional deletion of synaptotagmin-10, the Ca 2+ sensor for IGF1 secretion from mitral cells, or deletion of IGF1 receptor in the olfactory bulb prevented the socially relevant GABAergic LTP and impaired memory formation after STFP. Conversely, the addition of IGF1 to acute olfactory bulb slices elicited the GABAergic LTP in mitral cells by enhancing postsynaptic GABA receptor responses. Thus, our data reveal a synaptic substrate for a socially conditioned long-term memory that operates at the level of the initial processing of sensory information. Copyright © 2017 Elsevier Inc. All rights reserved.

  11. The association between insulin-like growth factor 1 (IGF-1), IGF-binding proteins (IGFBPs), and the carboxyterminal propeptide of type I procollagen (PICP) in pre- and postmenopausal women with rheumatoid arthritis.

    Science.gov (United States)

    Szeremeta, A; Jura-Półtorak, A; Komosińska-Vassev, K; Zoń-Giebel, A; Kapołka, D; Olczyk, K

    2017-05-01

    To assess the association between plasma levels of the insulin-like growth factor (IGF) system including IGF-1, IGF-binding proteins (IGFBPs) including IGFBP-1, total (t-)IGFBP-3 and functional (f-)IGFBP-3, and the carboxyterminal propeptide of type I procollagen (PICP) in pre- and postmenopausal women with rheumatoid arthritis (RA). Plasma concentrations of IGF-1, IGFBP-1, t-IGFBP-3, f-IGFBP-3, and PICP were measured by immunoassay. No significant difference was observed in plasma IGF-1 levels between pre- and postmenopausal subjects. Plasma levels of IGFBP-1 were elevated in RA. PICP and f-IGFBP-3 were greatly affected by menopausal status. Of the three IGFBPs tested, only f-IGFBP-3 plasma levels in RA women correlated negatively with age and disease duration. A positive correlation was demonstrated between PICP and erythrocyte sedimentation rate (ESR) in RA. Moreover, there was no correlation between PICP and IGF-1 and any of the IGFBPs in RA women. Considerable disruption of the IGF system in RA was found to be related to disease activity and duration. Changes in the IGF-IGFBP axis and PICP levels were different in pre- and postmenopausal women with RA. Elevated plasma PICP concentrations may indicate an increased rate of bone formation in postmenopausal RA women. Additionally, the observed changes in the IGF/IGFBP system did not affect bone formation during RA.

  12. IGF-1 Prevents Diastolic and Systolic Dysfunction Associated with Cardiomyopathy and Preserves Adrenergic Sensitivity

    Science.gov (United States)

    Roof, Steve R.; Boslett, James; Russell, Duncan; del Rio, Carlos; Alecusan, Joe; Zweier, Jay L.; Ziolo, Mark T.; Hamlin, Robert; Mohler, Peter J.; Curran, Jerry

    2015-01-01

    Aims Insulin-like growth factor 1 (IGF-1)-dependent signaling promotes exercise-induced physiological cardiac hypertrophy. However, the in vivo therapeutic potential of IGF-1 for heart disease is not well established. Here we test the potential therapeutic benefits of IGF-1 on cardiac function using an in vivo model of chronic catecholamine-induced cardiomyopathy. Methods Rats were perfused with isoproterenol via osmotic pump (1 mg/kg/day) and treated with 2 mg/kg IGF-1 (2 mg/kg/day, 6 days a week) for 2 or 4 weeks. Echocardiography, ECG, and blood pressure were assessed. In vivo pressure-volume loop studies were conducted at 4 weeks. Heart sections were analyzed for fibrosis and apoptosis, and relevant biochemical signaling cascades were assessed. Results After 4 weeks, diastolic function (EDPVR, EDP, tau, E/A ratio), systolic function (PRSW, ESPVR, dP/dtmax), and structural remodeling (LV chamber diameter, wall thickness) were all adversely affected in isoproterenol-treated rats. All these detrimental effects were attenuated in rats treated with Iso+IGF-1. Isoproterenol-dependent effects on BP were attenuated by IGF-1 treatment. Adrenergic sensitivity was blunted in isoproterenol-treated rats but was preserved by IGF-1 treatment. Immunoblots indicate that cardioprotective p110α signaling and activated Akt are selectively upregulated in Iso+IGF-1 treated hearts. Expression of iNOS was significantly increased in both the Iso and Iso+IGF-1 groups, however tetrahydrobiopterin (BH4) levels were decreased in the Iso group and maintained by IGF-1 treatment. Conclusion IGF-1 treatment attenuates diastolic and systolic dysfunction associated with chronic catecholamine-induced cardiomyopathy while preserving adrenergic sensitivity and promoting BH4 production. These data support the potential use of IGF-1 therapy for clinical applications for cardiomyopathies. PMID:26399932

  13. Expression of insulin-like growth factor-1 and insulin-like growth factor-1 receptors in EL4 lymphoma cells overexpressing growth hormone.

    Science.gov (United States)

    Weigent, Douglas A; Arnold, Robyn E

    2005-03-01

    Almost all of the previous studies with growth hormone (GH) have been done with exogenously supplied GH and, therefore, involve actions of the hormone through its receptor. However, the actions of endogenous or lymphocyte GH are still unclear. In a previous study, we showed that overexpression of GH (GHo) in a lymphoid cell line resulted in protection of the cells to apoptosis mediated by nitric oxide (NO). In the present study, we show that the protection from apoptosis could be transferred to control cells with culture fluids obtained from GHo cells and blocked by antibodies to the insulin-like growth factor-1 (IGF-1) or antibodies to the IGF-1-receptor (IGF-1R). Northern and Western blot analysis detected significantly higher levels of IGF-1 in cells overexpressing GH. An increase in the expression of the IGF-1R in GHo cells was also detected by Western blot analysis, (125)I-IGF-1 binding and analysis of IGF-1R promoter luciferase constructs. Transfection of GHo cells with a dominant negative IGF-1R mutant construct blocked the generation of NO and activation of Akt seen in GHo cells compared to vector alone control EL4 cells. The results suggest that one of the consequences of the overexpression of GH, in cells lacking the GH receptor, is an increase in the expression of IGF-1 and the IGF-1R which mediate the protection of EL4 lymphoma cells from apoptosis.

  14. Blood Brain Barrier and Neuroinflammation Are Critical Targets of IGF-1-Mediated Neuroprotection in Stroke for Middle-Aged Female Rats

    Science.gov (United States)

    Bake, Shameena; Selvamani, Amutha; Cherry, Jessica; Sohrabji, Farida

    2014-01-01

    Ischemia-induced cerebral infarction is more severe in older animals as compared to younger animals, and is associated with reduced availability of insulin-like growth factor (IGF)-1. This study determined the effect of post-stroke IGF-1 treatment, and used microRNA profiling to identify mechanisms underlying IGF-1’s neuroprotective actions. Post-stroke ICV administration of IGF-1 to middle-aged female rats reduced infarct volume by 39% when measured 24h later. MicroRNA analyses of ischemic tissue collected at the early post-stroke phase (4h) indicated that 8 out of 168 disease-related miRNA were significantly downregulated by IGF-1. KEGG pathway analysis implicated these miRNA in PI3K-Akt signaling, cell adhesion/ECM receptor pathways and T-and B-cell signaling. Specific components of these pathways were subsequently analyzed in vehicle and IGF-1 treated middle-aged females. Phospho-Akt was reduced by ischemia at 4h, but elevated by IGF-1 treatment at 24h. IGF-1 induced Akt activation was preceded by a reduction of blood brain barrier permeability at 4h post-stroke and global suppression of cytokines including IL-6, IL-10 and TNF-α. A subset of these cytokines including IL-6 was also suppressed by IGF-1 at 24h post-stroke. These data are the first to show that the temporal and mechanistic components of post-stroke IGF-1 treatment in older animals, and that cellular components of the blood brain barrier may serve as critical targets of IGF-1 in the aging brain. PMID:24618563

  15. Early programming of the IGF-I axis

    DEFF Research Database (Denmark)

    Larnkjær, Anni; Ingstrup, Helga Kristensen; Schack-Nielsen, Lene

    2009-01-01

    -I production. Conversely, studies suggest that later in childhood, those breastfed are taller and have higher IGF-I levels. Therefore, it has been suggested that the IGF-I axis may be programmed by diet during infancy. The association between IGF-I in infancy and later life is not known. OBJECTIVE: To examine...... for gender, breastfeeding, and other covariates. Likelihood ratio test based on residual log likelihood was applied for analysis including all measurements during infancy. RESULTS: There was an inverse association between IGF-I at 9 months and 17 years (r=-0.39, P=0.014, and n=40). A 1 ng/ml higher IGF...... covariates except IGF-I at 2 months which was significantly negatively associated with IGF-I at 17 years (P=0.030) corresponding to a 0.96 ng/ml lower IGF-I concentration at 17 years per ng/ml IGF-I at 2 months. Inclusion of all measurements during infancy showed a negative association with 17-year values (r...

  16. Role of insulin-like growth factor-1 (IGF-1) in regulating cell cycle progression

    Energy Technology Data Exchange (ETDEWEB)

    Ma, Qi-lin; Yang, Tian-lun [Department of Cardiology, Xiangya Hospital, Central South University, Changsha 410008, Hunan (China); Yin, Ji-ye [Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Xiangya School of Medicine, Central South University, Changsha 410078, Hunan (China); Peng, Zhen-yu [Department of Cardiology, Xiangya Hospital, Central South University, Changsha 410008, Hunan (China); Yu, Min [Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Xiangya School of Medicine, Central South University, Changsha 410078, Hunan (China); Liu, Zhao-qian, E-mail: liuzhaoqian63@126.com [Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Xiangya School of Medicine, Central South University, Changsha 410078, Hunan (China); Chen, Fang-ping, E-mail: xychenfp@public.cs.hn.Cn [Department of Haematology, Xiangya Hospital, Central South University, Changsha 410008, Hunan (China)

    2009-11-06

    Aims: Insulin-like growth factor-1 (IGF-1) is a polypeptide protein hormone, similar in molecular structure to insulin, which plays an important role in cell migration, cell cycle progression, cell survival and proliferation. In this study, we investigated the possible mechanisms of IGF-1 mediated cell cycle redistribution and apoptosis of vascular endothelial cells. Method: Human umbilical vein endothelial cells (HUVECs) were pretreated with 0.1, 0.5, or 2.5 {mu}g/mL of IGF-1 for 30 min before the addition of Ang II. Cell cycle redistribution and apoptosis were examined by flow cytometry. Expression of Ang II type 1 (AT{sub 1}) mRNA and cyclin E protein were determined by RT-PCR and Western blot, respectively. Results: Ang II (1 {mu}mol/L) induced HUVECs arrested at G{sub 0}/G{sub 1}, enhanced the expression level of AT{sub 1} mRNA in a time-dependent manner, reduced the enzymatic activity of nitric oxide synthase (NOS) and nitric oxide (NO) content as well as the expression level of cyclin E protein. However, IGF-1 enhanced NOS activity, NO content, and the expression level of cyclin E protein, and reduced the expression level of AT{sub 1} mRNA. L-NAME significantly counteracted these effects of IGF-1. Conclusions: Our data suggests that IGF-1 can reverse vascular endothelial cells arrested at G{sub 0}/G{sub 1} and apoptosis induced by Ang II, which might be mediated via a NOS-NO signaling pathway and is likely associated with the expression levels of AT1 mRNA and cyclin E proteins.

  17. Profile of mecasermin for the long-term treatment of growth failure in children and adolescents with severe primary IGF-1 deficiency

    Directory of Open Access Journals (Sweden)

    Danilo Fintini

    2009-07-01

    Full Text Available Danilo Fintini, Claudia Brufani, Marco CappaEndocrinology Unit, “Bambino Gesù” Children’s Hospital-IRCCS, Rome, ItalyAbstract: Growth hormone insensitivity syndrome (GHI or insulin-like growth factor-1 (IGF-1 deficiency (IGFD is characterized by deficit of IGF-1 production due to alteration of response of growth hormone (GH receptor to GH. This syndrome is due to mutation of GH receptor or IGF-1 gene and patients affected showed no response to GH therapy. The only treatment is recombinant IGF-1 (mecasermin, which has been available since 1986, but approved in the United States by the US Food and Drug Administration only in 2005 and in Europe by the European Medicines Agency in 2007. To date, few studies are available on long-term treatment with mecasermin in IGFD patients and some of them have a very small number of subjects. In this review we discuss briefly clinical features of severe primary IGFD, laboratory findings, and indications for treatment. Results of long-term therapy with rhIGF1 (mecasermin in patients affected by severe primary IGFD and possible side effects are explained.Keywords: mecasermin, therapy, Laron syndrome, IGF-1

  18. IGF-1 has sexually dimorphic, pleiotropic, and time-dependent effects on healthspan, pathology, and lifespan.

    Science.gov (United States)

    Ashpole, Nicole M; Logan, Sreemathi; Yabluchanskiy, Andriy; Mitschelen, Matthew C; Yan, Han; Farley, Julie A; Hodges, Erik L; Ungvari, Zoltan; Csiszar, Anna; Chen, Sixia; Georgescu, Constantin; Hubbard, Gene B; Ikeno, Yuji; Sonntag, William E

    2017-04-01

    Reduced circulating levels of IGF-1 have been proposed as a conserved anti-aging mechanism that contributes to increased lifespan in diverse experimental models. However, IGF-1 has also been shown to be essential for normal development and the maintenance of tissue function late into the lifespan. These disparate findings suggest that IGF-1 may be a pleiotropic modulator of health and aging, as reductions in IGF-1 may be beneficial for one aspect of aging, but detrimental for another. We postulated that the effects of IGF-1 on tissue health and function in advanced age are dependent on the tissue, the sex of the animal, and the age at which IGF-1 is manipulated. In this study, we examined how alterations in IGF-1 levels at multiple stages of development and aging influence overall lifespan, healthspan, and pathology. Specifically, we investigated the effects of perinatal, post-pubertal, and late-adult onset IGF-1 deficiency using genetic and viral approaches in both male and female igf f/f C57Bl/6 mice. Our results support the concept that IGF-1 levels early during lifespan establish the conditions necessary for subsequent healthspan and pathological changes that contribute to aging. Nevertheless, these changes are specific for each sex and tissue. Importantly, late-life IGF-1 deficiency (a time point relevant for human studies) reduces cancer risk but does not increase lifespan. Overall, our results indicate that the levels of IGF-1 during development influence late-life pathology, suggesting that IGF-1 is a developmental driver of healthspan, pathology, and lifespan.

  19. Proportionate Dwarfism in Mice Lacking Heterochromatin Protein 1 Binding Protein 3 (HP1BP3) Is Associated With Alterations in the Endocrine IGF-1 Pathway.

    Science.gov (United States)

    Garfinkel, Benjamin P; Arad, Shiri; Le, Phuong T; Bustin, Michael; Rosen, Clifford J; Gabet, Yankel; Orly, Joseph

    2015-12-01

    Heterochromatin protein 1 binding protein 3 (HP1BP3) is a recently described histone H1-related protein with roles in chromatin structure and transcriptional regulation. To explore the potential physiological role of HP1BP3, we have previously described an Hp1bp3(-/-) mouse model with reduced postnatal viability and growth. We now find that these mice are proportionate dwarfs, with reduction in body weight, body length, and organ weight. In addition to their small size, microcomputed tomography analysis showed that Hp1bp3(-/-) mice present a dramatic impairment of their bone development and structure. By 3 weeks of age, mice of both sexes have severely impaired cortical and trabecular bone, and these defects persist into adulthood and beyond. Primary cultures of both osteoblasts and osteoclasts from Hp1bp3(-/-) bone marrow and splenocytes, respectively, showed normal differentiation and function, strongly suggesting that the impaired bone accrual is due to noncell autonomous systemic cues in vivo. One major endocrine pathway regulating both body growth and bone acquisition is the IGF regulatory system, composed of IGF-1, the IGF receptors, and the IGF-binding proteins (IGFBPs). At 3 weeks of age, Hp1bp3(-/-) mice exhibited a 60% reduction in circulating IGF-1 and a 4-fold increase in the levels of IGFBP-1 and IGFBP-2. These alterations were reflected in similar changes in the hepatic transcripts of the Igf1, Igfbp1, and Igfbp2 genes. Collectively, these results suggest that HP1BP3 plays a key role in normal growth and bone development by regulating transcription of endocrine IGF-1 components.

  20. Changes in circulating level of IGF-I and IGF-binding protein-1 from the first to second trimester as predictors of preeclampsia

    DEFF Research Database (Denmark)

    Vatten, Lars J; Nilsen, Tom I L; Juul, Anders

    2008-01-01

    OBJECTIVE: To assess whether circulating IGF-I and IGF-binding protein-1 (IGFBP-1) in the first and second trimester are associated with subsequent risk of preterm and term preeclampsia. METHODS: Nested case-control study within a cohort of 29 948 pregnant women. Cases were women, who later...... developed preeclampsia, and controls were randomly selected women, who did not develop preeclampsia. IGF-I and IGFBP-1 were measured with ELISA in maternal blood samples that were collected in the first and second trimesters. We assessed associations of IGF-I and IGFBP-1 concentrations with later...... development of preterm (before the 37th week of gestation) and term preeclampsia. RESULTS: An increase in IGF-I from the first to second trimester was associated with higher risk of preterm preeclampsia; the odds ratio (OR) for the highest compared with lowest quartile of increase was 4.9 (95% confidence...

  1. Rosiglitazone Inhibits Adrenocortical Cancer Cell Proliferation by Interfering with the IGF-IR Intracellular Signaling

    Directory of Open Access Journals (Sweden)

    Luconi Michaela

    2008-07-01

    Full Text Available Rosiglitazone (RGZ, a thiazolidinedione ligand of the peroxisome proliferator-activated receptor (PPAR-γ, has been recently described as possessing antitumoral properties. We investigated RGZ effect on cell proliferation in two cell line models (SW13 and H295R of human adrenocortical carcinoma (ACC and its interaction with the signaling pathways of the activated IGF-I receptor (IGF-IR. We demonstrate a high expression of IGF-IR in the two cell lines and in ACC. Cell proliferation is stimulated by IGF-I in a dose- and time-dependent manner and is inhibited by RGZ. The analysis of the main intracellular signaling pathways downstream of the activated IGF-IR, phosphatidyl inositol 3-kinase (PI3K-Akt, and extracellular signal-regulated kinase (ERK1/2 cascades reveals that RGZ rapidly interferes with the Akt and ERK1/2 phosphorylation/activation which mediates IGF-I stimulated proliferation. In conclusion, our results suggest that RGZ exerts an inhibitory effect on human ACC cell proliferation by interfering with the PI3K/Akt and ERK1/2 signaling pathways downstream of the activated IGF-IR.

  2. Cardioprotective role of IGF-1 in the hypertrophied myocardium of the spontaneously hypertensive rats: A key effect on NHE-1 activity.

    Science.gov (United States)

    Yeves, A M; Burgos, J I; Medina, A J; Villa-Abrille, M C; Ennis, I L

    2018-05-13

    Myocardial Na + /H + exchanger-1 (NHE-1) hyperactivity and oxidative stress are interrelated phenomena playing pivotal roles in the development of pathological cardiac hypertrophy and heart failure. Exercise training is effective to convert pathological into physiological hypertrophy in the spontaneously hypertensive rats (SHR), and IGF-1-key humoral mediator of exercise training-inhibits myocardial NHE-1, at least in normotensive rats. Therefore, we hypothesize that IGF-1 by hampering NHE-1 hyperactivity and oxidative stress should exert a cardioprotective effect in the SHR. NHE-1 activity [proton efflux (JH+) mmol L -1  min -1 ], expression and phosphorylation; H 2 O 2 production; superoxide dismutase (SOD) activity; contractility and calcium transients were measured in SHR hearts in the presence/absence of IGF-1. IGF-1 significantly decreased NHE-1 activity (JH+ at pH i 6.95: 1.39 ± 0.32, n = 9 vs C 3.27 ± 0.3, n = 20, P IGF-1 receptor (2.7 ± 0.4, n = 7); by the PI3K inhibitor wortmannin (3.14 ± 0.41, n = 7); and the AKT inhibitor MK2206 (3.37 ± 0.43, n = 14). Moreover, IGF-1 exerted an antioxidant effect revealed by a significant reduction in H 2 O 2 production accompanied by an increase in SOD activity. In addition, IGF-1 improved cardiomyocyte contractility as evidenced by an increase in sarcomere shortening and a decrease in the relaxation constant, underlined by an increase in the amplitude and rate of decay of the calcium transients. IGF-1 exerts a cardioprotective role on the hypertrophied hearts of the SHR, in which the inhibition of NHE-1 hyperactivity, as well as the positive inotropic and antioxidant effects, emerges as key players. © 2018 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.

  3. Bioactive insulin-like growth factor (IGF) I and IGF-binding protein-1 in anorexia nervosa

    DEFF Research Database (Denmark)

    Støving, René; Chen, Jian-Wen; Glintborg, Dorte

    2007-01-01

    CONTEXT: Regulation of IGF-I activity appears crucial in anorexia nervosa (AN) during adaptation to chronic starvation as well as during the regenerative processes on nutritional restoration. OBJECTIVE: The objective of this study was to examine the relationship between IGF-I bioactivity and IGF...

  4. Intrauterine low-functional programming of IGF1 by prenatal nicotine exposure mediates the susceptibility to osteoarthritis in female adult rat offspring.

    Science.gov (United States)

    Tie, Kai; Zhang, Xianrong; Tan, Yang; Deng, Yu; Li, Jing; Ni, Qubo; Wang, Hui; Chen, Liaobin

    2016-02-01

    This study aimed to evaluate whether female adult offspring born with intrauterine growth retardation induced by prenatal nicotine exposure (PNE) are susceptible to osteoarthritis (OA) and to explore the underlying programming mechanisms. Pregnant rats were treated with nicotine or saline at 2.0 mg/kg/d from gestational d 11 to 20. The female adult offspring with or without PNE were forced with a strenuous treadmill running for 6 wk to induce OA. Nicotine's effects on fetal articular chondrocytes were studied by exposing chondrocytes to nicotine for 10 d, and dihydro-β-erythroidine, a selective α4β2-nicotinic acetylcholine receptor (nAChR) inhibitor, was used to identify the change of nicotine's effect. For adult offspring, increased cartilage destruction and accelerated OA progression were observed in the PNE group with running; the expression of α1 chain of type II collagen (Col2A1), aggrecan, SRY-type high mobility group box 9 (Sox9), and IGF1 signaling molecules in the cartilage of PNE offspring were decreased. For fetuses, elevated serum corticosteroid and nicotine levels and suppressed IGF1 levels were observed; expression of Col2A1, aggrecan, Sox9, and IGF1 were reduced. The result of chondrocytes revealed that nicotine impeded the expression of Col2A1, aggrecan, and IGF1; blocking α4β2-nAChR rescued nicotine's suppression. In conclusion, PNE increases the susceptibility of adult offspring to OA; the potential mechanism involves IGF1 low-functional programming in articular cartilage caused directly by the action of nicotine on α4β2-nAChR. © FASEB.

  5. Novel functional polymorphism in IGF-1 gene associated with multiple sclerosis: A new insight to MS.

    Science.gov (United States)

    Shahbazi, Majid; Abdolmohammadi, Reza; Ebadi, Hamid; Farazmandfar, Touraj

    2017-04-01

    Interactions between several genes and environment may play a role in susceptibility to multiple sclerosis (MS). The IGF-1 plays a key role in proliferation, maintenance and survival of nerve cells. Therefore, we hypothesized that IGF-1 may be a target for prediction and control MS. We aimed to analysis IGF-1 gene promoter sequence, to investigate the effect of the single nucleotide variants on IGF-1 expression and its association with MS. We enrolled 339 MS patients and 431 healthy controls. A specific region in IGF-1 gene promoter was investigated by SSCP analysis. All samples were genotyped by SSP-PCR. In-vitro and in-vivo IGF-1 production was measured by ELISA assay. IGF-1 expression in PBMCs was measured using real-time PCR. We identified a T to C single nucleotide substitution at position -1089 and a C to T at position -383 from transcription start site in the IGF-1 gene promoter. There was a significant association between MS and genotypes IGF-1(-383) C/T (p=0.001) and IGF-1(-383) C/C (pMS (p=0.001). In-vitro and in-vivo IGF-1 level showed that IGF-1 production in samples with genotype IGF-1(-383) C/C significantly was less than T/T (p=0.004) but not T/C (p=0.220). According to IGF-1 roles in CNS and our results, this study suggests that low IGF-1 level may be associated with susceptibility to MS. Copyright © 2017 Elsevier B.V. All rights reserved.

  6. Clonage de l'IGF-I et de son récepteur chez le turbot (Psetta maxima

    Directory of Open Access Journals (Sweden)

    ELIES G.

    1998-07-01

    Full Text Available Les IGF, leurs récepteurs et leurs protéines de liaison constituent une famille moléculaire qui joue un rôle essentiel dans la régulation de la croissance et du développement. Nous nous sommes intéressés à la caractérisation moléculaire de l'IGF-l et de son récepteur (IGF-1R chez le turbot (Psetta maxima, un poisson plat téléostéen. Par RT-PCR, nous avons clone un ADNc codant pour les quatre domaines de l'IGF-l mature. La protéine présente 70 à 96 % d'identité avec les autres IGF-I de vertébrés. Le clonage de la séquence codante entière du récepteur a nécessité la construction d'une banque d'ADNc d'embryons de turbots. Le récepteur est organisé en domaines dont la taille et les caractéristiques sont semblables à celles des autres récepteurs aux IGF de type 1 décrits chez les mammifères et le poulet. La région catalytique est particulièrement conservée. Dans certains domaines, notamment dans la région C-terminale du précurseur, quelques différences qui pourraient avoir une importance fonctionnelle sont cependant observées. Enfin, par RT-PCR, nous avons mis en évidence une régulation ontogénique du statut de polyadénylation des ARNm IGF-1R.

  7. Involvement of IGF-1/IGFBP-3 signaling on the conspicuousness of facial pores.

    Science.gov (United States)

    Sugiyama-Nakagiri, Yoriko; Ohuchi, Atsushi; Hachiya, Akira; Kitahara, Takashi

    2010-11-01

    Conspicuous facial pores are one type of serious esthetic defects for many women. We previously reported that the severity of impairment of skin architecture around facial pores correlates well with the appearance of facial pores in several ethnic groups. In our last report, we showed that serum levels of insulin-like growth factor-1 (IGF-1) correlate well with facial pore size and with the severity of impairment of epidermal architecture around facial pores. However, our results could not fully explain the implication between facial pores and IGF signaling. In this study, we conducted a histological analysis of facial skin to determine whether potential changes in IGF-1 availability occur in the skin with or without conspicuous pores. Immunohistochemical observations showed that expression of insulin-like growth factor binding protein-3 (IGFBP-3) is limited to the suprapapillary epidermis around facial pores and to basal cells of rete pegs without tips in epidermis with conspicuous pores. In contrast, in basal cells of skin without conspicuous pores, IGFBP-3 expression is very low. Ki-67 and IGF-1 receptor-positive cells are abundant in basal cells in the tips of the rete pegs in skin with typical epidermal architecture around facial pores. No obvious differences were observed in the expression of filaggrin, involucrin, K1, K6 or K17 in skin with or without conspicuous pores. However, increased expression of K16 was observed in skin with conspicuous pores suggesting hyperproliferation. These results suggest that the IGF-1/IGFBP-3 signaling pathway is involved in the formation of conspicuous facial pores due to the epidermal architecture around facial pores.

  8. Therapy of Prostate Cancer Using a Human Antibody Targeting the Type 1 Insulin-Like Growth Factor Receptor (IGF-IR)

    Science.gov (United States)

    2009-09-01

    delayed Majeed et al., 2005). All these studies suggest an essential role of IGF-IR in cellular transformation. Hongo et al. [1998] have identified...62:2942–2950. Hongo A, Yumet G, Resnicoff M, Romano G, O’Connor R, Baserga R. 1998. Inhibition of tumorigenesis and induc- tion of apoptosis in human...essential role of IGF-IR in cellular transformation. Hongo et al. [1998] have identified specific tyrosine residues on the b-subunit of the IGF-IR that

  9. Gut microbiota induce IGF-1 and promote bone formation and growth

    Science.gov (United States)

    Yan, Jing; Herzog, Jeremy W.; Tsang, Kelly; Brennan, Caitlin A.; Bower, Maureen A.; Garrett, Wendy S.; Sartor, Balfour R.; Charles, Julia F.

    2016-01-01

    Appreciation of the role of the gut microbiome in regulating vertebrate metabolism has exploded recently. However, the effects of gut microbiota on skeletal growth and homeostasis have only recently begun to be explored. Here, we report that colonization of sexually mature germ-free (GF) mice with conventional specific pathogen-free (SPF) gut microbiota increases both bone formation and resorption, with the net effect of colonization varying with the duration of colonization. Although colonization of adult mice acutely reduces bone mass, in long-term colonized mice, an increase in bone formation and growth plate activity predominates, resulting in equalization of bone mass and increased longitudinal and radial bone growth. Serum levels of insulin-like growth factor 1 (IGF-1), a hormone with known actions on skeletal growth, are substantially increased in response to microbial colonization, with significant increases in liver and adipose tissue IGF-1 production. Antibiotic treatment of conventional mice, in contrast, decreases serum IGF-1 and inhibits bone formation. Supplementation of antibiotic-treated mice with short-chain fatty acids (SCFAs), products of microbial metabolism, restores IGF-1 and bone mass to levels seen in nonantibiotic-treated mice. Thus, SCFA production may be one mechanism by which microbiota increase serum IGF-1. Our study demonstrates that gut microbiota provide a net anabolic stimulus to the skeleton, which is likely mediated by IGF-1. Manipulation of the microbiome or its metabolites may afford opportunities to optimize bone health and growth. PMID:27821775

  10. IGF-1 Promotes Brn-4 Expression and Neuronal Differentiation of Neural Stem Cells via the PI3K/Akt Pathway

    Science.gov (United States)

    Zhang, Xinhua; Zhang, Lei; Cheng, Xiang; Guo, Yuxiu; Sun, Xiaohui; Chen, Geng; Li, Haoming; Li, Pengcheng; Lu, Xiaohui; Tian, Meiling; Qin, Jianbing; Zhou, Hui; Jin, Guohua

    2014-01-01

    Our previous studies indicated that transcription factor Brn-4 is upregulated in the surgically denervated hippocampus in vivo, promoting neuronal differentiation of hippocampal neural stem cells (NSCs) in vitro. The molecules mediating Brn-4 upregulation in the denervated hippocampus remain unknown. In this study we examined the levels of insulin-like growth factor-1 (IGF-1) in hippocampus following denervation. Surgical denervation led to a significant increase in IGF-1 expression in vivo. We also report that IGF-1 treatment on NSCs in vitro led to a marked acceleration of Brn-4 expression and cell differentiation down neuronal pathways. The promotion effects were blocked by PI3K-specific inhibitor (LY294002), but not MAPK inhibitor (PD98059); levels of phospho-Akt were increased by IGF-1 treatment. In addition, inhibition of IGF-1 receptor (AG1024) and mTOR (rapamycin) both attenuated the increased expression of Brn-4 induced by IGF-1. Together, the results demonstrated that upregulation of IGF-1 induced by hippocampal denervation injury leads to activation of the PI3K/Akt signaling pathway, which in turn gives rise to upregulation of the Brn-4 and subsequent stem cell differentiation down neuronal pathways. PMID:25474202

  11. Clinical significance of serum circulating insulin-like growth factor-1 (IGF-1) mRNA in hepatocellular carcinoma.

    Science.gov (United States)

    Karabulut, S; Duranyıldız, D; Tas, F; Gezer, U; Akyüz, F; Serilmez, M; Ozgür, E; Yasasever, C T; Vatansever, S; Aykan, N F

    2014-03-01

    The principal aim of our study was to investigate the usefulness of serum protein and circulating mRNA of insulin-like growth factor-1 (IGF-1) as a diagnostic and prognostic tool in hepatocellular carcinoma (HCC). Fifty-four HCC patients and age- and sex-matched 20 healthy controls were enrolled into this study. Pretreatment serum IGF-1 and IGF-1 mRNA were determined by the solid-phase sandwich ELISA and quantitative RT-PCR method, respectively. The median age at diagnosis was 60 years, range 36-77 years; where majority of group were male (n = 48, 88.8%). All patients had cirrhotic history. Forty-six percent (n = 25) of patients had Child-Pugh score A, 30% (n = 16) had score B or C. All of the patients were treated with local therapies and none of them received sorafenib. The baseline serum IGF-1 mRNA levels were significantly higher in HCC patients than in the control group (p = 0.04), whereas no significant difference was observed for IGF-1 protein levels between the two group (p = 0.18). Patients with history of HBV infection, who were not treated, and who received multiple palliative treatment for HCC had higher serum IGF-1 mRNA levels (p = 0.03, 0.03, and 0.05, respectively). Poor performance status (p IGF-1 nor serum IGF-1 mRNA had significantly adverse effect on survival (p = 0.53 and 0.42, respectively).

  12. The Effects of IGF-1 on Trk Expressing DRG Neurons with HIV-gp120- Induced Neurotoxicity.

    Science.gov (United States)

    Li, Hao; Liu, Zhen; Chi, Heng; Bi, Yanwen; Song, Lijun; Liu, Huaxiang

    2016-01-01

    HIV envelope glycoprotein gp120 is the main protein that causes HIVassociated sensory neuropathy. However, the underlying mechanisms of gp120-induced neurotoxicity are still unclear. There are lack effective treatments for relieving HIV-related neuropathic symptoms caused by gp120-induced neurotoxicity. In the present study, tyrosine kinase receptor (Trk)A, TrkB, and TrkC expression in primary cultured dorsal root ganglion (DRG) neurons with gp120-induced neurotoxicity was investigated. The effects of IGF-1 on distinct Trk-positive DRG neurons with gp120-induced neurotoxicity were also determined. The results showed that gp120 not only dose-dependently induced DRG neuronal apoptosis and inhibited neuronal survival and neurite outgrowth, but also decreased distinct Trk expression levels. IGF-1 rescued DRG neurons from apoptosis and improved neuronal survival of gp120 neurotoxic DRG neurons in vitro. IGF-1 also improved TrkA and TrkB, but not TrkC, expression in gp120 neurotoxic conditions. The effects of IGF-1 could be blocked by preincubation with the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002. These results suggested that gp120 may have a wide range of neurotoxicity on different subpopulations of DRG neurons, while IGF-1 might only relieve some subpopulations of DRG neurons with gp120-induced neurotoxicity. These data provide novel information of mechanisms of gp120 neurotoxicity on primary sensory neurons and the potential therapeutic effects of IGF-1 on gp120-induced neurotoxicity.

  13. INFLUENCE OF INTRAMUSCULAR APPLICATION OF AUTOLOGOUS CONDITIONED PLASMA ON SYSTEMIC CIRCULATING IGF-1

    Directory of Open Access Journals (Sweden)

    Gert Schippinger

    2011-09-01

    Full Text Available Platelet-rich plasma (PRP to increase levels of platelets and growth factors has been used for the treatment of sports injuries suggesting to improve healing and regeneration. This method offers some potential especially for elite athletes. However, the insulin like growth factor-1 (IGF-1 is prohibited by the World Anti Doping Agency and, in addition, there may be a possible link between increased levels of IGF-1 and cancer risk. Aim of the study was to evaluate a systemic increase of IGF-1 after local intramuscular administration of PRP in young healthy moderately trained male subjects. Blood samples were drawn and PRP preparation was performed by means of centrifugation. Enriched plasma was injected into the gluteus muscle. Venous blood was collected and serum prepared before as well as after 0.5, 3 and 24 hours after PRP administration. IGF-1 analysis was performed applying an ELISA test kit. No significant systemic increase of mean IGF-1 was found after the PRP injection. Only one subject showed an increase after 24 h, but all IGF-1 values were found within reference limits. We conclude that a single intramuscular application of PRP does not significantly increase systemic IGF-1 levels. Therefore, a single application of PRP is safe with respect to systemic IGF-1 response and cancer risk and this should be allowed for treatment of muscle injuries in elite athletes

  14. Possible effects of insulin-like growth factor-I, IGF-binding protein-3 and IGF-1/IGFBP-3 molar ratio on mammographic density: a cross-sectional study.

    Science.gov (United States)

    Meggiorini, M L; Cipolla, V; Borgoni, G; Nofroni, I; Pala, A; de Felice, C

    2012-01-01

    The purpose of this study was to examine the possible effects of IGF-1, IGFBP-3 and IGF-1/IGFBP-3 molar ratio on mammographic density and assess whether this relationship was similar in subgroups of pre- and postmenopausal women. A group of 341 Italian women of childbearing age or naturally postmenopausal who had performed mammographic examination at the section of radiology of our department a maximum three months prior to recruitment were enrolled. A blood sample was drawn for determination of IGF-1, IGFBP-3 levels and IGF-1/IGFBP-3 molar ratio was calculated. On the basis of recent mammograms the women were divided into two groups: dense breast (DB) and non-dense breast (NDB). To assess the association between mammographic density and IGF-1, IGFBP-3 and Molar ratio Student's t-test was employed before and after stratified by menopausal status. The analysis of the relationship between mammographic density and plasma levels of IGF-1, IGFBP-3 and IGF-1/IGFBP-3 molar ratio showed that IGF-1 levels and molar ratio varied in the two groups resulting in higher mean values in the DB group whereas IGFBP-3 showed similar values in both groups (DB and NDB). After stratification of the study population by menopausal status, no association was found. Our study provides strong evidence of a crude association between breast density, and plasma levels of IGF-1 and molar ratio. IGF-1 and molar ratio might increase mammographic density and thus the risk of developing breast cancer.

  15. Effects of short-term caloric restriction on circulating free IGF-I, acid-labile subunit, IGF-binding proteins (IGFBPs)-1-4, and IGFBPs-1-3 protease activity in obese subjects

    DEFF Research Database (Denmark)

    Rasmussen, Michael Højby; Juul, Anders; Kjems, Lise Lund

    2006-01-01

    , no published data exist on free IGF-I levels, acid labile subunit (ALS), or IGFBP protease activity in relation to GH release during a hypocaloric diet. The main purpose of this study was to determine free IGF-I, ALS, IGFBPs-1-4, and IGFBPs-1-3 protease activity in relation to 24-h GH release before and after......Decreased levels of GH and total IGF-I have been reported in obesity. It has been hypothesized that increased free (biologically active) IGF-I levels generated from IGF-binding protein (IGFBP) protease activity could be the mechanism for the low GH release in dieting obese subjects. However...... a short-term very low-calorie diet (VLCD)....

  16. Effects of short-term caloric restriction on circulating free IGF-I, acid-labile subunit, IGF-binding proteins (IGFBPs)-1-4, and IGFBPs-1-3 protease activity in obese subjects

    DEFF Research Database (Denmark)

    Rasmussen, Michael Højby; Juul, Anders; Kjems, Lise Lund

    2006-01-01

    Decreased levels of GH and total IGF-I have been reported in obesity. It has been hypothesized that increased free (biologically active) IGF-I levels generated from IGF-binding protein (IGFBP) protease activity could be the mechanism for the low GH release in dieting obese subjects. However......, no published data exist on free IGF-I levels, acid labile subunit (ALS), or IGFBP protease activity in relation to GH release during a hypocaloric diet. The main purpose of this study was to determine free IGF-I, ALS, IGFBPs-1-4, and IGFBPs-1-3 protease activity in relation to 24-h GH release before and after...... a short-term very low-calorie diet (VLCD)....

  17. Genetic Mutations, Birth Lengths, Weights and Head Circumferences of Children with IGF-I Receptor Defects. Comparison with other Congenital Defects in the GH/IGF-I axis.

    Science.gov (United States)

    Essakow, Jenna Lee; Lauterpacht, Aharon; Lilos, Pearl; Kauli, Rivka; Laron, Zvi

    2016-09-01

    In recent years more and more genetic defects along the GHRH-GH-IGF-I axis have been reported. Mutations of the IGF-I receptor (R) are a rare abnormality of whom only the heterozygote progenies survive. To summarize, from the literature, data on birth length, weight and head circumference of neonates with IGF-I-R mutations, and to correlate the data with that of other types of mutations in the GH/IGF-I axis. Sixty seven neonates from 24 published articles were included and forty seven different mutations of the IGF-I (R) located on chromosome 15 have been identified. Mean (±SD) birth length (BL), available for 26, (10 M, 16F) neonates with a gestational age of 34-41weeks, was 44.2±4cm; one was premature (30cm at 31 weeks). There was a significant correlation between birth length and gestational age (GA) r=0.71 (p>.001). Mean birth weight (BW) of 41 neonates (18M, 23F) was 2388±743gr. Two premature neonates weighed 650gr and 950gr respectively. The BW correlated significantly with gestational age, (males: r=0.68; p=0.007, females: r=0.49; p=0.024). The BMI of 25 neonates ranged from 6 to 13. In 22 records marked microcephaly was ascertained or stated. Nine of 16 mothers were short (133 -148cm), m±SD = 150.5±7.3cm. Copyright© of YS Medical Media ltd.

  18. Estrogen-IGF-1 interactions in neuroprotection: Ischemic Stroke as a case study

    Science.gov (United States)

    Sohrabji, Farida

    2014-01-01

    The steroid hormone 17b-estradiol and the peptide hormone insulin-like growth factor (IGF)-1 independently exert neuroprotective actions in neurologic diseases such as stroke. Only a few studies have directly addressed the interaction between the two hormone systems, however, there is a large literature that indicates potentially greater interactions between the 17b-estradiol and IGF-1 systems. The present review focuses on key issues related to this interaction including IGF-1 and sex differences and common activation of second messenger systems. Using ischemic stroke as a case study, this review also focuses on independent and cooperative actions of estrogen and IGF-1 on neuroprotection, blood brain barrier integrity, angiogenesis, inflammation and post-stroke epilepsy. Finally, the review also focuses on the astrocyte, a key mediator of post stroke repair, as a local source of 17b-estradiol and IGF-1. This review thus highlights areas where significant new research is needed to clarify the interactions between these two neuroprotectants. PMID:24882635

  19. Diagnostic value of a single determination of serum insulin-like growth factor-1 (IGF-1) and IGF binding protein-3 (IGFBP-3) levels in children with growth hormone deficiency (GHD)

    International Nuclear Information System (INIS)

    Lin Gang; Yao Wei; Pan Furong

    2005-01-01

    Objective: To explore the diagnostic value of a single determination of IGF-1 and IGFBP-3 levels for children with GHD. Methods: Serum IGF-1 and IGFBP-3 levels were determined with IRMA in 32 children with GHD, 35 children with idiopathic short-small syndrome (ISS) and 30 controls. Results: Serum IGF-1 and IGFBP-3 levels in children with GHD were significantly lower than those in children with ISS and controls (P 0.05). Conclusion: Determination of serum IGF-1 and IGFBP-3 levels could be applied for screening and diagnosis of GHD, even possibly replacing the classic GH provocative test. (authors)

  20. Serum IGF-1, IGFBP-3 and their ratio: Potential biochemical growth maturity indicators.

    Science.gov (United States)

    Jain, Nimisha; Tripathi, Tulika; Gupta, S K; Rai, Priyank; Kanase, Anup; Kalra, Shilpa

    2017-12-01

    Determination of skeletal maturation and remaining growth potential is an essential part of treatment planning in orthodontics. The aim of our study was to determine the relationship between IGF-1 levels, IGFBP-3 levels with CVM staging to track the pre pubertal and pubertal growth spurts in female patients in North Indian population. This cross-sectional study was conducted on ninety female subjects in the age group of 8-20 years. Blood samples were collected and centrifuged and serum samples were then analysed by Human IGF-1 and IGFBP-3 enzyme-linked immunosorbent assay kits, specific for IGF-1 and IGFBP-3, respectively. CVM staging on lateral cephalometric radiograph was determined for all patients. Analysis of variance test followed by a post hoc test was used to compare mean IGF-1 and IGFBP-3 corresponding to six stages of cervical vertebrae maturation stages. Linear Pearson's correlations were performed to determine the trends of IGF-1, IGFBP-3, and its ratio relating to CVM stage. The kappa statistic was used to measure inter and intra examiner reliability. P value IGF-1 levels were found to be highest (403.3 ± 12.3 ng/ml) at CVMI3 stage of CVMI. The post-hoc test revealed a significant difference in IGF-1 levels between all stages of CVMI, thereby indicating a specific range of IGF-1 levels for a specific skeletal stage. Mean serum IGFBP-3 levels were found to be highest (5186.8 ± 1384.2 ng/ml) at CVMI4 stage of CVMI. The mean serum IGFBP-3 levels at CVMI4 were found to be significantly higher than the levels at all other CVMI stages except CVMI3 stage. IGF-1 and IGFBP-3 can serve as a potential biochemical indicator for assessment of skeletal maturity.

  1. Plasma levels of IGF-1 and IGFBP-3 in patients with brain tumor

    International Nuclear Information System (INIS)

    Zhang Bin; Wu Yiwei; Li Xiangdong

    2004-01-01

    Objective: To determinate the plasma levels of Insulin like growth factor-1 (IGF-1) and Insulin like Growth Factor Binding Protein-3 (IGFBP-3) in patients with glioma and meningioma. Methods: IGF-1 and IGFBP-3 Immunoradiometric assay on coated tubes kits (BIOCODE-HYCEL Belgium) were used to determinate the plasma levels of IGF-1 and IGFBP-3 in 41 cases of glioma (12 cases age 40), 14 cases of meningioma(age>40), and 22 cases of healthy subjects (10 cases age 40). All the diagnosis of patients was confirmed by pathology. Cap-Ria 16 Gamma Counter (CAPINTEC, INC U.S.A) was used to count the radioactivity. Results: Plasma levels of IGF-1 and IGFBP-3 in patients with glioma were 322.20±80.89 ng/mL, 1524.63±373.18 ng/mL (age 40), respectively. Plasma levels of IGF-1 and IGFBP-3 in patients with meningioma were 211.06±75.11 ng/mL, 1403.08±350.78 ng/mL (age >40); control groups were 272.46±49.67 ng/mL, 1453.38±378.73 ng/mL (age 40), respectively. Plasma levels of IGF-1 and IGFBP-3 in patients with glioma(age>40) were significantly higher than in controls (P 0.05). Conclusion: IGF-1 is a risk factor for glioma and play important role in the pathophysiological process of glioma. Endogenous regulation of the balance between IGF-1 and IGFBP-3 may be a model of regulation of cellular growth in tumor cells. (authors)

  2. Insulin Resistance Negatively Influences the Muscle-Dependent IGF-1-Bone Mass Relationship in Premenarcheal Girls.

    Science.gov (United States)

    Kindler, J M; Pollock, N K; Laing, E M; Jenkins, N T; Oshri, A; Isales, C; Hamrick, M; Lewis, R D

    2016-01-01

    IGF-1 promotes bone growth directly and indirectly through its effects on skeletal muscle. Insulin and IGF-1 share a common cellular signaling process; thus, insulin resistance may influence the IGF-1-muscle-bone relationship. We sought to determine the effect of insulin resistance on the muscle-dependent relationship between IGF-1 and bone mass in premenarcheal girls. This was a cross-sectional study conducted at a university research center involving 147 girls ages 9 to 11 years. Glucose, insulin, and IGF-1 were measured from fasting blood samples. Homeostasis model assessment of insulin resistance (HOMA-IR) was calculated from glucose and insulin. Fat-free soft tissue (FFST) mass and bone mineral content (BMC) were measured by dual-energy x-ray absorptiometry. Our primary outcome was BMC/height. In our path model, IGF-1 predicted FFST mass (b = 0.018; P = .001), which in turn predicted BMC/height (b = 0.960; P IGF-1 predicted BMC/height (b = 0.001; P = .002), but not after accounting for the mediator of this relationship, FFST mass. The HOMA-IR by IGF-1 interaction negatively predicted FFST mass (b = -0.044; P = .034). HOMA-IR had a significant and negative effect on the muscle-dependent relationship between IGF-1 and BMC/height (b = -0.151; P = .047). Lean body mass is an important intermediary factor in the IGF-1-bone relationship. For this reason, bone development may be compromised indirectly via suboptimal IGF-1-dependent muscle development in insulin-resistant children.

  3. IGF-1 protects SH-SY5Y cells against MPP+-induced apoptosis via PI3K/PDK-1/Akt pathway.

    Science.gov (United States)

    Kim, Chanyang; Park, Seungjoon

    2018-03-01

    Insulin-like growth factor (IGF)-1 is a well-known anti-apoptotic pro-survival factor and phosphatidylinositol-3-kinase (PI3K)/Akt pathway is linked to cell survival induced by IGF-1. It is also reported that Akt signaling is modulated by 3-phosphoinositide-dependent kinase-1 (PDK1). In the current study, we investigated whether the anti-apoptotic effect of IGF-1 in SH-SY5Y cells exposed to 1-methyl-4-phenylpyridinium (MPP + ) is associated with the activity of PI3K/PDK1/Akt pathway. Treatment of cells with IGF-1 inhibited MPP + -induced apoptotic cell death. IGF-1-induced activation of Akt and the protective effect of IGF-1 on MPP + -induced apoptosis were abolished by chemical inhibition of PDK1 (GSK2334470) or PI3K (LY294002). The phosphorylated levels of Akt and PDK1 were significantly suppressed after MPP + exposure, while IGF-1 treatment completely restored MPP+-induced reductions in phosphorylation. IGF-1 protected cells from MPP + insult by suppressing intracellular reactive oxygen species (ROS) production and malondialdehyde levels and increasing superoxide dismutase activity. Mitochondrial ROS levels were also increased during MPP + exposure, which were attenuated by IGF-1 treatment. In addition, IGF-1-treated cells showed increased activities of succinate dehydrogenase and citrate synthase, stabilization of mitochondrial transmembrane potential, increased ratio of Bcl-2 to Bax, prevention of cytochrome c release and inhibition of caspase-3 activation with PARP cleavage. Furthermore, the protective effects of IGF-1 on oxidative stress and mitochondrial dysfunction were attenuated when cells were preincubated with GSK2334470 or LY294002. Our data suggest that IGF-1 protects SH-SY5Y cells against MPP + -associated oxidative stress by preserving mitochondrial integrity and inhibiting mitochondrial apoptotic cascades via the activation of PI3K/PDK1/Akt pathway. © 2018 The authors.

  4. AAV-mediated pancreatic overexpression of Igf1 counteracts progression to autoimmune diabetes in mice.

    Science.gov (United States)

    Mallol, Cristina; Casana, Estefania; Jimenez, Veronica; Casellas, Alba; Haurigot, Virginia; Jambrina, Claudia; Sacristan, Victor; Morró, Meritxell; Agudo, Judith; Vilà, Laia; Bosch, Fatima

    2017-07-01

    Type 1 diabetes is characterized by autoimmune destruction of β-cells leading to severe insulin deficiency. Although many improvements have been made in recent years, exogenous insulin therapy is still imperfect; new therapeutic approaches, focusing on preserving/expanding β-cell mass and/or blocking the autoimmune process that destroys islets, should be developed. The main objective of this work was to test in non-obese diabetic (NOD) mice, which spontaneously develop autoimmune diabetes, the effects of local expression of Insulin-like growth factor 1 (IGF1), a potent mitogenic and pro-survival factor for β-cells with immunomodulatory properties. Transgenic NOD mice overexpressing IGF1 specifically in β-cells (NOD-IGF1) were generated and phenotyped. In addition, miRT-containing, IGF1-encoding adeno-associated viruses (AAV) of serotype 8 (AAV8-IGF1-dmiRT) were produced and administered to 4- or 11-week-old non-transgenic NOD females through intraductal delivery. Several histological, immunological, and metabolic parameters were measured to monitor disease over a period of 28-30 weeks. In transgenic mice, local IGF1 expression led to long-term suppression of diabetes onset and robust protection of β-cell mass from the autoimmune insult. AAV-mediated pancreatic-specific overexpression of IGF1 in adult animals also dramatically reduced diabetes incidence, both when vectors were delivered before pathology onset or once insulitis was established. Transgenic NOD-IGF1 and AAV8-IGF1-dmiRT-treated NOD animals had much less islet infiltration than controls, preserved β-cell mass, and normal insulinemia. Transgenic and AAV-treated islets showed less expression of antigen-presenting molecules, inflammatory cytokines, and chemokines important for tissue-specific homing of effector T cells, suggesting IGF1 modulated islet autoimmunity in NOD mice. Local expression of Igf1 by AAV-mediated gene transfer counteracts progression to diabetes in NOD mice. This study suggests a

  5. Targeting Extracellular DNA to Deliver IGF-1 to the Injured Heart

    Science.gov (United States)

    Khan, Raffay S.; Martinez, Mario D.; Sy, Jay C.; Pendergrass, Karl D.; Che, Pao-Lin; Brown, Milton E.; Cabigas, E. Bernadette; Dasari, Madhuri; Murthy, Niren; Davis, Michael E.

    2014-03-01

    There is a great need for the development of therapeutic strategies that can target biomolecules to damaged myocardium. Necrosis of myocardium during a myocardial infarction (MI) is characterized by extracellular release of DNA, which can serve as a potential target for ischemic tissue. Hoechst, a histological stain that binds to double-stranded DNA can be conjugated to a variety of molecules. Insulin-like growth factor-1 (IGF-1), a small protein/polypeptide with a short circulating-half life is cardioprotective following MI but its clinical use is limited by poor delivery, as intra-myocardial injections have poor retention and chronic systemic presence has adverse side effects. Here, we present a novel delivery vehicle for IGF-1, via its conjugation to Hoechst for targeting infarcted tissue. Using a mouse model of ischemia-reperfusion, we demonstrate that intravenous delivery of Hoechst-IGF-1 results in activation of Akt, a downstream target of IGF-1 and protects from cardiac fibrosis and dysfunction following MI.

  6. Increased cardiogenesis in P19-GFP teratocarcinoma cells expressing the propeptide IGF-1Ea

    Energy Technology Data Exchange (ETDEWEB)

    Poudel, Bhawana [Heart Science Centre, National Heart and Lung Institute, Imperial College, London (United Kingdom); Bilbao, Daniel [EMBL, Mouse Biology Unit, Monterotondo (Italy); Sarathchandra, Padmini; Germack, Renee [Heart Science Centre, National Heart and Lung Institute, Imperial College, London (United Kingdom); Rosenthal, Nadia [Heart Science Centre, National Heart and Lung Institute, Imperial College, London (United Kingdom); Australian Regenerative Medicine Institute, Monash University, Melbourne (Australia); Santini, Maria Paola, E-mail: m.santini@imperial.ac.uk [Heart Science Centre, National Heart and Lung Institute, Imperial College, London (United Kingdom)

    2011-12-16

    Highlights: Black-Right-Pointing-Pointer In this study, we explored the function of IGF-1Ea propeptide in inducing cardiogenesis of stem cells. Black-Right-Pointing-Pointer IGF-1Ea promoted cardiac mesodermal induction in uncommitted cells. Black-Right-Pointing-Pointer Under differentiation condition, IGF-1Ea increased expression of cardiac differentiation markers. Black-Right-Pointing-Pointer Furthermore, it promoted formation of finely organized sarcomeric structure. Black-Right-Pointing-Pointer IGF-1Ea propeptide may be a good candidate to improve production of cardiomyocytes from pluripotent cells. -- Abstract: The mechanism implicated in differentiation of endogenous cardiac stem cells into cardiomyocytes to regenerate the heart tissue upon an insult remains elusive, limiting the therapeutical goals to exogenous cell injection and/or gene therapy. We have shown previously that cardiac specific overexpression of the insulin-like growth factor 1 propeptide IGF-1Ea induces beneficial myocardial repair after infarct. Although the mechanism is still under investigation, the possibility that this propeptide may be involved in promoting stem cell differentiation into the cardiac lineage has yet to be explored. To investigate whether IGF-1Ea promote cardiogenesis, we initially modified P19 embryonal carcinoma cells to express IGF-1Ea. Taking advantage of their cardiomyogenic nature, we analyzed whether overexpression of this propeptide affected cardiac differentiation program. The data herein presented showed for the first time that constitutively overexpressed IGF-1Ea increased cardiogenic differentiation program in both undifferentiated and DMSO-differentiated cells. In details, IGF-1Ea overexpression promoted localization of alpha-actinin in finely organized sarcomeric structure compared to control cells and upregulated the cardiac mesodermal marker NKX-2.5 and the ventricular structural protein MLC2v. Furthermore, activated IGF-1 signaling promoted cardiac

  7. Increased cardiogenesis in P19-GFP teratocarcinoma cells expressing the propeptide IGF-1Ea

    International Nuclear Information System (INIS)

    Poudel, Bhawana; Bilbao, Daniel; Sarathchandra, Padmini; Germack, Renee; Rosenthal, Nadia; Santini, Maria Paola

    2011-01-01

    Highlights: ► In this study, we explored the function of IGF-1Ea propeptide in inducing cardiogenesis of stem cells. ► IGF-1Ea promoted cardiac mesodermal induction in uncommitted cells. ► Under differentiation condition, IGF-1Ea increased expression of cardiac differentiation markers. ► Furthermore, it promoted formation of finely organized sarcomeric structure. ► IGF-1Ea propeptide may be a good candidate to improve production of cardiomyocytes from pluripotent cells. -- Abstract: The mechanism implicated in differentiation of endogenous cardiac stem cells into cardiomyocytes to regenerate the heart tissue upon an insult remains elusive, limiting the therapeutical goals to exogenous cell injection and/or gene therapy. We have shown previously that cardiac specific overexpression of the insulin-like growth factor 1 propeptide IGF-1Ea induces beneficial myocardial repair after infarct. Although the mechanism is still under investigation, the possibility that this propeptide may be involved in promoting stem cell differentiation into the cardiac lineage has yet to be explored. To investigate whether IGF-1Ea promote cardiogenesis, we initially modified P19 embryonal carcinoma cells to express IGF-1Ea. Taking advantage of their cardiomyogenic nature, we analyzed whether overexpression of this propeptide affected cardiac differentiation program. The data herein presented showed for the first time that constitutively overexpressed IGF-1Ea increased cardiogenic differentiation program in both undifferentiated and DMSO-differentiated cells. In details, IGF-1Ea overexpression promoted localization of alpha-actinin in finely organized sarcomeric structure compared to control cells and upregulated the cardiac mesodermal marker NKX-2.5 and the ventricular structural protein MLC2v. Furthermore, activated IGF-1 signaling promoted cardiac mesodermal induction in undifferentiated cells independently of cell proliferation. This analysis suggests that IGF-1Ea may be a

  8. Role of the Insulin-Like Growth Factor Type 1 Receptor in the Pathogenesis of Diabetic Encephalopathy

    Directory of Open Access Journals (Sweden)

    Duo Zhang

    2015-01-01

    Full Text Available Defective cognitive function is common in patients with diabetes, suggesting that insulin normally exerts anabolic actions in neuron, namely, diabetic encephalopathy. However, because insulin can cross-activate the insulin-like growth factor type 1 receptor (IGF-1R, which also functions in most of tissues, such as muscle and bone, it has been difficult to establish the direct (IGF-1-independent actions of insulin in the pathogenesis of diabetic encephalopathy. To overcome this problem, we examined insulin signaling and action in primary PC-12 cells engineered for conditional disruption of the IGF-1 receptorIGF-1R. The results showed that the lower glucose metabolism and high expression of IGF-1R occurred in the brain of the DE rat model. The results also showed the defect of IGF-1R could significantly improve the ability of glucose consumption and enhance sensitivity to insulin-induced IR and Akt phosphorylation in PC12 cells. And meanwhile, IGF-1R allele gene knockout (IGF-1Rneo mice treated with HFD/STZ had better cognitive abilities than those of wild mice. Those results indicate that insulin exerts direct anabolic actions in neuron-like cells by activation of its cognate receptor and prove that IGF-1R plays an important role in the pathogenesis of diabetic encephalopathy.

  9. IGF-1 promotes Brn-4 expression and neuronal differentiation of neural stem cells via the PI3K/Akt pathway.

    Directory of Open Access Journals (Sweden)

    Xinhua Zhang

    Full Text Available Our previous studies indicated that transcription factor Brn-4 is upregulated in the surgically denervated hippocampus in vivo, promoting neuronal differentiation of hippocampal neural stem cells (NSCs in vitro. The molecules mediating Brn-4 upregulation in the denervated hippocampus remain unknown. In this study we examined the levels of insulin-like growth factor-1 (IGF-1 in hippocampus following denervation. Surgical denervation led to a significant increase in IGF-1 expression in vivo. We also report that IGF-1 treatment on NSCs in vitro led to a marked acceleration of Brn-4 expression and cell differentiation down neuronal pathways. The promotion effects were blocked by PI3K-specific inhibitor (LY294002, but not MAPK inhibitor (PD98059; levels of phospho-Akt were increased by IGF-1 treatment. In addition, inhibition of IGF-1 receptor (AG1024 and mTOR (rapamycin both attenuated the increased expression of Brn-4 induced by IGF-1. Together, the results demonstrated that upregulation of IGF-1 induced by hippocampal denervation injury leads to activation of the PI3K/Akt signaling pathway, which in turn gives rise to upregulation of the Brn-4 and subsequent stem cell differentiation down neuronal pathways.

  10. Targeting non-small cell lung cancer cells by dual inhibition of the insulin receptor and the insulin-like growth factor-1 receptor.

    Directory of Open Access Journals (Sweden)

    Emma E Vincent

    Full Text Available Phase III trials of the anti-insulin-like growth factor-1 receptor (IGF1R antibody figitumumab in non-small cell lung cancer (NSCLC patients have been discontinued owing to lack of survival benefit. We investigated whether inhibition of the highly homologous insulin receptor (IR in addition to the IGF1R would be more effective than inhibition of the IGF1R alone at preventing the proliferation of NSCLC cells. Signalling through IGF1R and IR in the NSCLC cell lines A549 and Hcc193 was stimulated by a combination of IGF1, IGF2 and insulin. It was inhibited by antibodies that block ligand binding, αIR3 (IGF1R and IR47-9 (IR, and by the ATP-competitive small molecule tyrosine kinase inhibitors AZ12253801 and NVPAWD742 which inhibit both IGF1R and IR tyrosine kinases. The effect of inhibitors was determined by an anchorage-independent proliferation assay and by analysis of Akt phosphorylation. In Hcc193 cells the reduction in cell proliferation and Akt phosphorylation due to anti-IGF1R antibody was enhanced by antibody-mediated inhibition of the IR whereas in A549 cells, with a relatively low IR:IGF1R expression ratio, it was not. In each cell line proliferation and Akt phosphorylation were more effectively inhibited by AZ12253801 and NVPAWD742 than by combined αIR3 and IR47-9. When the IGF1R alone is inhibited, unencumbered signalling through the IR can contribute to continued NSCLC cell proliferation. We conclude that small molecule inhibitors targeting both the IR and IGF1R more effectively reduce NSCLC cell proliferation in a manner independent of the IR:IGF1R expression ratio, providing a therapeutic rationale for the treatment of this disease.

  11. Elevated serum IGF-1 level enhances retinal and choroidal thickness in untreated acromegaly patients.

    Science.gov (United States)

    Zhang, Xia; Ma, Jin; Wang, Yuhan; Li, Lüe; Gao, Lu; Guo, Xiaopeng; Xing, Bing; Zhong, Yong

    2018-03-01

    1) To compare the retinal, choroidal, Haller's layer, and Sattler's/choriocapillaris thicknesses of untreated acromegaly patients without chiasm compression or diabetes mellitus and healthy controls. 2) To evaluate the correlations of retinal and choroidal thicknesses with serum growth hormone (GH) and insulin-like growth factor 1 (IGF) burden. This prospective, case-control study included 27 untreated acromegaly patients and 27 sex-matched and age-matched controls. Subfoveal choroidal, Haller's layer and Sattler's/choriocapillaris thicknesses were determined by enhanced-depth imaging optical coherence tomography (EDI-OCT). Foveal and macular retinal thicknesses were determined with SD-OCT. GH and IGF-1 burdens were defined as the product of disease duration and treatment-naïve serum GH and IGF-1 levels. Compared with healthy controls, patients with acromegaly exhibited significantly increased foveal retinal (p = 0.003), subfoveal choroidal (p IGF-1 level (p = 0.03) and IGF-1 burden (p = 0.009). No significant correlations were detected between choroidal thickness and GH burden (p = 0.44). Retinal thickness was not significantly correlated with any factor. The choroidal thickness of acromegaly patients was greater than that of healthy controls and was significantly correlated with disease duration, IGF-1 level and IGF-1 burden, indicating that excessive serum IGF-1 and its exposure time have a combined effect on choroidal thickness.

  12. The relationship between serum IGF-1, handgrip strength, physical performance and falls in elderly men and women.

    Science.gov (United States)

    Van Nieuwpoort, Caroline; Vlot, Mariska; Schaap, Laura; Lips, Paul; Drent, Madeleine

    2018-05-22

    Human aging is accompanied by a decrease in growth hormone secretion and serum IGF-1 levels. Also, loss of muscle mass, strength and impairment of physical performance, ending in a state of frailty, are seen in elderly. We aimed to investigate whether handgrip strength, physical performance and recurrent falls are related to serum IGF-1 levels in community dwelling elderly. Observational cohort study (cross-sectional and prospective). We studied the association between IGF-1 and handgrip strength, physical performance and falls in participants of the Longitudinal Aging Study Amsterdam. 1292 participants were included (633 men, 659 women). Serum IGF-1 levels were divided into quartiles (IGF-1-Q1 to IGF-1-Q4). Data on falls were collected prospectively for a period of three years. All analyses were stratified for age and physical activity and adjusted for relevant confounders. Men with a low physical activity score in IGF-1-Q1 and IGF-1-Q2 of the younger age group had a lower handgrip strength compared to IGF-1-Q4. In younger more active males in IGF-1-Q2 physical performance was worse. Recurrent fallers were less prevalent in older, low active males with low IGF-1 levels. In females, recurrent fallers were more prevalent in older, more active females in IGF-1-Q2. IGF-1 quartile may predict changes in handgrip strength and physical performance in men and women. Our results indicate that lower IGF-1 levels are associated with lower handgrip strength and worse physical performance, but less recurrent fallers especially in men. Associations were often more robust in IGF-1-Q2. Future studies on this topic are desirable.

  13. Partial IGF-1 deficiency induces brain oxidative damage and edema, which are ameliorated by replacement therapy.

    Science.gov (United States)

    Puche, Juan E; Muñoz, Úrsula; García-Magariño, Mariano; Sádaba, María C; Castilla-Cortázar, Inma

    2016-01-01

    Insulin-like growth factor 1 (IGF-1) induces multiple cytoprotective effects on every tissue, including the brain. Since the mechanisms by which IGF-1 produces neuroprotection are not fully understood, the aim of this work was to delve into the underlying mechanisms. IGF-1 deficient mice (Hz) were compared with wild type (WT) and Hz mice treated with low doses of IGF-1 (2 µg/100 g body weight/day) for 10 days (Hz + IGF). Gene expression, quantitative PCR, histology, and magnetic resonance imaging were performed in the three groups. IGF-1 deficiency induced increased oxidative damage determined by markers of lipid peroxidation and hypoxia, as well as gene expression of heat shock proteins, antioxidant enzymes, and molecules involved in inflammation, apoptosis, and mitochondrial protection. These changes correlated with edema and learning impairment in Hz mice. IGF-1 therapy improved all these alterations. In conclusion, IGF-1 deficiency is responsible for increased brain oxidative damage, edema, and impaired learning and memory capabilities which are rescued by IGF-1 replacement therapy. © 2016 International Union of Biochemistry and Molecular Biology.

  14. Differential effects of casein versus whey on fasting plasma levels of insulin, IGF-1 and IGF-1/IGFBP-3

    DEFF Research Database (Denmark)

    Hoppe, Camilla; Mølgaard, Christian; Dalum, Cathrine

    2009-01-01

    to the identification of which components in milk that stimulate growth, we have performed an intervention study with 57 eight-year-old boys in which we examined the effects of the two major milk protein fractions, whey and casein, and milk minerals (Ca and P) in a 2x2 factorial design on IGFs and glucose......–insulin metabolism. The amounts of whey and casein were identical to the content in 1.5 l skim milk. The amounts of Ca and P were similar to 1.5 l skim milk in the high-mineral drinks, whereas the amounts of Ca and P were reduced in the low-mineral drinks. Results: There were no interactions between milk mineral...... groups (high, low) and milk protein groups (whey, casein). Serum IGF-1 increased by 15% (P...

  15. Possible roles of insulin, IGF-1 and IGFBPs in initiation and progression of colorectal cancer

    Science.gov (United States)

    Jiang, Bo; Zhang, Xin; Du, Li-Li; Wang, Yan; Liu, Dong-Bo; Han, Cun-Zhi; Jing, Jie-Xian; Zhao, Xian-Wen; Xu, Xiao-Qin

    2014-01-01

    AIM: To investigate the roles of serum insulin, insulin-like growth factor-1 (IGF-1), and insulin-like growth factor binding proteins (IGFBPs) in the initiation and progression of colorectal cancer. METHODS: We determined serum insulin, IGF-1 and IGFBPs levels in 615 colorectal cancer patients and 650 control healthy donors by enzyme-linked immunosorbent assay (ELISA). In the meantime, their body mass index (BMI) and waist-to-hip ratio (WHR) were measured. RESULTS: Serum levels of insulin and IGF-1 as well as IGF-1/IGFBP-3 ratio in pre-operation patients were significantly elevated, but the level of IGFBP-3 was significantly decreased compared with normal controls and post-operation patients (P 0.05) in the levels of insulin, IGF-1, IGFBP-1, IGFBP-3 and IGF-1/IGFBP-3 between the patients with and without hepatic as well as distal abdominal metastases. WHR and BMI of colon cancer patients were positively and significantly correlated with the levels of insulin and IGF-1/IGFBP-3. In contrast, WHR and BMI were negatively correlated with IGFBP-3 level. CONCLUSION: The elevation of insulin, IGF-1 as well as IGF-1/IGFBP-3 ratio and the reduction of IGFBP-3 may be related to the initiation of colorectal cancer, but they are not related to the progression and outcome of the disease. PMID:24587638

  16. The potential role of IGF-I receptor mRNA in rats with diabetic retinopathy

    Institute of Scientific and Technical Information of China (English)

    匡洪宇; 邹伟; 刘丹; 史榕荇; 程丽华; 殷慧清; 刘晓民

    2003-01-01

    Objective To evaluate the potential role of insulin-like growth factor-1 receptor mRNA(IGF-IR mRNA) in the onset and development of retinopathy in diabetic rats.Methods A diabetic model was duplicated in Wistar rats. The early changes in the retina were examined using light and transmission electron microscopy. Expression of IGF-IR mRNA was analyzed using in situ hybridization.Results Weak expression of IGF-IR mRNA(5%) was found in retinas of normal rats, but was significantly increased (15% and 18%) in the retinas of diabetic rats after 3 and 6 months of diabetes (P<0.01). In situ hybridization and morphological study demonstrated that there was a positive correlation between IGF-IR mRNA expression and retinal changes at various stages.Conclusion Increased IGF-IR mRNA might play an important role in the onset and development of diabetic retinopathy.

  17. Recombinant human IGF-1 produced by transgenic plant cell suspension culture enhances new bone formation in calvarial defects.

    Science.gov (United States)

    Poudel, Sher Bahadur; Bhattarai, Govinda; Kook, Sung-Ho; Shin, Yun-Ji; Kwon, Tae-Ho; Lee, Seung-Youp; Lee, Jeong-Chae

    2017-10-01

    Transgenic plant cell suspension culture systems have been utilized extensively as convenient and efficient expression systems for the production of recombinant human growth factors. We produced insulin-like growth factor-1 using a plant suspension culture system (p-IGF-1) and explored its effect on new bone formation in calvarial defects. We also compared the bone regenerating potential of p-IGF-1 with commercial IGF-1 derived from Escherichia coli (e-IGF-1). Male C57BL/6 mice underwent calvarial defect surgery, and the defects were loaded with absorbable collagen sponge (ACS) only (ACS group) or ACS impregnated with 13μg of p-IGF-1 (p-IGF-1 group) or e-IGF-1 (e-IGF-1 group). The sham group did not receive any treatment with ACS or IGFs after surgery. Live μCT and histological analyses showed critical-sized bone defects in the sham group, whereas greater bone formation was observed in the p-IGF-1 and e-IGF-1 groups than the ACS group both 5 and 10weeks after surgery. Bone mineral density, bone volume, and bone surface values were also higher in the IGF groups than in the ACS group. Local delivery of p-IGF-1 or e-IGF-1 more greatly enhanced the expression of osteoblast-specific markers, but inhibited osteoclast formation, in newly formed bone compared with ACS control group. Specifically, p-IGF-1 treatment induced higher expression of alkaline phosphatase, osteocalcin, and osteopontin in the defect site than did e-IGF-1. Furthermore, treatment with p-IGF-1, but not e-IGF-1, increased mineralization of MC3T3-E1 cells, with the attendant upregulation of osteogenic marker genes. Collectively, our findings suggest the potential of p-IGF-1 in promoting the processes required for bone regeneration. Copyright © 2017. Published by Elsevier Ltd.

  18. Over-stimulation of insulin/IGF-1 signaling by western diet may promote diseases of civilization: lessons learnt from laron syndrome

    OpenAIRE

    Schmitz Gerd; John Swen; Melnik Bodo C

    2011-01-01

    Abstract The insulin/insulin-like growth factor-1 (IGF-1) pathway drives an evolutionarily conserved network that regulates lifespan and longevity. Individuals with Laron syndrome who carry mutations in the growth hormone receptor (GHR) gene that lead to severe congenital IGF-1 deficiency with decreased insulin/IGF-1 signaling (IIS) exhibit reduced prevalence rates of acne, diabetes and cancer. Western diet with high intake of hyperglycemic carbohydrates and insulinotropic dairy over-stimulat...

  19. Relationship between adiponectin, leptin, IGF-1 and total lipid peroxides plasma concentrations in patients with systemic sclerosis: possible role in disease development.

    Science.gov (United States)

    Winsz-Szczotka, Katarzyna; Kuźnik-Trocha, Kornelia; Komosińska-Vassev, Katarzyna; Kucharz, Eugeniusz; Kotulska, Anna; Olczyk, Krystyna

    2016-07-01

    The relationship between adiponectin, leptin, insulin-like growth factor-1 (IGF-1) and total lipid peroxide (TLP) concentrations, and its possible role in the development of diffuse cutaneous systemic sclerosis (dcSSc), were evaluated in this study. Plasma adipokines and IGF-1 levels were determined using the enzyme-linked immunosorbent assay method, whereas TLP levels were determined using a photometric test, in 36 dcSSc patients and 40 healthy controls matched by age, sex and body mass index (BMI). Plasma levels of adipokines were significantly lowered, while TLP and IGF-1 were increased in dcSSc patients compared to controls. Adiponectin correlated significantly with leptin (r = 0.44), TLP (r = -0.54), CRP (r = -0.47), erythrocyte sedimentation rate (ESR) (r = -0.40) and duration of disease (r = -0.44). A significant relationship was found between leptinemia and IGF-1 (r = -0.40), TLP (r = 0.44), duration of disease (r = -0.38) and BMI (r = 0.65). TLP correlated with IGF-1 (r = -0.43), C-reactive protein (r = 0.47), ESR (r = 0.49) and duration of disease (r = 0.46), while IGF-1 correlated with ESR (r = -0.40). Adipose tissue may play a complex role in the development of dcSSc, affecting both the metabolic state of the organism, as well as free radical-induced connective tissue degradation. Although, leptin seems to exert a pro-oxidative effect and both adiponectin and IGF-1 appear to prevent free radical damage, confirmation of the above effects requires further research. © 2014 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd.

  20. IGFBP-1 and IGF-I as markers for advanced fibrosis in NAFLD - a pilot study.

    Science.gov (United States)

    Hagström, Hannes; Stål, Per; Hultcrantz, Rolf; Brismar, Kerstin; Ansurudeen, Ishrath

    2017-12-01

    Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease globally. Advanced fibrosis (stage 3-4) is the most robust marker for future mortality, but diagnosis requires liver biopsy. Current non-invasive scoring systems aimed to identify advanced fibrosis are imperfect. Insulin-like growth factor I (IGF-I) and its binding protein IGFBP-1 are liver derived proteins, that are involved in various liver disorders. The aim of this study was to examine the possible association between advanced fibrosis and IGF-I and IGFBP-1 in NAFLD. Fasting blood samples were obtained from 52 patients diagnosed with NAFLD by liver biopsy. Total IGF-I and IGFBP-1 concentrations were determined in serum by in-house radio-immuno-assays. IGF-I levels were age-standardized (IGF-SD). A logistic regression model was used to investigate the association of IGF-SD and IGFBP-1 with advanced fibrosis (stage 3-4). Patients with advanced fibrosis (stage 3-4 vs. 0-2) had lower IGF-SD (-1.17 vs. 0.11, p = .01) and higher mean levels of IGFBP-1 (29.9 vs. 18.8 µg/l, p = .02). IGFBP-1 was associated with presence of advanced fibrosis (OR 1.04 per unit increase, 95%CI 1.0-1.07, p = .05), while IGF-1 was negatively associated with advanced fibrosis (OR 0.63 per standard deviation, 95%CI 0.44-0.92, p = .02). This pilot study suggests an association between serum IGFBP-1 and IGF-I levels with advanced fibrosis in NAFLD patients. IGFBP1 and IGF-1 could be of interest as future biomarkers. Similar studies in larger cohorts are needed.

  1. Comparison of acid ethanol extraction and acid gel filtration prior to IGF-I and IGF-II radioimmunoassays

    International Nuclear Information System (INIS)

    Bang, P.; Eriksson, U.; Wivall, I.-L.; Hall, K.; Sara, V.

    1991-01-01

    Insulin-like growth factor binding proteins interfere in the IGF-I and -II radioimmunoassays. In an attempt to overcome this problem, we have compared the use of truncated IGF-I, with reduced IGFBP affinity, and IGF-I as radioligands for IGF-I RIA measurements in serum separated by acid gel filtration or acid ethanol extraction followed by cryo-precipitation. With truncated IGF-I as radioligand the IGF-I measurements in acid gel filtrates and acid ethanol extracts were significantly correlated in healthy subjects (N=42, r=0.91, p<0.001) and in patients with acromegaly (N=10, r=0.85, p<0.01), GH deficiency (N=10, r=0.88, p<0.001) or Type I diabetes mellitus (N=10, r=0.90, p<0.001). In contrast, the IGF-I concentrations in acid ethanol extracts determined with IGF-I as radioligand did not correlate with those in acid gel filtrates using truncated IGF-I radioligand in patients with acromegaly (r=0.61, NS) or GH deficiency (r=0.46, NS). In the latter group the mean IGF-I concentrations measured in acid ethanol extracts were erroneously elevated by 112%. Low-affinity antibodies used for IGF-II RIA determinations failed to give reliable results in acid ethanol extracts from patients with Type I diabetes mellitus or GH deficiency. In conclusion, erroneously high IGF-I concentrations owing to binding of the radioligand to IGFBPs not completely removed by acid ethanol extraction can be avoided by the use of truncated IGF-I as radioligand. (author)

  2. Activity-Dependent IGF-1 Exocytosis is Controlled by the Ca2+-Sensor Synaptotagmin-10

    Science.gov (United States)

    Cao, Peng; Maximov, Anton; Südhof, Thomas C.

    2011-01-01

    Synaptotagmins Syt1, Syt2, Syt7, and Syt9 act as Ca2+-sensors for synaptic and neuroendocrine exocytosis, but the function of other synaptotagmins remains unknown. Here, we show that olfactory bulb neurons secrete IGF-1 by an activity-dependent pathway of exocytosis, and that Syt10 functions as the Ca2+-sensor that triggers IGF-1 exocytosis in these neurons. Deletion of Syt10 impaired activity-dependent IGF-1 secretion in olfactory bulb neurons, resulting in smaller neurons and an overall decrease in synapse numbers. Exogenous IGF-1 completely reversed the Syt10 knockout phenotype. Syt10 co-localized with IGF-1 in somatodendritic vesicles of olfactory bulb neurons, and Ca2+-binding to Syt10 caused these vesicles to undergo exocytosis, thereby secreting IGF-1. Thus, Syt10 controls a previously unrecognized pathway of Ca2+-dependent exocytosis that is spatially and temporally distinct from Ca2+-dependent synaptic vesicle exocytosis controlled by Syt1 in the same neurons, and two different synaptotagmins regulate distinct Ca2+-dependent membrane fusion reactions during exocytosis in the same neuron. PMID:21496647

  3. Local myocardial insulin-like growth factor 1 (IGF-1) delivery with biotinylated peptide nanofibers improves cell therapy for myocardial infarction

    Science.gov (United States)

    Davis, Michael E.; Hsieh, Patrick C. H.; Takahashi, Tomosaburo; Song, Qing; Zhang, Shuguang; Kamm, Roger D.; Grodzinsky, Alan J.; Anversa, Piero; Lee, Richard T.

    2006-05-01

    Strategies for cardiac repair include injection of cells, but these approaches have been hampered by poor cell engraftment, survival, and differentiation. To address these shortcomings for the purpose of improving cardiac function after injury, we designed self-assembling peptide nanofibers for prolonged delivery of insulin-like growth factor 1 (IGF-1), a cardiomyocyte growth and differentiation factor, to the myocardium, using a "biotin sandwich" approach. Biotinylated IGF-1 was complexed with tetravalent streptavidin and then bound to biotinylated self-assembling peptides. This biotin sandwich strategy allowed binding of IGF-1 but did not prevent self-assembly of the peptides into nanofibers within the myocardium. IGF-1 that was bound to peptide nanofibers activated Akt, decreased activation of caspase-3, and increased expression of cardiac troponin I in cardiomyocytes. After injection into rat myocardium, biotinylated nanofibers provided sustained IGF-1 delivery for 28 days, and targeted delivery of IGF-1 in vivo increased activation of Akt in the myocardium. When combined with transplanted cardiomyocytes, IGF-1 delivery by biotinylated nanofibers decreased caspase-3 cleavage by 28% and increased the myocyte cross-sectional area by 25% compared with cells embedded within nanofibers alone or with untethered IGF-1. Finally, cell therapy with IGF-1 delivery by biotinylated nanofibers improved systolic function after experimental myocardial infarction, demonstrating how engineering the local cellular microenvironment can improve cell therapy. engineering | maturation | scaffold

  4. INSULIN-LIKE GROWTH FACTOR-1 (IGF-1: DEMOGRAPHIC, CLINICAL AND LABORATORY DATA IN 120 CONSECUTIVE ADULT PATIENTS WITH THALASSAEMIA MAJOR

    Directory of Open Access Journals (Sweden)

    V. De Sanctis

    2014-11-01

    Full Text Available Introduction:  Insulin-like growth factor 1 (IGF-1 is a key peptide involved in cell growth and protein turnover, acting as the primary mediator of many of the responses regulated by growth hormone (GH in tissues. Signs and symptoms of adult GH deficiency (AGHD in patients with β-thalassaemia major (TM  may be subtle and overlap with those of the disease itself; therefore, the diagnosis may be missed or delayed, with potentially serious consequences. The diagnosis of AGHD requires an appropriate clinical setting and is confirmed through biochemical testing. The  aim of this study  was  to measure IGF-1 values and other clinical data in a large number of adult  patients with TM and to  evaluate whether an  IGF-1 concentration 2 SDs below normative values  could be used as an effective index supporting  the probable presence of  AGHD. Patients and Methods: A cohort of 120 adult patients with TM was studied for plasma levels of IGF-1. Plasma total IGF-1 was determined by chemiluminescent immunometric assay (CLIA method. In eleven patients (4 males the GH response during glucagon stimulation test (GST was also evaluated.  Results:  Fifty percent of patients (33 males and 27 females had IGF-1 levels   -2SDs. In multivariate regression analyses,  height, weight, BMI, serum ferritin, ALT, HCV serology and left ventricular ejection fraction (LVEF were not significantly related to IGF-1,  but a significant correlation was found in females between HCV-RNA positivity and IGF-1, ALT and serum ferritin (p= 0.043. AGHD was diagnosed in 6 (4 males out of 11 patients (54.5% who had glucagon stimulation tests and in 5 out of 8 (62.5% with IGF-1 <-2SD. The mean age of patients with GHD was 39.3 years (range: 25-49 years versus 35.8 years (range: 27-45 years in non-GHD patients. A positive correlation between GH peak after GST and IGF-1 level was found (r: 0.6409; p: < 0.05. Conclusions: On the basis of the present results and data from the

  5. IGF1 as predictor of all cause mortality and cardiovascular disease in an elderly population

    DEFF Research Database (Denmark)

    Andreassen, Mikkel; Raymond, Ilan; Kistorp, Caroline

    2009-01-01

    BACKGROUND: IGF1 is believed to influence ageing and development of cardiovascular disease (CVD) through complex mechanisms. Reduced IGF1 levels might be causally associated with conditions accompanying ageing including development of CVD. However, in animal models reduced GH-IGF1 signalling...... increases lifespan. Reduced IGF1 activity might also be associated with longevity in humans. OBJECTIVE: The objective was to investigate if plasma IGF1 levels were associated with all cause mortality, and the development of chronic heart failure (CHF) and a major CV event. PATIENTS AND DESIGN: A population...... systolic function and without prevalent CVD. Outcomes were ascertained after 5 years using hospital discharge diagnoses. RESULTS: Adjustment for risk factors IGF1 values in the fourth quartile versus values below the fourth quartile was associated with increased mortality (n=103), hazard ratio (HR) 1...

  6. Synergistic effect of DHT and IGF-1 hyperstimulation in human peripheral blood lymphocytes.

    Science.gov (United States)

    Imperlini, Esther; Spaziani, Sara; Mancini, Annamaria; Caterino, Marianna; Buono, Pasqualina; Orrù, Stefania

    2015-06-01

    The abuse of mixed or combined performance-enhancing drugs is widespread among athletes and amateurs, adults and adolescents. Clinical studies demonstrated that misuse of these doping agents is associated with serious adverse effects to many organs in human. Previously, we demonstrated in human peripheral blood lymphocytes that high doses of anabolic androgenic steroids, such as dihydrotestosterone (DHT) and growth factors, such as insulin-like growth factor-1 (IGF-1), have effects at gene and protein levels. Supraphysiological treatments of DHT and IGF-1 affected the expression of genes involved in skeletal muscle disorders as well as in cell-mediated immunological response. At protein level, DHT hyperdosage affects cell motility and apoptosis; IGF-1 hyperstimulation triggers an active cytoskeletal reorganization and an overproduction of immune response- and inflammation-related cytokines. In this study, we investigate the combined effects of DHT and IGF-1 hyperdosage in peripheral blood lymphocytes using a differential proteomic approach. DHT and IGF-1 combined treatment affects cell adhesion, migration, and survival through modulation of expression levels of cytokines and paxillin-signaling-related proteins, and activation of several pathways downstream focal adhesion kinase. Our results indicate a synergistic effect of DHT and IGF-1 which has potential implications for health risk factors. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  7. Co-inhibition of epidermal growth factor receptor and insulin-like growth factor receptor 1 enhances radiosensitivity in human breast cancer cells

    International Nuclear Information System (INIS)

    Li, Ping; Veldwijk, Marlon R; Zhang, Qing; Li, Zhao-bin; Xu, Wen-cai; Fu, Shen

    2013-01-01

    Over-expression of epidermal growth factor receptor (EGFR) or insulin-like growth factor-1 receptor (IGF-1R) have been shown to closely correlate with radioresistance of breast cancer cells. This study aimed to investigate the impact of co-inhibition of EGFR and IGF-1R on the radiosensitivity of two breast cancer cells with different profiles of EGFR and IGF-1R expression. The MCF-7 (EGFR +/−, IGF-1R +++) and MDA-MB-468 (EGFR +++, IGF-1R +++) breast cancer cell lines were used. Radiosensitizing effects were determined by colony formation assay. Apoptosis and cell cycle distribution were measured by flow cytometry. Phospho-Akt and phospho-Erk1/2 were quantified by western blot. In vivo studies were conducted using MDA-MB-468 cells xenografted in nu/nu mice. In MDA-MB-468 cells, the inhibition of IGF-1R upregulated the p-EGFR expression. Either EGFR (AG1478) or IGF-1R inhibitor (AG1024) radiosensitized MDA-MB-468 cells. In MCF-7 cells, radiosensitivity was enhanced by AG1024, but not by AG1478. Synergistical radiosensitizing effect was observed by co-inhibition of EGFR and IGF-1R only in MDA-MB-468 cells with a DMF 10% of 1.90. The co-inhibition plus irradiation significantly induced more apoptosis and arrested the cells at G0/G1 phase in MDA-MB-468 cells. Only co-inhibition of EGFR and IGF-1R synergistically diminished the expression of p-Akt and p-Erk1/2 in MDA-MB-468 cells. In vivo studies further verified the radiosensitizing effects by co-inhibition of both pathways in a MDA-MB-468 xenograft model. Our data suggested that co-inhibition of EGFR and IGF-1R synergistically radiosensitized breast cancer cells with both EGFR and IGF-1R high expression. The approach may have an important therapeutic implication in the treatment of breast cancer patients with high expression of EGFR and IGF-1R

  8. Reduced utility of serum IGF-1 levels in predicting retinopathy of prematurity reflects maternal ethnicity.

    Science.gov (United States)

    Reddy, M Ashwin; Patel, Himanshu I; Karim, Shah M; Lock, Helen; Perry, Leslie; Bunce, Catey; Kempley, Steve; Sinha, Ajay K

    2016-04-01

    To validate known risk factors and identify a threshold level for serum insulin-like growth factor 1 (IGF-1) in the development of severe retinopathy of prematurity (ROP) in an ethnically diverse population at a tertiary neonatal unit, 2011-2013. A prospective cohort masked study was conducted. Serum IGF-1 levels at 31, 32 and 33 weeks were measured and risk factor data collected including gestational age (GA), birth weight (BW), absolute weight gain (AWG) and maternal ethnicity. The eventual ROP outcome was divided into two groups: minimal ROP (Stages 0 and 1) and severe ROP (Stage 2 or worse including Type 1 ROP). 36 patients were recruited: 14 had minimal ROP and 22 severe ROP. Significant differences between the groups were found in GA, BW, AWG and IGF-1 at 32 and 33 weeks. There was minimal rise in IGF-1 in Stage 2 patients and/or black patients (p=0.0013) between 32 and 33 weeks but no pragmatic threshold level of IGF-1 that could distinguish between minimal or severe ROP. There were significant differences in GA, BW, AWG and IGF-1 at 32 and 33 weeks between those babies with severe ROP and those with minimal ROP. However, there was no threshold level of IGF-1 at a time point between 31 and 33 weeks that can be used to exclude a large proportion of babies from screening. We also found ethnic differences in IGF-1 levels with infants born to black mothers having significantly lower IGF-1 levels at 32 and 33 weeks gestation. The determination of ROP risk using IGF-1 is a race-specific phenomenon. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

  9. Possible role of IGF2 receptors in regulating selection of 2 dominant follicles in cattle selected for twin ovulations and births

    Science.gov (United States)

    Abundance of IGF-2 receptor (IGF2R), FSH receptor (FSHR), and LH receptor (LHCGR) mRNA in granulosa cells (GCs) or theca cells (TCs) or both cells as well as estradiol (E2), progesterone (P4), and androstenedione concentrations in follicular fluid were compared in cows genetically selected (Twinner)...

  10. Function of Matrix IGF-1 in Coupling Bone Resorption and Formation

    Science.gov (United States)

    Crane, Janet L.; Cao, Xu

    2013-01-01

    Balancing bone resorption and formation is the quintessential component for the prevention of osteoporosis. Signals that determine the recruitment, replication, differentiation, function, and apoptosis of osteoblasts and osteoclasts direct bone remodeling and determine whether bone tissue is gained, lost, or balanced. Therefore understanding the signaling pathways involved in the coupling process will help develop further targets for osteoporosis therapy, by blocking bone resorption or enhancing bone formation in a space and time dependent manner. Insulin-like growth factor type 1 (IGF-1) has long been known to play a role in bone strength. It is one of the most abundant substances in the bone matrix, circulates systemically and is secreted locally, and has a direct relationship with bone mineral density. Recent data has helped further our understanding of the direct role of IGF-1 signaling in coupling bone remodeling which will be discussed in this review. The bone marrow microenvironment plays a critical role in the fate of MSCs and HSCs and thus how IGF-1 interacts with other factors in the microenvironment are equally important. While previous clinical trials with IGF-1 administration have been unsuccessful at enhancing bone formation, advances in basic science studies have provided insight into further mechanisms that should be considered for future trials. Additional basic science studies dissecting the regulation and the function of matrix IGF-1 in modeling and remodeling will continue to provide further insight for future directions for anabolic therapies for osteoporosis. PMID:24068256

  11. Function of matrix IGF-1 in coupling bone resorption and formation.

    Science.gov (United States)

    Crane, Janet L; Cao, Xu

    2014-02-01

    Balancing bone resorption and formation is the quintessential component for the prevention of osteoporosis. Signals that determine the recruitment, replication, differentiation, function, and apoptosis of osteoblasts and osteoclasts direct bone remodeling and determine whether bone tissue is gained, lost, or balanced. Therefore, understanding the signaling pathways involved in the coupling process will help develop further targets for osteoporosis therapy, by blocking bone resorption or enhancing bone formation in a space- and time-dependent manner. Insulin-like growth factor type 1 (IGF-1) has long been known to play a role in bone strength. It is one of the most abundant substances in the bone matrix, circulates systemically and is secreted locally, and has a direct relationship with bone mineral density. Recent data has helped further our understanding of the direct role of IGF-1 signaling in coupling bone remodeling which will be discussed in this review. The bone marrow microenvironment plays a critical role in the fate of mesenchymal stem cells and hematopoietic stem cells and thus how IGF-1 interacts with other factors in the microenvironment are equally important. While previous clinical trials with IGF-1 administration have been unsuccessful at enhancing bone formation, advances in basic science studies have provided insight into further mechanisms that should be considered for future trials. Additional basic science studies dissecting the regulation and the function of matrix IGF-1 in modeling and remodeling will continue to provide further insight for future directions for anabolic therapies for osteoporosis.

  12. Overexpression of Insulin-like Growth Factor-1 Receptor Is Associated With Penile Cancer Progression.

    Science.gov (United States)

    Ball, Mark W; Bezerra, Stephania M; Chaux, Alcides; Faraj, Sheila F; Gonzalez-Roibon, Nilda; Munari, Enrico; Sharma, Rajni; Bivalacqua, Trinity J; Netto, George J; Burnett, Arthur L

    2016-06-01

    To evaluate insulin-like growth factor-1 receptor (IGF1R) expression in penile cancer and its association with oncologic outcomes. Tissue microarrays were constructed from 53 patients treated at our institution. Expression of IGF1R was evaluated using a Her2-like scoring system. Overexpression was defined as 1+ or greater membranous staining. Association of IGF1R expression with pathologic features was assessed with comparative statistics, and association with local recurrence, progression to nodal or distance metastases, or death was assessed with Kaplan-Meier survival analysis and Cox proportional hazard regression models. Overall, IGF1R overexpression was seen in 33 (62%) cases. With a median follow-up of 27.8 months, IGF1R overexpression was associated with inferior progression-free survival (PFS) (P  =  .003). In a multivariable model controlling for grade, T stage, perineural invasion, and lymphovascular invasion, IGF1R expression was independently associated with disease progression (hazard ratio 2.3, 95% confidence interval 1.1-5.1, P  =  .03. Comparing patients without IGF1R overexpression to those with overexpression, 5-year PFS was 94.1% vs 45.8%. IGF1R overexpression was associated with inferior PFS in penile cancer. Drugs that target IGF1R and downstream messengers may have a therapeutic benefit in patients that exhibit IGF1R overexpression. Copyright © 2016 Elsevier Inc. All rights reserved.

  13. Role of IGF-1 in cortical plasticity and functional deficit induced by sensorimotor restriction.

    Science.gov (United States)

    Mysoet, Julien; Dupont, Erwan; Bastide, Bruno; Canu, Marie-Hélène

    2015-09-01

    In the adult rat, sensorimotor restriction by hindlimb unloading (HU) is known to induce impairments in motor behavior as well as a disorganization of somatosensory cortex (shrinkage of the cortical representation of the hindpaw, enlargement of the cutaneous receptive fields, decreased cutaneous sensibility threshold). Recently, our team has demonstrated that IGF-1 level was decreased in the somatosensory cortex of rats submitted to a 14-day period of HU. To determine whether IGF-1 is involved in these plastic mechanisms, a chronic cortical infusion of this substance was performed by means of osmotic minipump. When administered in control rats, IGF-1 affects the size of receptive fields and the cutaneous threshold, but has no effect on the somatotopic map. In addition, when injected during the whole HU period, IGF-1 is interestingly implied in cortical changes due to hypoactivity: the shrinkage of somatotopic representation of hindlimb is prevented, whereas the enlargement of receptive fields is reduced. IGF-1 has no effect on the increase in neuronal response to peripheral stimulation. We also explored the functional consequences of IGF-1 level restoration on tactile sensory discrimination. In HU rats, the percentage of paw withdrawal after a light tactile stimulation was decreased, whereas it was similar to control level in HU-IGF-1 rats. Taken together, the data clearly indicate that IGF-1 plays a key-role in cortical plastic mechanisms and in behavioral alterations induced by a decrease in sensorimotor activity. Copyright © 2015 Elsevier B.V. All rights reserved.

  14. Insulin-like growth factor (IGF)-I obliterates the pregnancy-associated protection against mammary carcinogenesis in rats: evidence that IGF-I enhances cancer progression through estrogen receptor-α activation via the mitogen-activated protein kinase pathway

    International Nuclear Information System (INIS)

    Thordarson, Gudmundur; Slusher, Nicole; Leong, Harriet; Ochoa, Dafne; Rajkumar, Lakshmanaswamy; Guzman, Raphael; Nandi, Satyabrata; Talamantes, Frank

    2004-01-01

    Pregnancy protects against breast cancer development in humans and rats. Parous rats have persistently reduced circulating levels of growth hormone, which may affect the activity of the growth hormone/insulin-like growth factor (IGF)-I axis. We investigated the effects of IGF-I on parity-associated protection against mammary cancer. Three groups of rats were evaluated in the present study: IGF-I-treated parous rats; parous rats that did not receive IGF-I treatment; and age-matched virgin animals, which also did not receive IGF-I treatment. Approximately 60 days after N-methyl-N-nitrosourea injection, IGF-I treatment was discontinued and all of the animal groups were implanted with a silastic capsule containing 17β-estradiol and progesterone. The 17β-estradiol plus progesterone treatment continued for 135 days, after which the animals were killed. IGF-I treatment of parous rats increased mammary tumor incidence to 83%, as compared with 16% in parous rats treated with 17β-estradiol plus progesterone only. Tumor incidence and average number of tumors per animal did not differ between IGF-I-treated parous rats and age-matched virgin rats. At the time of N-methyl-N-nitrosourea exposure, DNA content was lowest but the α-lactalbumin concentration highest in the mammary glands of untreated parous rats in comparison with age-matched virgin and IGF-I-treated parous rats. The protein levels of estrogen receptor-α in the mammary gland was significantly higher in the age-matched virgin animals than in untreated parous and IGF-I-treated parous rats. Phosphorylation (activation) of the extracellular signal-regulated kinase-1/2 (ERK1/2) and expression of the progesterone receptor were both increased in IGF-I-treated parous rats, as compared with those in untreated parous and age-matched virgin rats. Expressions of cyclin D 1 and transforming growth factor-β 3 in the mammary gland were lower in the age-matched virgin rats than in the untreated parous and IGF-I-treated parous

  15. Divergent effects of insulin-like growth factor-1 receptor expression on prognosis of estrogen receptor positive versus triple negative invasive ductal breast carcinoma

    NARCIS (Netherlands)

    Hartog, Hermien; Horlings, Hugo M; van der Vegt, Bert; Kreike, Bas; Ajouaou, Abderrahim; van de Vijver, Marc J; Boezen, Hendrika; de Bock, Geertruida H; van der Graaf, Wilhelmina; Wesseling, Jelle

    2011-01-01

    The insulin-like growth factor type 1 receptor (IGF1R) is involved in progression of breast cancer and resistance to systemic treatment. Targeting IGF1R signaling may, therefore, be beneficial in systemic treatment. We report the effect of IGF1R expression on prognosis in invasive ductal breast

  16. What Happened to the IGF Binding Proteins?

    Science.gov (United States)

    Bach, Leon A

    2018-02-01

    Insulinlike growth factor (IGF) binding proteins (IGFBPs) 1 to 6 are high-affinity regulators of IGF activity. They generally inhibit IGF actions by preventing binding to the IGF-I receptor but can also enhance their actions under some conditions. Posttranslational modifications such as glycosylation and phosphorylation modulate IGFBP properties, and IGFBP proteolysis results in IGF release. IGFBPs have more recently been shown to have IGF-independent actions. A number of mechanisms are involved, including modulation of other growth factor pathways, nuclear localization and transcriptional regulation, interaction with the sphingolipid pathway, and binding to non-IGF biomolecules in the extracellular space and matrix, on the cell surface and intracellularly. IGFBPs modulate important biological processes, including cell proliferation, survival, migration, senescence, autophagy, and angiogenesis. Their actions have been implicated in growth, metabolism, cancer, stem cell maintenance and differentiation, and immune regulation. Recent studies have shown that epigenetic mechanisms are involved in the regulation of IGFBP abundance. A more complete understanding of IGFBP biology is necessary to further define their cellular roles and determine their therapeutic potential. Copyright © 2018 Endocrine Society.

  17. Decreased IGF-1 concentration during the first trimester of pregnancy in women with normal somatotroph function.

    Science.gov (United States)

    Persechini, Marie-Laure; Gennero, Isabelle; Grunenwald, Solange; Vezzosi, Delphine; Bennet, Antoine; Caron, Philippe

    2015-08-01

    A decrease of insulin-like growth factor-I levels (IGF-I) has been reported during the first trimester of pregnancy in women with acromegaly before the secretion of placental growth hormone (GH) progressively increases IGF-1 concentration. To evaluate variations of concentrations of IGF-1, insulin-like growth factor (IGF)-binding protein-3 (IGF-BP3) and GH during the first trimester of pregnancy in women with normal somatotroph function. Sixteen women (median age 31 years) with as who were followed for benign thyroid disorders (n = 15) or prolactin-secreting microadenoma (n = 1) were evaluated before and in the first trimester of pregnancy. Serum concentrations of GH, IGF-1, IGF-BP3, TSH and estradiol (E2) were measured before and in the first trimester (5.4 ± 2.2 weeks of gestation). Before pregnancy, somatotroph and thyroid functions (median TSH 1.2 mU/L) were normal in all women. At the first trimester IGF-1 levels decreased significantly (before = 210 ng/mL, first trimester = 145 ng/mL, p function, IGF-1 levels decrease in the first trimester of pregnancy without changes in GH or IGF-BP3 levels. These results confirm liver resistance to GH as a consequence of the physiological increase of estrogens during the first trimester.

  18. Increased expression of insulin-like growth factor-1 receptor is correlated with worse survival in canine appendicular osteosarcoma.

    Science.gov (United States)

    Maniscalco, Lorella; Iussich, Selina; Morello, Emanuela; Martano, Marina; Gattino, Francesca; Miretti, Silvia; Biolatti, Bartolomeo; Accornero, Paolo; Martignani, Eugenio; Sánchez-Céspedes, Raquel; Buracco, Paolo; De Maria, Raffaella

    2015-08-01

    Insulin-like growth factor 1 receptor (IGF-1R) is a cell membrane receptor widely expressed in tissues and involved in different cancers in humans. IGF-1R expression in human osteosarcoma has been associated with the development of tumour metastasis and with prognosis, and represents an attractive therapeutic target. The goal of this study was to investigate the expression of IGF-1R in canine osteosarcoma tissues and cell lines and assess its role and prognostic value. Samples from 34 dogs were examined by immunohistochemistry for IGF-1R expression. IGF-1R/AKT/MAPK signalling was evaluated by western blot and quantitative polymerase chain reaction in the cell lines. In addition, the in vitro inhibition of IGF-1R with pycropodophillin (PPP) was used to evaluate molecular and biological effects. Immunohistochemical data showed that IGF-1R was expressed in 71% of the analysed osteosarcoma samples and that dogs with higher levels of IGF-IR expression (47% of cases) had decreased survival (P canine osteosarcoma IGF-IR is activated by IGF-1 mostly in a paracrine or endocrine (rather than autocrine) manner, leading to activation of AKT/MAPK signalling. PPP caused p-IGF-1R dephosphorylation with partial blocking of p-MAPK and p-AKT, as well as apoptosis. It was concluded that IGF-1R is expressed and plays a role in canine osteosarcoma and that its expression is correlated with a poor prognosis. As in humans, IGF-1R may represent a good therapeutic target and a prognostic factor for canine osteosarcoma. Copyright © 2014 Elsevier Ltd. All rights reserved.

  19. [Differences in dynamics of insulin and insulin-like growth I (IGF-I) receptors internalization in isolated rat hepatocytes].

    Science.gov (United States)

    Kolychev, A P; Ternovskaya, E E; Arsenieva, A V; Shapkina, E V

    2013-01-01

    Insulin and IGF-I are two related peptides performing in the mammalian body functionally different roles of the metabolic and growth hormones, respectively. Internalization of the insulin-receptor complex (IRC) is the most important chain of mechanism of the action of hormone. To elucidate differences in the main stages of internalization of the two related hormones, the internalization dynamics of 125I-insulin and 125I-IGF-I was traced in isolated rat hepatocytes at 37 and 12 degrees C. There were established marked differences in the process of internalization of labeled hormones, which is stimulated by insulin and IGF-I. At 37 degrees C the insulin-stimulated internalization, unlike the process initiated by IGF-I, did not reach the maximal level for 1 h of incubation. However, essential differences in the internalization course of these two related peptide were obvious at the temperature of 12 degrees C. The internalization level of insulin receptors at 12 degrees C decreased by one third in spite of a significant increase of the insulin receptor binding on the hepatocytes plasma membrane. At 12 degrees C a slight decrease of the proportion of intracellular 125I-IGF-I correlated with a decrease in the 125I-IGF-I binding to receptors on the cell membrane. Internalization of IGF-I receptors was not affected by low temperature, as neither its level, nor the rate changed at 12 degrees C. The paradoxical decrease of the insulin-stimulated internalization at low temperature seems to represent a peculiar "inhibition mechanism" of immersion of IRC into the cell, which leads to accumulation of the complexes on the cell surface and possibly to a readjustment of the insulin biological activity. The resistance of internalization of the IGF-I receptor to cold seems to be related to the more ancient origin of this mechanism in the poikilothermal vertebrates.

  20. Role of insulin-like growth factor-I receptor (IGF-IR) in survival kinetics and radioresistance of mouse embryo fibroblasts in a hypoxic environment

    International Nuclear Information System (INIS)

    Okochi, Kiyoshi

    2002-01-01

    The role of insulin-like growth factor-I receptor (IGF-IR) in survival kinetics and radioresistance of fibroblasts in a severely hypoxic environment (partial oxygen pressure of less than 3 mmHg) was analyzed, in both low and high cell-density conditions. Mouse embryonic fibroblasts R(-), with a targeted disruption of the IGF-IR gene, and R(+) cells, derived from R(-) cells stably transfected with a plasmid containing a human IGF-IR cDNA, were used for this purpose. Survival time in hypoxia was longer in R(+) cells than R(-) cells, which correlated with highly elevated expression of caspase 3-like activity in R(-) cells, but not with HIF-Iα expression. Under euoxia, R(+) cells were more radioresistant, by a factor of 1.9, than R(-) cells. Under hypoxia, R(+) cells became more radioresistant, with an oxygen-enhancement ratio (OER) of 2.7, than R(-) cells, with an OER of 1.5, in a low cell density. However, unexpected hyper-radiosensitivity in hypoxia was observed for both R(+) and R(-) cells in a high cell density, which further increased with incubation time in hypoxia following X-irradiation. The hyper-radiosensitivity was more pronounced for R(-) cells. The result thus implies that IGF-IR may be an important target molecule for radioresistant tumors in radiotherapy. (author)

  1. IGF-1 attenuates LPS induced pro-inflammatory cytokines expression in buffalo (Bubalus bubalis) granulosa cells.

    Science.gov (United States)

    Onnureddy, K; Ravinder; Onteru, Suneel Kumar; Singh, Dheer

    2015-03-01

    Interaction between immune and endocrine system is a diverse process influencing cellular function and homeostasis in animals. Negative energy balance (NEB) during postpartum period in dairy animals usually suppresses these systems resulting in reproductive tract infection and infertility. These negative effects could be due to competition among endocrine and immune signaling pathways for common signaling molecules. The present work studied the effect of IGF-1 (50 ng/ml) on LPS (1 μg/ml) mediated pro-inflammatory cytokine expression (IL-1β, TNF-α, IL-6) and aromatase (CYP19A1) genes' expressions as well as proliferation of buffalo granulosa cells. The crosstalk between LPS and IGF-1 was also demonstrated through studying the activities of downstream signaling molecules (ERK1/2, Akt, NF-κB) by western blot and immunostaining. Gene expression analysis showed that IGF-1 significantly reduced the LPS induced expression of IL-1β, TNF-α and IL-6. LPS alone inhibited the CYP19A1 expression. However, co-treatment with IGF-1 reversed the inhibitory effect of LPS on CYP19A1 expression. LPS alone did not affect granulosa cell proliferation, but co-treatment with IGF-1, and IGF-1 alone enhanced the proliferation. Western blot results demonstrated that LPS caused the nuclear translocation of the NF-κB and increased the phosphorylation of ERK1/2 and Akt maximum at 15 min and 60 min, respectively. Nonetheless, co-treatment with IGF-1 delayed LPS induced phosphorylation of ERK1/2 (peak at 120 min), while promoting early Akt phosphorylation (peak at 5 min) with no effect on NF-κB translocation. Overall, IGF-1 delayed and reversed the effects of LPS, suggesting that high IGF-1 levels may combat infection during critical periods like NEB in postpartum dairy animals. Copyright © 2014 Elsevier Ltd. All rights reserved.

  2. Recombinant bovine growth hormone (rBGH) enhances somatic growth by regulating the GH-IGF axis in fingerlings of gilthead sea bream (Sparus aurata).

    Science.gov (United States)

    Vélez, Emilio J; Perelló, Miquel; Azizi, Sheida; Moya, Alberto; Lutfi, Esmail; Pérez-Sánchez, Jaume; Calduch-Giner, Josep A; Navarro, Isabel; Blasco, Josefina; Fernández-Borràs, Jaume; Capilla, Encarnación; Gutiérrez, Joaquim

    2018-02-01

    The growth hormone (GH)/insulin-like growth factors (IGFs) endocrine axis is the main growth-regulator system in vertebrates. Some authors have demonstrated the positive effects on growth of a sustained-release formulation of a recombinant bovine GH (rBGH) in different fish species. The aim of this work was to characterize the effects of a single injection of rBGH in fingerlings of gilthead sea bream on growth, GH-IGF axis, and both myogenic and osteogenic processes. Thus, body weight and specific growth rate were significantly increased in rBGH-treated fish respect to control fish at 6weeks post-injection, whereas the hepatosomatic index was decreased and the condition factor and mesenteric fat index were unchanged, altogether indicating enhanced somatic growth. Moreover, rBGH injection increased the plasma IGF-I levels in parallel with a rise of hepatic mRNA from total IGF-I, IGF-Ic and IGF-II, the binding proteins IGFBP-1a and IGFBP-2b, and also the receptors IGF-IRb, GHR-I and GHR-II. In skeletal muscle, the expression of IGF-Ib and GHR-I was significantly increased but that of IGF-IRb was reduced; the mRNA levels of myogenic regulatory factors, proliferation and differentiation markers (PCNA and MHC, respectively), or that of different molecules of the signaling pathway (TOR/AKT) were unaltered. Besides, the growth inhibitor myostatin (MSTN1 and MSTN2) and the hypertrophic marker (MLC2B) expression resulted significantly enhanced, suggesting altogether that the muscle is in a non-proliferative stage of development. Contrarily in bone, although the expression of most molecules of the GH/IGF axis was decreased, the mRNA levels of several osteogenic genes were increased. The histology analysis showed a GH induced lipolytic effect with a clear decrease in the subcutaneous fat layer. Overall, these results reveal that a better growth potential can be achieved on this species and supports the possibility to improve growth and quality through the optimization of its

  3. Cardiac remodeling after myocardial infarction is impaired in IGF-1 deficient mice

    NARCIS (Netherlands)

    Palmen, M.; Daemen, M. J.; Bronsaer, R.; Dassen, W. R.; Zandbergen, H. R.; Kockx, M.; Smits, J. F.; van der Zee, R.; Doevendans, P. A.

    2001-01-01

    To obtain more insight in the role of IGF-1 in cardiac remodeling and function after experimental myocardial infarction. We hypothesized that cardiac remodeling is altered in IGF-1 deficient mice, which may affect cardiac function. A myocardial infarction was induced by surgical coronary artery

  4. The role for IGF-1-derived small neuropeptides as a therapeutic target for neurological disorders.

    Science.gov (United States)

    Guan, Jian; Harris, Paul; Brimble, Margaret; Lei, Yang; Lu, Jun; Yang, Yang; Gunn, Alistair J

    2015-06-01

    Exogenous IGF-1 protects the brain from ischemic injury and improves function. However, its clinical application to neurological disorders is limited by its large molecular size, poor central uptake and mitogenic potential. In this review, the authors have discussed the efficacy, pharmacokinetics and mechanisms of IGF-1 derivatives on protecting acute brain injury, preventing memory impairment and improving recovery from neurological degenerative conditions evaluated in various animal models. We have included natural metabolites of IGF-1, glycine-proline-glutamate (GPE), cleaved from N-terminal IGF-1 and cyclic glycine-proline (cGP) as well as the structural analogues of GPE and cGP, glycine-2-methyl-proline-glutamate and cyclo-l-glycyl-l-2-allylproline, respectively. In addition, the regulatory role for cGP in bioavailability of IGF-1 has also been discussed. These small neuropeptides provide effective neuroprotection by offering an improved pharmacokinetic profile and more practical route of administration compared with IGF-1 administration. Developing modified neuropeptides to overcome the limitations of their endogenous counterparts represents a novel strategy of pharmaceutical discovery for neurological disorders. The mechanism of action may involve a regulation of IGF-1 bioavailability.

  5. The effect of growth hormone on bioactive IGF in overweight/obese women.

    Science.gov (United States)

    Dichtel, Laura E; Bjerre, Mette; Schorr, Melanie; Bredella, Miriam A; Gerweck, Anu V; Russell, Brian M; Frystyk, Jan; Miller, Karen K

    2018-03-10

    Overweight/obesity is characterized by decreased growth hormone (GH) secretion whereas circulating IGF-I levels are less severely reduced. Yet, the activity of the circulating IGF-system appears to be normal in overweight/obese subjects, as estimated by the ability of serum to activate the IGF-I receptor in vitro (bioactive IGF). We hypothesized that preservation of bioactive IGF in overweight/obese women is regulated by an insulin-mediated suppression of IGF-binding protein-1 (IGFBP-1) and IGFBP-2, and by suppression of IGFBP-3, mediated by low GH. We additionally hypothesized that increases in bioactive IGF would drive changes in body composition with low-dose GH administration. Cross-sectional analysis and 3-month interim analysis of a 6-month randomized, placebo-controlled study of GH administration in 50 overweight/obese women without diabetes mellitus. Bioactive IGF (kinase receptor activation assay) and body composition (DXA) were measured. Prior to treatment, IGFBP-3 (r = -0.33, p = 0.02), but neither IGFBP-1 nor IGFBP-2, associated inversely with bioactive IGF. In multivariate analysis, lower IGFBP-3 correlated with lower peak stimulated GH (r = 0.45, p = 0.05) and higher insulin sensitivity (r = -0.74, p = 0.003). GH administration resulted in an increase in mean serum IGF-I concentrations (144 ± 56 to 269 ± 66 μg/L, p IGF (1.29 ± 0.39 to 2.60 ± 1.12 μg/L, p IGF, but not total IGF-I concentration, predicted an increase in lean mass (r = 0.31, p = 0.03) and decrease in total adipose tissue/BMI (r = -0.43, p = 0.003). Our data suggest that in overweight/obesity, insulin sensitivity and GH have opposing effects on IGF bioactivity through effects on IGFBP-3. Furthermore, increases in bioactive IGF, rather than IGF-I concentration, predicted GH administration-related body composition changes. NCT00131378. Copyright © 2018. Published by Elsevier Ltd.

  6. The role of the IGF-1 Ec in myoskeletal system and osteosarcoma pathophysiology.

    Science.gov (United States)

    Armakolas, Nikolaos; Armakolas, Athanasios; Antonopoulos, Athanasios; Dimakakos, Andreas; Stathaki, Martha; Koutsilieris, Michael

    2016-12-01

    Growth hormone (GH) regulated mainly liver-produced insulin-like growth factor 1 (IGF-1) is a key molecule in embryonic & post embryonic development that is also involved in cancer biology. Herein we review new insights of the role of igf-1 gene products and of the IGF-1Ec isoform in muscle and bone development/repair and its role in osteosarcoma pathophysiology, underlying the possible role of the Ec peptide as a future therapeutic target. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  7. Differential requirement for nitric oxide in IGF-1-induced anti-apoptotic, anti-oxidant and anti-atherosclerotic effects

    Science.gov (United States)

    Sukhanov, Sergiy; Higashi, Yusuke; Shai, Shaw-Yung; Blackstock, Christopher; Galvez, Sarah; Vaughn, Charlotte; Titterington, Jane; Delafontaine, Patrick

    2011-01-01

    We have shown previously that insulin like-growth factor I (IGF-1) suppressed atherosclerosis in Apoe−/− mice and activated endothelial nitric oxide (NO) synthase. To determine whether IGF-1-induced atheroprotection depends on NO, IGF-1- or saline-infused mice were treated with L-NAME, the pan-NO synthase inhibitor or with D-NAME (control). IGF-1 reduced atherosclerosis in both the D-NAME and L-NAME groups suggesting that IGF-1’s anti-atherogenic effect was NO-independent. IGF-1 increased plaque smooth muscle cells, suppressed cell apoptosis and downregulated lipoprotein lipase and these effects were also NO-independent. On the contrary, IGF-1 decreased oxidative stress and suppressed TNF-α levels and these effects were blocked by L-NAME. Thus IGF-1’s anti-oxidant effect is dependent on its ability to increase NO but is distinct from its anti-atherosclerotic effect which is NO-independent. PMID:21872589

  8. IGF binding protein alterations on periplaque oligodendrocytes in multiple sclerosis : Implications for remyelination

    NARCIS (Netherlands)

    Wilczak, Nadine; Chesik, Daniel; Hoekstra, Dick; De Keyser, Jacques

    Why myelin repair greatly fails in multiple sclerosis (MS) is unclear. The insulin-like growth factor (IGF) system plays vital roles in oligodendrocyte development, survival, and myelin synthesis. We used immunohistochemistry to study IGF-I, IGF-I receptors and IGF binding proteins (IGFBPs) 1-6 on

  9. MMP-2 participates in the sclera of guinea pig with form-deprivation myopia via IGF-1/STAT3 pathway.

    Science.gov (United States)

    Liu, Y-X; Sun, Y

    2018-05-01

    To investigate the expression changes of MMP-2 (matrix metalloproteinases-2) mediated by IGF-1 (insulin-like growth factors-1) STAT3 (signal transducer and activator of transcription 3) pathway in the sclera of the form-deprivation myopia guinea pigs. Twenty-four three-week-old guinea pigs were randomly divided into 4 groups: group A (Control), B, C and D. Guinea pigs in group A were sacrificed after 21 days without any special treatment. Guinea pigs in group B were sacrificed 7 days after receiving stitch in the right eye. Guinea pigs in group C were sacrificed 14 days after receiving stitch in the right eye. Guinea pigs in group D were sacrificed 21 days after receiving stitch in the right eye. Eyeball refraction and axial length of guinea pigs were measured before sacrifice. Eyeballs of guinea pigs were enucleated after sacrifice. The expressions of IGF-1, STAT3 and MMP-2 in scleral tissue were detected by Western blot. Axial length extension and myopia appeared in the right eye of guinea pigs in group B. The expressions of IGF-1, STAT3 and MMP-2 in the sclera significantly increased after 7 days of occlusion compared with that in control group A (pIGF-1, STAT3 and MMP-2 in sclera significantly increased compared with that in group A (pIGF-1, STAT3 and MMP-2 in scleral significantly upregulated 21 days after occlusion (pIGF-1 in sclera were positively correlated (r = 0.962, pIGF-1, STAT3 and MMP-2 in the sclera and myopia of guinea pigs. The expressions of IGF-1, STAT3 and MMP-2 increased progressively over the time of deprivation. Additionally, overexpression of MMP-2 mediated by IGF-1/STAT3 pathway in sclera might promote the formation of myopia.

  10. Insulin-like growth factor type-1 receptor down-regulation associated with dwarfism in Holstein calves.

    Science.gov (United States)

    Blum, J W; Elsasser, T H; Greger, D L; Wittenberg, S; de Vries, F; Distl, O

    2007-10-01

    Perturbations in endocrine functions can impact normal growth. Endocrine traits were studied in three dwarf calves exhibiting retarded but proportionate growth and four phenotypically normal half-siblings, sired by the same bull, and four unrelated control calves. Plasma 3,5,3'-triiodothyronine and thyroxine concentrations in dwarfs and half-siblings were in the physiological range and responded normally to injected thyroid-releasing hormone. Plasma glucagon concentrations were different (dwarfs, controls>half-siblings; Pcontrols, Pcontrols, P=0.08). Responses of GH to xylazine and to a GH-releasing-factor analogue were similar in dwarfs and half-siblings. Relative gene expression of IGF-1, IGF-2, GH receptor (GHR), insulin receptor, IGF-1 type-1 and -2 receptors (IGF-1R, IGF-2R), and IGF binding proteins were measured in liver and anconeus muscle. GHR mRNA levels were different in liver (dwarfsdwarfism in studied calves.

  11. Insulin-like growth factor (IGF-I and IGF binding proteins axis in diabetes mellitus

    Directory of Open Access Journals (Sweden)

    Min Sun Kim

    2015-06-01

    Full Text Available Increasing evidence suggests an important role of the insulin-like growth factor (IGF-IGF binding protein (IGFBP axis in the maintenance of normal glucose and lipid metabolism. Significant changes occur in the local IGF-I-IGFBPs environment in response to the diabetic milieu. A significant reduction of serum IGF-I levels was observed in patients with type 1 diabetes mellitus (T1DM. Inversely, considerably increased serum levels of IGF-I and IGFBP-3 levels were detected in individuals with glucose intolerance including T2DM. Recently, several prospective studies indicated that baseline levels of IGF-I and IGFBPs are associated with the development of diabetes. These findings suggest that disturbances in insulin and IGF-I-IGFBP axis can affect the development of glucose intolerance including diabetes.

  12. Investigating the role of the IGF axis as a predictor of biochemical recurrence in prostate cancer patients post-surgery.

    Science.gov (United States)

    Breen, Kieran J; O'Neill, Amanda; Murphy, Lisa; Fan, Yue; Boyce, Susie; Fitzgerald, Noel; Dorris, Emma; Brady, Lauren; Finn, Stephen P; Hayes, Brian D; Treacy, Ann; Barrett, Ciara; Aziz, Mardiana Abdul; Kay, Elaine W; Fitzpatrick, John M; Watson, R William G

    2017-09-01

    Between 20% and 35% of prostate cancer (PCa) patients who undergo treatment with curative intent (ie, surgery or radiation therapy) for localized disease will experience biochemical recurrence (BCR). Alterations in the insulin-like growth factor (IGF) axis and PTEN expression have been implicated in the development and progression of several human tumors including PCa. We examined the expression of the insulin receptor (INSR), IGF-1 receptor (IGF-1R), PTEN, and AKT in radical prostatectomy tissue of patients who developed BCR post-surgery. Tissue microarrays (TMA) of 130 patients post-radical prostatectomy (65 = BCR, 65 = non-BCR) were stained by immunohistochemistry for INSR, IGF-1R, PTEN, and AKT using optimized antibody protocols. INSR, IGF1-R, PTEN, and AKT expression between benign and cancerous tissue, and different Gleason grades was assessed. Kaplan-Meier survival curves were used to examine the relationship between proteins expression and BCR. INSR (P IGF-1R (P IGF-1R, or AKT expression in the cancerous tissue of non-BCR versus BCR patients (P = 0.149, P = 0.990, P = 0.399, respectively). There was a significant decrease in PTEN expression in the malignant tissue of BCR versus non-BCR patients (P = 0.011). Combinational analysis of the tissue proteins identified a combination of decreased PTEN and increased AKT or increased INSR was associated with worst outcome. We found that in each case, our hypothesized worst group was most likely to experience BCR and this was significant for combinations of PTEN+INSR and PTEN+AKT but not PTEN+IGF-1R (P = 0.023, P = 0.028, P = 0.078, respectively). Low PTEN is associated with BCR and this association is strongly modified by high INSR and high AKT expression. Measurement of these proteins could help inform appropriate patient selection for postoperative adjuvant therapy and prevent BCR. © 2017 Wiley Periodicals, Inc.

  13. Biochemical characterization of individual human glycosylated pro-insulin-like growth factor (IGF)-II and big-IGF-II isoforms associated with cancer.

    Science.gov (United States)

    Greenall, Sameer A; Bentley, John D; Pearce, Lesley A; Scoble, Judith A; Sparrow, Lindsay G; Bartone, Nicola A; Xiao, Xiaowen; Baxter, Robert C; Cosgrove, Leah J; Adams, Timothy E

    2013-01-04

    Insulin-like growth factor II (IGF-II) is a major embryonic growth factor belonging to the insulin-like growth factor family, which includes insulin and IGF-I. Its expression in humans is tightly controlled by maternal imprinting, a genetic restraint that is lost in many cancers, resulting in up-regulation of both mature IGF-II mRNA and protein expression. Additionally, increased expression of several longer isoforms of IGF-II, termed "pro" and "big" IGF-II, has been observed. To date, it is ambiguous as to what role these IGF-II isoforms have in initiating and sustaining tumorigenesis and whether they are bioavailable. We have expressed each individual IGF-II isoform in their proper O-glycosylated format and established that all bind to the IGF-I receptor and both insulin receptors A and B, resulting in their activation and subsequent stimulation of fibroblast proliferation. We also confirmed that all isoforms are able to be sequestered into binary complexes with several IGF-binding proteins (IGFBP-2, IGFBP-3, and IGFBP-5). In contrast to this, ternary complex formation with IGFBP-3 or IGFBP-5 and the auxillary protein, acid labile subunit, was severely diminished. Furthermore, big-IGF-II isoforms bound much more weakly to purified ectodomain of the natural IGF-II scavenging receptor, IGF-IIR. IGF-II isoforms thus possess unique biological properties that may enable them to escape normal sequestration avenues and remain bioavailable in vivo to sustain oncogenic signaling.

  14. Biochemical Characterization of Individual Human Glycosylated pro-Insulin-like Growth Factor (IGF)-II and big-IGF-II Isoforms Associated with Cancer

    Science.gov (United States)

    Greenall, Sameer A.; Bentley, John D.; Pearce, Lesley A.; Scoble, Judith A.; Sparrow, Lindsay G.; Bartone, Nicola A.; Xiao, Xiaowen; Baxter, Robert C.; Cosgrove, Leah J.; Adams, Timothy E.

    2013-01-01

    Insulin-like growth factor II (IGF-II) is a major embryonic growth factor belonging to the insulin-like growth factor family, which includes insulin and IGF-I. Its expression in humans is tightly controlled by maternal imprinting, a genetic restraint that is lost in many cancers, resulting in up-regulation of both mature IGF-II mRNA and protein expression. Additionally, increased expression of several longer isoforms of IGF-II, termed “pro” and “big” IGF-II, has been observed. To date, it is ambiguous as to what role these IGF-II isoforms have in initiating and sustaining tumorigenesis and whether they are bioavailable. We have expressed each individual IGF-II isoform in their proper O-glycosylated format and established that all bind to the IGF-I receptor and both insulin receptors A and B, resulting in their activation and subsequent stimulation of fibroblast proliferation. We also confirmed that all isoforms are able to be sequestered into binary complexes with several IGF-binding proteins (IGFBP-2, IGFBP-3, and IGFBP-5). In contrast to this, ternary complex formation with IGFBP-3 or IGFBP-5 and the auxillary protein, acid labile subunit, was severely diminished. Furthermore, big-IGF-II isoforms bound much more weakly to purified ectodomain of the natural IGF-II scavenging receptor, IGF-IIR. IGF-II isoforms thus possess unique biological properties that may enable them to escape normal sequestration avenues and remain bioavailable in vivo to sustain oncogenic signaling. PMID:23166326

  15. Targeting Insulin-Like Growth Factor 1 Receptor Inhibits Pancreatic Cancer Growth and Metastasis

    Science.gov (United States)

    Subramani, Ramadevi; Lopez-Valdez, Rebecca; Arumugam, Arunkumar; Nandy, Sushmita; Boopalan, Thiyagarajan; Lakshmanaswamy, Rajkumar

    2014-01-01

    Pancreatic cancer is one of the most lethal cancers. Increasing incidence and mortality indicates that there is still much lacking in detection and management of the disease. This is partly due to a lack of specific symptoms during early stages of the disease. Several growth factor receptors have been associated with pancreatic cancer. Here, we have investigated if an RNA interference approach targeted to IGF-IR could be effective and efficient against pancreatic cancer growth and metastasis. For that, we evaluated the effects of IGF-1R inhibition using small interfering RNA (siRNAs) on tumor growth and metastasis in HPAC and PANC-1 pancreatic cancer cell lines. We found that silencing IGF-1R inhibits pancreatic cancer growth and metastasis by blocking key signaling pathways such AKT/PI3K, MAPK, JAK/STAT and EMT. Silencing IGF-1R resulted in an anti-proliferative effect in PANC-1 and HPAC pancreatic cancer cell lines. Matrigel invasion, transwell migration and wound healing assays also revealed a role for IGF-1R in metastatic properties of pancreatic cancer. These results were further confirmed using Western blotting analysis of key intermediates involved in proliferation, epithelial mesenchymal transition, migration, and invasion. In addition, soft agar assays showed that silencing IGF-1R also blocks the colony forming capabilities of pancreatic cancer cells in vitro. Western blots, as well as, flow cytometric analysis revealed the induction of apoptosis in IGF-1R silenced cells. Interestingly, silencing IGF-1R also suppressed the expression of insulin receptor β. All these effects together significantly control pancreatic cancer cell growth and metastasis. To conclude, our results demonstrate the significance of IGF-1R in pancreatic cancer. PMID:24809702

  16. Role of IGF-I in follistatin-induced skeletal muscle hypertrophy.

    Science.gov (United States)

    Barbé, Caroline; Kalista, Stéphanie; Loumaye, Audrey; Ritvos, Olli; Lause, Pascale; Ferracin, Benjamin; Thissen, Jean-Paul

    2015-09-15

    Follistatin, a physiological inhibitor of myostatin, induces a dramatic increase in skeletal muscle mass, requiring the type 1 IGF-I receptor/Akt/mTOR pathway. The aim of the present study was to investigate the role of IGF-I and insulin, two ligands of the IGF-I receptor, in the follistatin hypertrophic action on skeletal muscle. In a first step, we showed that follistatin increases muscle mass while being associated with a downregulation of muscle IGF-I expression. In addition, follistatin retained its full hypertrophic effect toward muscle in hypophysectomized animals despite very low concentrations of circulating and muscle IGF-I. Furthermore, follistatin did not increase muscle sensitivity to IGF-I in stimulating phosphorylation of Akt but, surprisingly, decreased it once hypertrophy was present. Taken together, these observations indicate that increased muscle IGF-I production or sensitivity does not contribute to the muscle hypertrophy caused by follistatin. Unlike low IGF-I, low insulin, as obtained by streptozotocin injection, attenuated the hypertrophic action of follistatin on skeletal muscle. Moreover, the full anabolic response to follistatin was restored in this condition by insulin but also by IGF-I infusion. Therefore, follistatin-induced muscle hypertrophy requires the activation of the insulin/IGF-I pathway by either insulin or IGF-I. When insulin or IGF-I alone is missing, follistatin retains its full anabolic effect, but when both are deficient, as in streptozotocin-treated animals, follistatin fails to stimulate muscle growth. Copyright © 2015 the American Physiological Society.

  17. Tobacco Smoke Exposure Impairs Brain Insulin/IGF Signaling: Potential Co-Factor Role in Neurodegeneration.

    Science.gov (United States)

    Deochand, Chetram; Tong, Ming; Agarwal, Amit R; Cadenas, Enrique; de la Monte, Suzanne M

    2016-01-01

    Human studies suggest tobacco smoking is a risk factor for cognitive impairment and neurodegeneration, including Alzheimer's disease (AD). However, experimental data linking tobacco smoke exposures to underlying mediators of neurodegeneration, including impairments in brain insulin and insulin-like growth factor (IGF) signaling in AD are lacking. This study tests the hypothesis that cigarette smoke (CS) exposures can impair brain insulin/IGF signaling and alter expression of AD-associated proteins. Adult male A/J mice were exposed to air for 8 weeks (A8), CS for 4 or 8 weeks (CS4, CS8), or CS8 followed by 2 weeks recovery (CS8+R). Gene expression was measured by qRT-PCR analysis and proteins were measured by multiplex bead-based or direct binding duplex ELISAs. CS exposure effects on insulin/IGF and insulin receptor substrate (IRS) proteins and phosphorylated proteins were striking compared with the mRNA. The main consequences of CS4 or CS8 exposures were to significantly reduce insulin R, IGF-1R, IRS-1, and tyrosine phosphorylated insulin R and IGF-1R proteins. Paradoxically, these effects were even greater in the CS8+R group. In addition, relative levels of S312-IRS-1, which inhibits downstream signaling, were increased in the CS4, CS8, and CS8+R groups. Correspondingly, CS and CS8+R exposures inhibited expression of proteins and phosphoproteins required for signaling through Akt, PRAS40, and/or p70S6K, increased AβPP-Aβ, and reduced ASPH protein, which is a target of insulin/IGF-1 signaling. Secondhand CS exposures caused molecular and biochemical abnormalities in brain that overlap with the findings in AD, and many of these effects were sustained or worsened despite short-term CS withdrawal.

  18. IGF binding proteins.

    Science.gov (United States)

    Bach, Leon A

    2017-12-18

    Insulin-like growth factor binding proteins (IGFBPs) 1-6 bind IGFs but not insulin with high affinity. They were initially identified as serum carriers and passive inhibitors of IGF actions. However, subsequent studies showed that, although IGFBPs inhibit IGF actions in many circumstances, they may also potentiate these actions. IGFBPs are widely expressed in most tissues, and they are flexible endocrine and autocrine/paracrine regulators of IGF activity, which is essential for this important physiological system. More recently, individual IGFBPs have been shown to have IGF-independent actions. Mechanisms underlying these actions include (i) interaction with non-IGF proteins in compartments including the extracellular space and matrix, the cell surface and intracellularly; (ii) interaction with and modulation of other growth factor pathways including EGF, TGF- and VEGF; and (iii) direct or indirect transcriptional effects following nuclear entry of IGFBPs. Through these IGF-dependent and IGF-independent actions, IGFBPs modulate essential cellular processes including proliferation, survival, migration, senescence, autophagy and angiogenesis. They have been implicated in a range of disorders including malignant, metabolic, neurological and immune diseases. A more complete understanding of their cellular roles may lead to the development of novel IGFBP-based therapeutic opportunities.

  19. The role of insulin-like growth factor-1 (IGF-1) in growth and reproduction in female brown house snakes (Lamprophis fuliginosus).

    Science.gov (United States)

    Sparkman, A M; Byars, D; Ford, N B; Bronikowski, A M

    2010-09-15

    Insulin-like growth factor-1 (IGF-1) is a peptide hormone critically involved in the regulation of key life-history traits such as growth and reproduction. Its structure and function are well-characterized among diverse mammal, fish, and bird species; however, little is known regarding the activities of IGF-1 in non-avian reptiles, particularly snakes and lizards. Nevertheless, several unique characteristics of reptiles, such as high metabolic flexibility and remarkable diversity in life-history strategy, suggest that they are of great interest in the study of endocrinological mechanisms underlying the regulation and evolution of life-history traits. Here we test for a relationship between IGF-1 and individual feeding rate, growth rate and reproductive stage in lab-reared female offspring of wild-caught oviparous house snakes, Lamprophis fuliginosus. We confirm a positive correlation between IGF-1 and both feeding and growth rates in sexually immature snakes, similar to that reported in other taxa. We also show a family effect on IGF-1, suggesting that IGF-1 levels may be heritable in these snakes, and serve as an important target of selection to produce divergent life-history strategies. Furthermore, we provide evidence that suggests that IGF-1 may peak rapidly after first mating, and subsequently decline prior to egg-laying, a phenomenon not previously reported in other taxa. These findings suggest that further comparative study of IGF-1 in snakes may reveal both the extent to which IGF-1 function is conserved across major taxonomic groups, as well as novel and intriguing roles for IGF-1 in the regulation of reproductive activities. Copyright (c) 2010 Elsevier Inc. All rights reserved.

  20. Cerebellar Insulin/IGF-1 signaling in diabetic rats: Effects of exercise training.

    Science.gov (United States)

    Borges, Mariana Eiras; Ribeiro, Alessandra Mussi; Pauli, José Rodrigo; Arantes, Luciana Mendonça; Luciano, Eliete; de Moura, Leandro Pereira; de Almeida Leme, José Alexandre Curiacos; Medeiros, Alessandra; Bertolini, Natália Oliveira; Sibuya, Clarice Yoshiko; Gomes, Ricardo José

    2017-02-03

    The Diabetes Mellitus (DM) is a chronic disease associated with loss of brain regions such as the cerebellum, increasing the risk of developing neurodegenerative diseases such as Parkinson's disease (PD). In the brain of diabetic and PD organisms the insulin/IGF-1 signaling is altered. Exercise training is an effective intervention for the prevention of neurodegerative diseases since it release neurotrophic factors and regulating insulin/IGF-1 signaling in the brain. This study aimed to evaluate the proteins involved in the insulin/IGF-1 pathway in the cerebellum of diabetic rats subjected to exercise training protocol. Wistar rats were distributed in four groups: sedentary control (SC), trained control (TC), sedentary diabetic (SD) and trained diabetic (TD). Diabetes was induced by Alloxan (ALX) (32mg/kgb.w.). The training program consisted in swimming 5days/week, 1h/day, during 6 weeks, supporting an overload corresponding to 90% of the anaerobic threshold. At the end, cerebellum was extracted to determinate the protein expression of GSK-3β, IRβ and IGF-1R and the phosphorylation of β-amyloid, Tau, ERK1+ERK2 by Western Blot analysis. All dependent variables were analyzed by one-way analysis of variance with significance level of 5%. Diabetes causes hyperglycemia in both diabetic groups; however, in TD, there was a reduction in hyperglycemia compared to SD. Diabetes increased Tau and β-amyloid phosphorylation in both SD and TD groups. Furthermore, aerobic exercise increased ERK1+ERK2 expression in TC. The data showed that in cerebellum of diabetic rats induced by alloxan there are some proteins expression like Parkinson cerebellum increased, and the exercise training was not able to modulate the expression of these proteins. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  1. Do deficiencies in growth hormone and insulin-like growth factor-1 (IGF-1) shorten or prolong longevity?

    Science.gov (United States)

    Laron, Zvi

    2005-02-01

    Present knowledge on the effects of growth hormone (GH) and insulin-like growth factor-I (IGF-I) deficiency on aging and lifespan are controversial. Studying untreated patients with either isolated GH deficiency due to GH gene deletion, patients with multiple pituitary hormone deficiency due to PROP-1 gene mutation and patients with isolated IGF-I deficiency due to deletions or mutations of the GH receptor gene (Laron syndrome); it was found, that these patients despite signs of early aging (wrinkled skin, obesity, insulin resistance and osteopenia) have a long life span reaching ages of 80-90 years. Animal models of genetic GH deficiencies such as Snell mice (Pit-1 gene mutations) the Ames mice (PROP-1 gene mutation) and the Laron mice (GH receptor gene knock-out) have a statistically significant higher longevity compared to normal controls. On the contrary, mice transgenic for GH and acromegalic patients secreting high amounts of GH have premature death. Those data raise the question whether pharmacological GH administration to adults is deleterious, in contrast to policies advocating such therapies.

  2. Adiponectin, Leptin, IGF-1, and Tumor Necrosis Factor Alpha As Potential Serum Biomarkers for Non-Invasive Diagnosis of Colorectal Adenoma in African Americans.

    Science.gov (United States)

    Ashktorab, Hassan; Soleimani, Akbar; Nichols, Alexandra; Sodhi, Komal; Laiyemo, Adeyinka O; Nunlee-Bland, Gail; Nouraie, Seyed Mehdi; Brim, Hassan

    2018-01-01

    The potential role of adiponectin, leptin, IGF-1, and tumor necrosis factor alpha (TNF-α) as biomarkers in colorectal adenoma is not clear. Therefore, we aimed to investigate the blood serum levels of these biomarkers in colorectal adenoma. The case-control study consisted of serum from 180 African American patients with colon adenoma (cases) and 198 healthy African Americans (controls) at Howard University Hospital. We used ELISA for adiponectin, leptin, IGF-1, and TNF-α detection and quantification. Statistical analysis was performed by t -test and multivariate logistic regression. The respective differences in median leptin, adiponectin, IGF-1, and TNF-α levels between control and case groups (13.9 vs. 16.4), (11.3 vs. 46.0), (4.5 vs. 12.9), and (71.4 vs. 130.8) were statistically significant ( P  IGF-1 were 2.0 (95% CI = 1.6-2.5; P  IGF-1 concentrations with age ( r  = 0.17, P  IGF-1, and leptin concentration with body mass index (BMI) ( r  = 0.44, P  IGF-1, and TNF-α high levels correlate with higher risk of colon adenoma and can thus be used for colorectal adenomas risk assessment.

  3. Takifugu rubripes cation independent mannose 6-phosphate receptor: Cloning, expression and functional characterization of the IGF-II binding domain.

    Science.gov (United States)

    A, Ajith Kumar; Nadimpalli, Siva Kumar

    2018-07-01

    Mannose 6-phosphate/IGF-II receptor mediated lysosomal clearance of insulin-like growth factor-II is significantly associated with the evolution of placental mammals. The protein is also referred to as the IGF-II receptor. Earlier studies suggested relatively low binding affinity between the receptor and ligand in prototherian and metatherian mammals. In the present study, we cloned the IGF-II binding domain of the early vertebrate fugu fish and expressed it in bacteria. A 72000Da truncated receptor containing the IGF-II binding domain was obtained. Analysis of this protein (covering domains 11-13 of the CIMPR) for its affinity to fish and human IGF-II by ligand blot assays and ELISA showed that the expressed receptor can specifically bind to both fish and human IGF-II. Additionally, a peptide-specific antibody raised against the region of the IGF-II binding domain also was able to recognize the IGF-II binding regions of mammalian and non-mammalian cation independent MPR protein. These interactions were further characterized by Surface Plasma resonance support that the receptor binds to fish IGF-II, with a dissociation constant of 548nM. Preliminary analysis suggests that the binding mechanism as well as the affinity of the fish and human receptor for IGF-II may have varied according to different evolutionary pressures. Copyright © 2018. Published by Elsevier B.V.

  4. IGF1 as a Potential Treatment for Rett Syndrome: Safety Assessment in Six Rett Patients

    Directory of Open Access Journals (Sweden)

    Giorgio Pini

    2012-01-01

    Full Text Available Rett syndrome (RTT is a devastating neurodevelopmental disorder that affects one in ten thousand girls and has no cure. The majority of RTT patients display mutations in the gene that codes for the methyl-CpG-binding protein 2 (MeCP2. Clinical observations and neurobiological analysis of mouse models suggest that defects in the expression of MeCP2 protein compromise the development of the central nervous system, especially synaptic and circuit maturation. Thus, agents that promote brain development and synaptic function, such as insulin-like growth factor 1 (IGF1, are good candidates for ameliorating the symptoms of RTT. IGF1 and its active peptide, (1–3 IGF1, cross the blood brain barrier, and (1–3 IGF1 ameliorates the symptoms of RTT in a mouse model of the disease; therefore they are ideal treatments for neurodevelopmental disorders, including RTT. We performed a pilot study to establish whether there are major risks associated with IGF1 administration in RTT patients. Six young girls with classic RTT received IGF1 subcutaneous injections twice a day for six months, and they were regularly monitored by their primary care physicians and by the unit for RTT in Versilia Hospital (Italy. This study shows that there are no risks associated with IGF1 administration.

  5. Experimental Alcohol-Related Peripheral Neuropathy: Role of Insulin/IGF Resistance

    Directory of Open Access Journals (Sweden)

    James Gilchrist

    2012-08-01

    Full Text Available The mechanisms of alcohol-related peripheral neuropathy (ALPN are poorly understood. We hypothesize that, like alcohol-related liver and brain degeneration, ALPN may be mediated by combined effects of insulin/IGF resistance and oxidative stress. Adult male Long Evans rats were chronically pair-fed with diets containing 0% or 37% ethanol (caloric, and subjected to nerve conduction studies. Chronic ethanol feeding slowed nerve conduction in the tibial (p = 0.0021 motor nerve, and not plantar sensory nerve, but it did not affect amplitude. Histological studies of the sciatic nerve revealed reduced nerve fiber diameters with increased regenerative sprouts, and denervation myopathy in ethanol-fed rats. qRT-PCR analysis demonstrated reduced mRNA levels of insulin, IGF-1, and IGF-2 polypeptides, IGF-1 receptor, and IRS2, and ELISAs revealed reduced immunoreactivity for insulin and IGF-1 receptors, IRS-1, IRS-4, myelin-associated glycoprotein, and tau in sciatic nerves of ethanol-fed rats (all p < 0.05 or better. The findings suggest that ALPN is characterized by (1 slowed conduction velocity with demyelination, and a small component of axonal degeneration; (2 impaired trophic factor signaling due to insulin and IGF resistance; and (3 degeneration of myelin and axonal cytoskeletal proteins. Therefore, ALPN is likely mediated by molecular and signal transduction abnormalities similar to those identified in alcoholic liver and brain degeneration.

  6. Elevated insulin-like growth factor 1 receptor signaling induces antiestrogen resistance through the MAPK/ERK and PI3K/Akt signaling routes

    NARCIS (Netherlands)

    Zhang, Y.; Moerkens, M.; Ramaiahgari, S.; Bont, de H.J.G.M.; Price, L.; Meerman, J.H.N.; Water, van de B.

    2011-01-01

    INTRODUCTION: Insulin-like growth factor 1 (IGF-1) receptor (IGF-1R) is phosphorylated in all breast cancer subtypes. Past findings have shown that IGF-1R mediates antiestrogen resistance through cross-talk with estrogen receptor (ER) signaling and via its action upstream of the epidermal growth

  7. Involved mechanisms in the radioprotector effect of the insulinic-1 type growth factor (IGF-1) in the mucous of the small intestine; Mecanismos involucrados en el efecto radioprotector del factor de crecimiento tipo insulinico-1 (IGF-1) en la mucosa del intestino delgado

    Energy Technology Data Exchange (ETDEWEB)

    Mohamad, N.; Medina, V.; Sambuco, L.; Gutierrez, A.; Nunez, M.; Martin, G.; Cricco, G.; Rivera, E.; Bergoc, R. [Laboratorio de Radioisotopos, Facultad de Farmacia y Bioquimica, Universidad de Buenos Aires. Junin 956, Buenos Aires (Argentina); Croci, M.; Crescenti, E. [Instituto de Inmunooncologia, Cordoba 3200, Buenos Aires (Argentina)]. e-mail: rmbergoc@ffyb.uba.ar

    2006-07-01

    The use of radiant therapies in malignant tissues presents the inconvenience of affecting also to the healthy tissues, mainly when these present a high rate of proliferation like in the case of the mucous of the small intestine. The growth factor of insulinic-1 type (IGF-1) it has been pointed out as a possible protector of normal tissues under irradiation conditions. The objective of this work was to evaluate the effect of the IGF-1 like radioprotector of the mucous of the small intestine in mice irradiated with 10 Gy to whole body, determining the histological characteristics of the tissue, the presence of apoptotic cells, the expression of antigen of cellular proliferation (PCNA) and of anti-oxidant enzymes. Four groups of mice were used: control, treated with IGF-1, irradiated and irradiated and treated with IGF-1. The two treated groups were injected subcutaneously with two dose by day of 2.5 {mu}g of IGF-I /0.1ml during four days (days 1 at 4). The two irradiated groups 10 Gy received to whole body the day 2. The day 5 all the animals were sacrificed and cuts of the mucous of the small intestine were obtained. The histological cuts were evaluated by tint with hematoxyline-eosin; the presence of apoptotic cells its were determined by the Tunnel method (Apoptag kit); the expression of PCNA, superoxide dependent dismutase of copper and zinc (CuZnSOD), superoxide dependent dismutase of manganese (MnSOD), catalase (CAT) and glutathion peroxidase (GPX), by immunohistochemistry. The results demonstrated that the treatment with IGF-1 preserves the partially histology of the mucous of the intestine, the expression of PCNA and the presence of apoptotic cells in the crypts in front of the irradiation. The CuZnSOD it was expressed mainly in the hairiness and, in smaller measure, in the crypts increase in the group IR+IGF-1. The IGF-1 produced the expression of MnSOD in the crypts and in the intestinal hairiness. The expression of CAT in the hairiness increase

  8. Alternative splicing and expression of the insulin-like growth factor (IGF-1) gene in osteoblasts under mechanical stretch

    Institute of Scientific and Technical Information of China (English)

    XIAN Chengyu; WANG Yuanliang; ZHANG Bingbing; TANG Liling; PAN Jun; LUO Yanfeng; JIANG Peng; LI Dajun

    2006-01-01

    Insulin-like growth factor 1 (IGF-1) promotes osteoblasts differentiation and bone formation,and its expression is induced by mechanical stretch,thus IGF-1 has been considered an effector molecule that links mechanical stimulation and local tissue responses. In this study, a mechanical stretching device was designed to apply physiological level static or cyclic stretching stimulation to osteoblasts.Different isoforms of IGF-1 mRNA were amplified by RT-PCR from the cells using respective primers and these amplified products were sequenced. An isoform of IGF-1 splicing product was found to be selectively produced by osteoblasts under stretching stimulation. This IGF-1 isoform had identical sequence with the mechano growth factor (MGF) which was originally identified in muscle cells. Regulations of the expression of the liver-type IGF (L.IGF-1) and MGF in osteoblasts under stretch stimulation were further studied using semi-quantitative RT-PCR.Stretch stimulation was found to promot the expression of IGF-1 (L.IGF-1 and MGF), and for both isoforms expression was more effectively stimulated by cyclic stretch than static stretch. MGF was detected only in osteoblasts subjected to mechanical stretch,suggesting MGF was a stretch sensitive growth factor.Expression of MGF peaked earlier than that of L.IGF-1, which was similar to their regulation in muscie and suggested similar roles of MGF and L.IGF-1in bone as in muscle cells. The functions of MGF and L.IGF-1 in osteoblasts shall be established by further experimental studies.

  9. Glucagon Decreases IGF-1 Bioactivity in Humans, Independently of Insulin, by Modulating Its Binding Proteins.

    Science.gov (United States)

    Sarem, Zeinab; Bumke-Vogt, Christiane; Mahmoud, Ayman M; Assefa, Biruhalem; Weickert, Martin O; Adamidou, Aikatarini; Bähr, Volker; Frystyk, Jan; Möhlig, Matthias; Spranger, Joachim; Lieske, Stefanie; Birkenfeld, Andreas L; Pfeiffer, Andreas F H; Arafat, Ayman M

    2017-09-01

    Depending on its lipolytic activity, glucagon plays a promising role in obesity treatment. Glucagon-induced growth hormone (GH) release can promote its effect on lipid metabolism, although the underlying mechanisms have not been well-defined. The present study highlights the glucagon effect on the GH/insulinlike growth factor 1 (IGF-1)/IGF-binding protein (IGFBP) axis in vivo and in vitro, taking into consideration insulin as a confounding factor. In a double-blind, placebo-controlled study, we investigated changes in GH, IGFBP, and IGF-1 bioactivity after intramuscular glucagon administration in 13 lean controls, 11 obese participants, and 13 patients with type 1 diabetes mellitus (T1DM). The effect of glucagon on the transcription factor forkhead box protein O1 (FOXO1) translocation, the transcription of GH/IGF-1 system members, and phosphorylation of protein kinase B (Akt) was further investigated in vitro. Despite unchanged total IGF-1 and IGFBP-3 levels, glucagon decreased IGF-1 bioactivity in all study groups by increasing IGFBP-1 and IGFBP-2. The reduction in IGF-1 bioactivity occurred before the glucagon-induced surge in GH. In contrast to the transient increase in circulating insulin in obese and lean participants, no change was observed in those with T1DM. In vitro, glucagon dose dependently induced a substantial nuclear translocation of FOXO1 in human osteosarcoma cells and tended to increase IGFBP-1 and IGFBP-2 gene expression in mouse primary hepatocytes, despite absent Akt phosphorylation. Our data point to the glucagon-induced decrease in bioactive IGF-1 levels as a mechanism through which glucagon induces GH secretion. This insulin-independent reduction is related to increased IGFBP-1 and IGFBP-2 levels, which are most likely mediated via activation of the FOXO/mTOR (mechanistic target of rapamycin) pathway. Copyright © 2017 Endocrine Society

  10. Direct demonstration of rapid insulin-like growth factor II receptor internalization and recycling in rat adipocytes. Insulin stimulates 125I-insulin-like growth factor II degradation by modulating the IGF-II receptor recycling process

    International Nuclear Information System (INIS)

    Oka, Y.; Rozek, L.M.; Czech, M.P.

    1985-01-01

    The photoactive insulin-like growth factor (IGF)-II analogue 4-azidobenzoyl- 125 I-IGF-II was synthesized and used to label specifically and covalently the Mr = 250,000 Type II IGF receptor. When rat adipocytes are irradiated after a 10-min incubation with 4-azidobenzoyl- 125 I-IGF-II at 10 degrees C and immediately homogenized, most of the labeled IGF-II receptors are associated with the plasma membrane fraction, indicating that receptors accessible to the labeling reagent at low temperature are on the cell surface. However, when the photolabeled cells are incubated at 37 degrees C for various times before homogenization, labeled IGF-II receptors are rapidly internalized with a half-time of 3.5 min as evidenced by a loss from the plasma membrane fraction and a concomitant appearance in the low density microsome fraction. The steady state level of cell surface IGF-II receptors in the presence or absence of IGF-II remains constant under these conditions, demonstrating that IGF-II receptors rapidly recycle back to the cell surface at the same rate as receptor internalization. Using the above methodology, it is shown that acute insulin action: 1) increases the steady state number of cell surface IGF-II receptors; 2) increases the number of ligand-bound IGF-II receptors that are internalized per unit of time; and 3) increases the rate of cellular 125 I-IGF-II degradation by a process that is blocked by anti-IGF-II receptor antibody

  11. Over-stimulation of insulin/IGF-1 signaling by western diet may promote diseases of civilization: lessons learnt from laron syndrome

    Directory of Open Access Journals (Sweden)

    Schmitz Gerd

    2011-06-01

    Full Text Available Abstract The insulin/insulin-like growth factor-1 (IGF-1 pathway drives an evolutionarily conserved network that regulates lifespan and longevity. Individuals with Laron syndrome who carry mutations in the growth hormone receptor (GHR gene that lead to severe congenital IGF-1 deficiency with decreased insulin/IGF-1 signaling (IIS exhibit reduced prevalence rates of acne, diabetes and cancer. Western diet with high intake of hyperglycemic carbohydrates and insulinotropic dairy over-stimulates IIS. The reduction of IIS in Laron subjects unmasks the potential role of persistent hyperactive IIS mediated by Western diet in the development of diseases of civilization and offers a rational perspective for dietary adjustments with less insulinotropic diets like the Paleolithic diet.

  12. Over-stimulation of insulin/IGF-1 signaling by western diet may promote diseases of civilization: lessons learnt from laron syndrome.

    Science.gov (United States)

    Melnik, Bodo C; John, Swen Malte; Schmitz, Gerd

    2011-06-24

    The insulin/insulin-like growth factor-1 (IGF-1) pathway drives an evolutionarily conserved network that regulates lifespan and longevity. Individuals with Laron syndrome who carry mutations in the growth hormone receptor (GHR) gene that lead to severe congenital IGF-1 deficiency with decreased insulin/IGF-1 signaling (IIS) exhibit reduced prevalence rates of acne, diabetes and cancer. Western diet with high intake of hyperglycemic carbohydrates and insulinotropic dairy over-stimulates IIS. The reduction of IIS in Laron subjects unmasks the potential role of persistent hyperactive IIS mediated by Western diet in the development of diseases of civilization and offers a rational perspective for dietary adjustments with less insulinotropic diets like the Paleolithic diet.

  13. Growth hormone dose in growth hormone-deficient adults is not associated with IGF-1 gene polymorphisms

    NARCIS (Netherlands)

    S. Meyer (Silke); S. Schaefer (Stephan); D. Ivan (Diana); L. Stolk (Lisette); P.P. Arp (Pascal); A.G. Uitterlinden (André); P.P. Nawroth (Peter); U. Plöckinger (Ursula); G.K. Stalla (Günter); U. Tuschy (Ulrich); M.M. Weber (Matthias); W.J. Weise (Wolfgang); A. Pfützner (Andreas); P. Kann (Peter)

    2009-01-01

    textabstractAims: Several SNPs and a microsatellite cytosine-adenine repeat promoter polymorphisms of the IGF-1 gene have been reported to be associated with circulating IGF-1 serum concentrations. Variance in IGF-1 concentrations due to genetic variations may affect different response to growth

  14. Serum from Chronic Hepatitis B Patients Promotes Growth and Proliferation via the IGF-II/IGF-IR/MEK/ERK Signaling Pathway in Hepatocellular Carcinoma Cells.

    Science.gov (United States)

    Ji, Yuanyuan; Wang, Zhidong; Chen, Haiyan; Zhang, Lei; Zhuo, Fei; Yang, Qingqing

    2018-05-09

    Chronic hepatitis B virus (HBV) infection (CHB) plays a central role in the etiology of hepatocellular carcinoma (HCC). Emerging evidence implicates insulin-like growth factor (IGF)-II as a major risk factor for the growth and development of HCC. However, the relationship between HBV infection and IGF-II functions remains to be elucidated. Levels of circulating IGF-II and IGF-I receptor (IGF-IR) in healthy donors (HDs) and CHB patients were tested by ELISA. Human HCC cell lines (HepG-2, SMMC-7721, MHCC97-H) were incubated with serum from HDs and CHB patients at various concentrations for 24, 48, and 72 h. MTT and plate colony formation assays, BrdU ELISA, ELISA, small-interfering RNA (siRNA) transfection, quantitative real-time PCR, and western blot were applied to assess the functional and molecular mechanisms in HCC cell lines. Serum levels of IGF-II and IGF-IR were significantly higher in CHB patients than in HDs. Additionally, serum from CHB patients directly induced cell growth, proliferation, IGF-II secretion, and HDGF-related protein-2 (HRP-2) and nuclear protein 1 (NUPR1) mRNA and protein expression in HCC cells. Moreover, serum from CHB patients increased IGF-II-induced cell growth, proliferation, and HRP-2 and NUPR1 mRNA and protein expression in HCC cells. Blockade of IGF-IR clearly inhibited the above effects. Most importantly, interference with IGF-II function markedly repressed the cell proliferation and HRP-2 and NUPR1 mRNA and protein expression induced by serum from CHB patients. Furthermore, serum from CHB patients induced ERK phosphorylation via IGF-IR, with the MEK inhibitor PD98059 significantly decreasing CHB patient serum-induced IGF-II secretion, cell proliferation, and HRP-2 and NUPR1 mRNA and protein expression. Serum from CHB patients increases cell growth and proliferation and enhances HRP-2 and NUPR1 expression in HCC cells via the IGF-II/IGF-IR/MEK/ERK signaling pathway. These findings help to explain the molecular mechanisms

  15. IGF-IR targeted therapy: Past, present and future

    NARCIS (Netherlands)

    J.A.M.J.L. Janssen (Joseph); A.J. Varewijck (Aimee)

    2014-01-01

    textabstractThe IGF-I receptor (IGF-IR) has been studied as an anti-cancer target. However, monotherapy trials with IGF-IR targeted antibodies or with IGF-IR specific tyrosine kinase inhibitors have, overall, been very disappointing in the clinical setting. This review discusses potential reasons

  16. The IGF-Axis and Diabetic Retinopathy Before and After Gastric Bypass Surgery

    DEFF Research Database (Denmark)

    Brynskov, Troels; Laugesen, Caroline Schmidt; Floyd, Andrea Karen

    2017-01-01

    at the two postoperative visits (p ≤ 0.001). Total IGF-I showed no significant changes. HbA1c, glucose, HOMA-IR and lipids improved after surgery. Two patients did not complete the 12-month visit. CONCLUSIONS: In obese T2D patients, bioactive IGF is a potential biomarker for DR and levels tended to increase....... We aimed to evaluate baseline imbalances in the circulating IGF-system and changes after LGB in patients with T2D. METHODS: Prospective ocular examinations and measurement of the IGF-axis before and 3 and 12 months after LGB. IGF-bioactivity was measured by cell-based IGF-I receptor (IGF-IR) kinase...

  17. Comparison of acid ethanol extraction and acid gel filtration prior to IGF-I and IGF-II radioimmunoassays; Improvement of determinations in acid ethanol extracts by the use of truncated IGF-I as radioligand

    Energy Technology Data Exchange (ETDEWEB)

    Bang, P; Eriksson, U; Wivall, I -L; Hall, K [Department of Endocrinology, Karolinska Institute, Stockholm (Sweden); Sara, V [Department of Pathology, Karolinska Institute, Stockholm (Sweden)

    1991-01-01

    Insulin-like growth factor binding proteins interfere in the IGF-I and -II radioimmunoassays. In an attempt to overcome this problem, we have compared the use of truncated IGF-I, with reduced IGFBP affinity, and IGF-I as radioligands for IGF-I RIA measurements in serum separated by acid gel filtration or acid ethanol extraction followed by cryo-precipitation. With truncated IGF-I as radioligand the IGF-I measurements in acid gel filtrates and acid ethanol extracts were significantly correlated in healthy subjects (N=42, r=0.91, p<0.001) and in patients with acromegaly (N=10, r=0.85, p<0.01), GH deficiency (N=10, r=0.88, p<0.001) or Type I diabetes mellitus (N=10, r=0.90, p<0.001). In contrast, the IGF-I concentrations in acid ethanol extracts determined with IGF-I as radioligand did not correlate with those in acid gel filtrates using truncated IGF-I radioligand in patients with acromegaly (r=0.61, NS) or GH deficiency (r=0.46, NS). In the latter group the mean IGF-I concentrations measured in acid ethanol extracts were erroneously elevated by 112%. Low-affinity antibodies used for IGF-II RIA determinations failed to give reliable results in acid ethanol extracts from patients with Type I diabetes mellitus or GH deficiency. In conclusion, erroneously high IGF-I concentrations owing to binding of the radioligand to IGFBPs not completely removed by acid ethanol extraction can be avoided by the use of truncated IGF-I as radioligand. (author).

  18. Diosgenin induces apoptosis in IGF-1-stimulated human thyrocytes through two caspase-dependent pathways

    International Nuclear Information System (INIS)

    Mu, Shumin; Tian, Xingsong; Ruan, Yongwei; Liu, Yuantao; Bian, Dezhi; Ma, Chunyan; Yu, Chunxiao; Feng, Mei; Wang, Furong; Gao, Ling; Zhao, Jia-jun

    2012-01-01

    Highlights: ► Diosgenin induces apoptosis in IGF-1-treated thyrocytes through two caspase pathways. ► Diosgenin inhibits FLIP and activates caspase-8 in FAS related-pathway. ► Diosgenin increases ROS, regulates the ratio of Bax/Bcl-2 in mitochondrial pathway. -- Abstract: Insulin-like growth factor-1 (IGF-1) is a growth factor of the thyroid that has been shown in our previous study to possess proliferative and antiapoptotic effects in FRTL-5 cell lines through the upregulation of cyclin D and Fas-associated death domain-like interleukin-1-converting enzyme (FLICE)-inhibitory protein (FLIP). Diosgenin, a natural steroid sapogenin from plants, has been shown to induce apoptosis in many cell lines, with the exception of thyroid cells. In this report, we investigated the apoptotic effect and mechanism of diosgenin in IGF-1-stimulated primary human thyrocytes. Primary human thyrocytes were preincubated with or without IGF-1 for 24 h and subsequently exposed to varying concentrations of diosgenin for different times. We found that diosgenin induced apoptosis in human thyrocytes pretreated with IGF-1 in a dose-dependent manner through the activation of caspase cascades. Moreover, diosgenin inhibited FLIP and activated caspase-8 in the FAS-related apoptotic pathway. Diosgenin increased the production of ROS, regulated the balance of Bax and Bcl-2 and cleaved caspase-9 in the mitochondrial apoptotic pathway. These results indicate that diosgenin induces apoptosis in IGF-1-stimulated primary human thyrocytes through two caspase-dependent pathways.

  19. DYNAMICS OF INSULIN-LIKE GROWTH FACTOR-1 (IGF-1 IN CHILDREN AFTER AB0-INCOMPATIBLE LIVER TRANSPLANTATION

    Directory of Open Access Journals (Sweden)

    O.P. Shevchenko

    2014-01-01

    Full Text Available It is shown that liver transplantation (LT from donor with incompatible blood type (AB0i may be effective and safe, but the impact of such operation upon the various systems of the body has not been investigated yet. Insulinlike growth factor-1 (IGF-1 is synthesized in the liver and mediates the action of growth hormone. The level of IGF-1 is a marker of the processes of cell proliferation and tissue regeneration. Aim. To evaluate levels of IGF-1 in children-recipients with liver transplant from AB0i (incompatible and AB0c (compatible donors.Materials and methods. 140 children aged 3 to 36 (19,5 ± 16,5 months with congenital diseases of the hepatobiliar system, 58 of them boys, were surveyed. All patients underwent transplantation of left lateral liver sector from living related donors: 111 children were transplanted with fragment of the liver from AB0c donors, 29 – from AB0i donors; in 10 children with AB0i liver before and/or after LT operation anti-group antibodies (anti-A/B were revealed. The concentration of IGF-1 was determined by ELISA using specifi c kits (Immunodiagnostic System, USA in samples of blood plasma, which were received up to a month and a year after a liver transplant.Results. Average level of IGF-1 21,0 ± 29,5 μg/l in patients before LT was signifi cantly lower than in healthy children (52,2 ± 26,3 μg/l, p < 0,001 and did not vary in children, having received later a piece of liver from a compatible (AB0c donor and from donor AB0i (23,5 ± 30,9 and 21,2 ± 23,2 μg/l respectively, p = 0,70. In patients with anti-A/B prior to surgery average level of IGF-1 was not different from that of the patients without antibodies (32,6 ± 27,6 and 22,3 ± 29,6 μg/l respectively, p = 0,4. One month after LT level of IGF-1 has increased both in the general group, and in patients with AB0c and AV0i liver (92,1 ± 77,8 and 131,2 ± 106,7 μg/l respectively, p = 0,09. The level of IGF-1 was not varied in the group with antibodies

  20. Synthesis of insulin-like growth factor 1 analogue (188Re/99Tcm-IGF-1A) and the binding with pancreatic carcinoma cell

    International Nuclear Information System (INIS)

    Zhang Bin; Wu Yiwei; Fan Guanglei; Fan Wo

    2007-01-01

    Objective: An useful and stable method was developed for labeling insulin-like growth factor 1 analogue (IGF-1A) with 188 Re/ 99 Tc m , and its binding characteristic was studied with human pancreatic cancer cell Patu8988 in this study. Methods: The direct labeling method was adopted to label IGF- 1A under different conditions: 2 to 10 μl Tween80; 0.75 to 25 g/L SnCl 2 ·2H 2 O; 20 to 100 μg IGF-1A; 10 to 500 μl 188 ReO 4 - . The labeling rate was dynamically measured from 5 min to 6 h after labeling. The in vitro stabilities of 188 Re/ 99 Tc m -IGF-1A were accessed by dynamic labeling rates measured at 2 to 24 h. SPECT imaging after intravenous injection of 99 Tc m -IGF-1A and intratumoral injection of 188 Re-IGF-1A in nude mice was performed. Results: The best condition for labeling 188 Re was: 100 μl SnCl 2 ·2H 2 O (10 g/L), 50 μl IGF-1A (2 g/L), 300 μl Na 3 PO 4 , l0 μl 0.1% Tween80, 50 μl 188 ReO 4 - with 30 min reaction time at room temperature and pH 7.0. The maximum labeling rate of 188 Re-IGF-1A was (94.07 ± 0.32)%. The radiochemical purity was (76.57 ± 9.96)% at 24 h after mixing with human serum. The maximum binding efficiency of 188 Re-IGF-1A with Patu8988 cell was (24.13 ± 2.03)% , and the specific binding was 12.68%. The best labeling condition of 99 Tc m was: 100 μl SnCl 2 ·2H 2 O (3 g/L), 40 μl IGF-1A (2 g/L), 2 μl 0.1% Tween80, 50 μl 99 Tc m O - 4. The maximum labeling rate of 99 Tc m -IGF-1A was (94.43 ± 0.75)% and the radiochemical purity was (54.07 ± 3.86)% at 24 h after mixing with human serum. The maximum binding with Patu8988 cell was (22.95 ± 3.94)%, and the specific binding rate was 19.31%. The tumors in nude mice could be best imaged at 6 h after intravenous injection of 99 Tc m -IGF-1A and 48 h after intratumoral injection of 188 Re-IGF-1A. Conclusions: The presented method of labeling IGF-1A with 188 Re/ 99 Tc m was stable and efficient. 188 Re/ 99 Tc m -IGF-1A could bind with the pancreatic cancer cell Patu8988

  1. Crosstalk between adiponectin and IGF-IR in breast cancer

    Directory of Open Access Journals (Sweden)

    Loredana eMauro

    2015-07-01

    Full Text Available Obesity is a chronic and multifactorial disorder that is reaching epidemic proportions. It is characterized by an enlarged mass of adipose tissue caused by a combination of size increase of preexisting adipocytes (hypertrophy and de novo adipocyte differentiation (hyperplasia. Obesity is related to many metabolic disorders like hypertension, type 2 diabetes, metabolic syndrome, cardiovascular disease, and it is associated with an increased risk of cancer development in different tissues including breast. Adipose tissue is now regarded as not just a storage reservoir for excess energy, but rather as an endocrine organ, secreting a large number of bioactive molecules called adipokines. Among these, adiponectin represents the most abundant adipose tissue-excreted protein, which exhibits insulin-sensitizing, anti-inflammatory and antiatherogenic properties. The serum concentrations of adiponectin are inversely correlated with body mass index. Recently, low levels of plasma adiponectin have been associated with an increased risk for obesity-related cancers and development of more aggressive phenotype, concomitantly with alterations in the bioavailability of Insulin-like Growth Factor-I (IGF-I and IGF-I Receptor (IGF-IR signaling pathways. In this review we discuss the cross-talk between adiponectin/AdipoR1 and IGF-I/IGF-IR in breast cancer.

  2. Efficient and sustained IGF-1 expression in the adipose tissue-derived stem cells mediated via a lentiviral vector.

    Science.gov (United States)

    Chen, Ting; Huang, Dangsheng; Chen, Guanghui; Yang, Tingshu; Yi, Jun; Tian, Miao

    2015-02-01

    The adipose tissue-derived stem cells (ADSCs) represent a significant area of the cell therapy. Genetic modification of ADSCs may further improve their therapeutic potential. Here, we aimed to generate a lentiviral vector expressing insulin-like growth factor-I (IGF-1) and investigate the impact of IGF-1 transduction on the properties of cultured ADSCs. Isolated rat ADSCs were assessed by flow cytometric analysis. IGF-1 was cloned and inserted into the pLenO-DCE plasmid to acquire pLenO-DCE-IGF-1 plasmid. Lentivirus was enveloped with pRsv-REV, pMDlg-pRRE and pMD2G plasmids in 293T cells. The ADSCs were transfected with the vectors. And then IGF-1-induced anti-apoptosis was evaluated by annexin V-FITC. Besides, proliferation of cells was detected by MTT assay and EdU. Moreover, Akt phosphorylation was evaluated by Western blotting analysis. Stable expression of IGF-1 in ADSCs was confirmed. ADSCs were positive for CD90 and CD29, but negative for CD31, CD34 and CD45. The transduction of IGF-1 to the ADSCs caused a dramatic increase in P-Akt expression. Over-expression of IGF-1 in ADSCs could improve the paracine of IGF-1 in a time-dependent manner, but could not promote the proliferation of ADSCs. This study indicated that lentiviral vectors offered a promising mean of delivering IGF-1 to the ADSCs. Lentiviral-mediated over-expression of therapeutic IGF-1 gene in ADSCs could prolong the anti-apoptosis effect of IGF-1, which might be induced by the activation of the PI3K/Akt pathway. And our data would improve the efficacy of ADSC-based therapies.

  3. Astragalus Extract Mixture HT042 Increases Longitudinal Bone Growth Rate by Upregulating Circulatory IGF-1 in Rats

    Directory of Open Access Journals (Sweden)

    Donghun Lee

    2017-01-01

    Full Text Available Astragalus extract mixture HT042 is a standardized ingredient of health functional food approved by Korean FDA with a claim of “height growth of children.” HT042 stimulates bone growth rate and increases local IGF-1 expression in growth plate of rats which can be considered as direct stimulation of GH and its paracrine/autocrine actions. However, it remains unclear whether HT042 stimulates circulatory IGF-1 which also plays a major role to stimulate bone growth. To determine the effects on circulatory IGF-1, IGF-1 and IGFBP-3 expressions and phosphorylation of JAK2/STAT5 were evaluated in the liver after 10 days of HT042 administration. HT042 upregulated liver IGF-1 and IGFBP-3 mRNA expression, IGF-1 protein expression, and phosphorylation of JAK2/STAT5. HT042 also increased bone growth rate and proliferative zonal height in growth plate. In conclusion, HT042 stimulates bone growth rate via increment of proliferative rate by upregulation of liver IGF-1 and IGFBP-3 mRNA followed by IGF-1 protein expression through phosphorylation of JAK2/STAT5, which can be regarded as normal functioning of GH-dependent endocrine pathway.

  4. Effects of phosphorylatable short peptide-conjugated chitosan-mediated IL-1Ra and igf-1 gene transfer on articular cartilage defects in rabbits.

    Directory of Open Access Journals (Sweden)

    Ronglan Zhao

    Full Text Available Previously, we reported an improvement in the transfection efficiency of the plasmid DNA-chitosan (pDNA/CS complex by the utilization of phosphorylatable short peptide-conjugated chitosan (pSP-CS. In this study, we investigated the effects of pSP-CS-mediated gene transfection of interleukin-1 receptor antagonist protein (IL-1Ra combined with insulin-like growth factor-1 (IGF-1 in rabbit chondrocytes and in a rabbit model of cartilage defects. pBudCE4.1-IL-1Ra+igf-1, pBudCE4.1-IL-1Ra and pBudCE4.1-igf-1 were constructed and combined with pSP-CS to form pDNA/pSP-CS complexes. These complexes were transfected into rabbit primary chondrocytes or injected into the joint cavity. Seven weeks after treatment, all rabbits were sacrificed and analyzed. High levels of IL-1Ra and igf-1 expression were detected both in the cell culture supernatant and in the synovial fluid. In vitro, the transgenic complexes caused significant proliferation of chondrocytes, promotion of glycosaminoglycan (GAG and collagen II synthesis, and inhibition of chondrocyte apoptosis and nitric oxide (NO synthesis. In vivo, the exogenous genes resulted in increased collagen II synthesis and reduced NO and GAG concentrations in the synovial fluid; histological studies revealed that pDNA/pSP-CS treatment resulted in varying degrees of hyaline-like cartilage repair and Mankin score decrease. The co-expression of both genes produced greater effects than each single gene alone both in vitro and in vivo. The results suggest that pSP-CS is a good candidate for use in gene therapy for the treatment of cartilage defects and that igf-1 and IL-1Ra co-expression produces promising biologic effects on cartilage defects.

  5. Hepatic JAK2 protects against atherosclerosis through circulating IGF-1.

    Science.gov (United States)

    Sivasubramaniyam, Tharini; Schroer, Stephanie A; Li, Angela; Luk, Cynthia T; Shi, Sally Yu; Besla, Rickvinder; Dodington, David W; Metherel, Adam H; Kitson, Alex P; Brunt, Jara J; Lopes, Joshua; Wagner, Kay-Uwe; Bazinet, Richard P; Bendeck, Michelle P; Robbins, Clinton S; Woo, Minna

    2017-07-20

    Atherosclerosis is considered both a metabolic and inflammatory disease; however, the specific tissue and signaling molecules that instigate and propagate this disease remain unclear. The liver is a central site of inflammation and lipid metabolism that is critical for atherosclerosis, and JAK2 is a key mediator of inflammation and, more recently, of hepatic lipid metabolism. However, precise effects of hepatic Jak2 on atherosclerosis remain unknown. We show here that hepatic Jak2 deficiency in atherosclerosis-prone mouse models exhibited accelerated atherosclerosis with increased plaque macrophages and decreased plaque smooth muscle cell content. JAK2's essential role in growth hormone signalling in liver that resulted in reduced IGF-1 with hepatic Jak2 deficiency played a causal role in exacerbating atherosclerosis. As such, restoring IGF-1 either pharmacologically or genetically attenuated atherosclerotic burden. Together, our data show hepatic Jak2 to play a protective role in atherogenesis through actions mediated by circulating IGF-1 and, to our knowledge, provide a novel liver-centric mechanism in atheroprotection.

  6. Expression of IGF-1R and iNOS in nasal polyps; epithelial cell homeostasis and innate immune mechanisms in pathogenesis of nasal polyposis

    Czech Academy of Sciences Publication Activity Database

    Fundová, P.; Filipovský, T.; Funda, David P.; Hovorka, Ondřej; Holý, R.; Navara, M.; Tlaskalová, Helena

    2008-01-01

    Roč. 53, č. 6 (2008), s. 558-562 ISSN 0015-5632 R&D Projects: GA MZd NR8517 Institutional research plan: CEZ:AV0Z50200510 Keywords : nasal polyposis * igf -1r * inos Subject RIV: EC - Immunology Impact factor: 1.172, year: 2008

  7. Diagnostic value of combined tet of cPSA, IGF-1 and TGFα for prostate cancer

    International Nuclear Information System (INIS)

    Dai Feng; Yang Qingling

    2006-01-01

    To assess the clinical value of serum complexed prostate specific antigen (cPSA), insulinlike growth factor(IGF-1),transforming growth factor a (TGFα) in the diagnosis of pros- tate cancer (PCα), serum samples were obtained from 46 men with PCa, 64 men with untreated benign prostatic hyperplasia(BPH) and 73 men of a healthy control group. The levels of cPSA, IGF-1 and TGFα were determined by autoimmunochemistry luminescence method, IRMA and RIA method. Postoperative observation was conducted for the change of cPSA, IGF-1 and TGFa in the serum from men with PCa obtained in one month, three months and six months after the operations. Results showed that the levels of cPSA, IGF-1 and TGFα in PCa serum were significantly higher than the BPH group and control group(P 0.05). The combined test of cPSA, IGF-1 and TGFα is meaningful for the prevision, diagnosis and therapy of PCa. (authors)

  8. The regulation of reproductive neuroendocrine function by insulin and insulin-like growth factor-1 (IGF-1).

    Science.gov (United States)

    Wolfe, Andrew; Divall, Sara; Wu, Sheng

    2014-10-01

    The mammalian reproductive hormone axis regulates gonadal steroid hormone levels and gonadal function essential for reproduction. The neuroendocrine control of the axis integrates signals from a wide array of inputs. The regulatory pathways important for mediating these inputs have been the subject of numerous studies. One class of proteins that have been shown to mediate metabolic and growth signals to the CNS includes Insulin and IGF-1. These proteins are structurally related and can exert endocrine and growth factor like action via related receptor tyrosine kinases. The role that insulin and IGF-1 play in controlling the hypothalamus and pituitary and their role in regulating puberty and nutritional control of reproduction has been studied extensively. This review summarizes the in vitro and in vivo models that have been used to study these neuroendocrine structures and the influence of these growth factors on neuroendocrine control of reproduction. Copyright © 2014 Elsevier Inc. All rights reserved.

  9. Normal Values of Circulating IGF-I Bioactivity in the Healthy Population: Comparison with five widely used IGF-I immunoassays

    NARCIS (Netherlands)

    M.P. Brugts (Michael); M.B. Ranke (Michael); L.J. Hofland (Leo); K. van der Wansem (Katy); K. Weber (Karin); J. Frystyk (Jan); S.W.J. Lamberts (Steven); J.A.M.J.L. Janssen (Joseph)

    2008-01-01

    textabstractBackground: IGF-I immunoassays are primarily used to estimate IGF-I bioactivity. Recently, an IGFI specific Kinase Receptor Activation Assay (KIRA) has been developed as an alternative method. However, no normative values have been established for the IGF-I KIRA. Objective: To

  10. Higher TNF-α, IGF-1 and leptin levels are found in tasters than non-tasters

    Directory of Open Access Journals (Sweden)

    Rui eWang

    2014-07-01

    Full Text Available Taste perception is controlled by taste cells that are present in the tongue and produce and secrete various metabolic hormones. Recent studies have demonstrated that taste receptors in tongue, gut and the pancreas are associated with local hormone secretion. The aim of this study was to determine whether there is a link between taste sensitivity and levels of circulating metabolic hormones in human and whether taste sensitivity is potentially related to peripheral metabolic regulation. 31 subjects were recruited and separated into tasters and non-tasters based on their phenol thiocarbamide (PTC bitter taste test results. Fasting plasma and saliva were collected and levels of hormones and cytokines were assayed. We observed significant differences in both hormone levels and hormone-body mass index (BMI correlation between tasters and non-tasters. Tasters had higher plasma levels of leptin (p=0.05, tumor necrosis factor-α (TNF-α (p=0.04, and Insulin-like growth factor 1 (IGF-1 (p=0.03. There was also a trend towards increased IGF-1 levels in the saliva of tasters (p=0.06. We found a positive correlation between plasma levels of glucose and BMI (R=0.4999, p=0.04 exclusively in non-tasters, not in tasters. In contrast, plasma C-peptide levels were found to be positively correlated to BMI (R=0.5563, p=0.03 in tasters. Saliva TNF-α levels were negatively correlated with BMI in tasters (R= -0.5908, p=0.03. Our findings demonstrate that there are differences in circulating levels of leptin, TNF-α and IGF-1 between tasters and non-tasters. These findings indicate that in addition to regulate eating behaviours, taste perception could also affect energy metabolism by controlling hormone secretion. People with different taste sensitivity may respond differently to the nutrient stimulation. Further work investigating the link between taste perception and peripheral metabolic control could potentially lead to the development of novel therapies for obese

  11. Effects of age and insulin-like growth factor-1 on rat neurotrophin receptor expression after nerve injury.

    Science.gov (United States)

    Luo, T David; Alton, Timothy B; Apel, Peter J; Cai, Jiaozhong; Barnwell, Jonathan C; Sonntag, William E; Smith, Thomas L; Li, Zhongyu

    2016-10-01

    Neurotrophin receptors, such as p75(NTR) , direct neuronal response to injury. Insulin-like growth factor-1 receptor (IGF-1R) mediates the increase in p75(NTR) during aging. The aim of this study was to examine the effect of aging and insulin-like growth factor-1 (IGF-1) treatment on recovery after peripheral nerve injury. Young and aged rats underwent tibial nerve transection with either local saline or IGF-1 treatment. Neurotrophin receptor mRNA and protein expression were quantified. Aged rats expressed elevated baseline IGF-1R (34% higher, P = 0.01) and p75(NTR) (68% higher, P < 0.01) compared with young rats. Post-injury, aged animals expressed significantly higher p75(NTR) levels (68.5% above baseline at 4 weeks). IGF-1 treatment suppressed p75(NTR) gene expression at 4 weeks (17.2% above baseline, P = 0.002) post-injury. Local IGF-1 treatment reverses age-related declines in recovery after peripheral nerve injuries by suppressing p75(NTR) upregulation and pro-apoptotic complexes. IGF-1 may be considered a viable adjuvant therapy to current treatment modalities. Muscle Nerve 54: 769-775, 2016. © 2016 Wiley Periodicals, Inc.

  12. IGF-1 abuse in sport: clinical and medico-legal aspects.

    Science.gov (United States)

    Molinelli, A; Bonsignore, A; Cicconi, M; Cioè, A; Traverso, A

    2010-12-01

    The frequent revisions of prohibited substances list established by WADA are aimed at keeping up with those drugs that, being increasingly used in medicine and in sports, play on one side a therapeutic role and, on the other, a doping role. Among the various hormone substances widely used in sports, the authors draw particular attention on IGF-1, a growth factor that is rapidly widespreading among athletes. Moreover, IGF-1 diffusion is not exclusively correlated with the doping phenomenon, being various the pathological conditions that may require the therapeutic use of this substance. As a consequence, during pathologies or medical treatments of various nature, the athletes should be informed of the IGF-1 administration because, if they are not duly apprised, they risk undergoing unjust sanctions from the competent authority. In fact, the athlete is given the possibility of communicating, before using, he is taking a medication of the WADA list for therapeutic reasons by applying for a TUE (Therapeutic Use Exemption). If this application is accepted on certified clinical grounds, the athlete will be allowed to use that substance even during sports competitions. However, the IGF-1 detection in the athlete's body shows, at the present state-of-art, two different problems: the first one has a technical character and concerns the differential diagnosis between the quantity of the physiologically produced substance and the quantity of the exogenously administrated substance; the second problem has an economic character and regards to the high cost of the analysis and, consecutively, the necessity of finding a well-equipped laboratory centre.

  13. Enhanced mesenchymal cell engraftment by IGF-1 improves left ventricular function in rats undergoing myocardial infarction.

    Science.gov (United States)

    Enoki, Chiharu; Otani, Hajime; Sato, Daisuke; Okada, Takayuki; Hattori, Reiji; Imamura, Hiroji

    2010-01-07

    We hypothesized that enhanced mesenchymal cell (MC) engraftment with insulin-like growth factor-1 (IGF-1) improves left ventricular (LV) function and survival. IGF-1 (10 microg/ml) increased adhesion and inhibited apoptosis under hypoxia in vitro through activation of phosphatidylinositol 3-kinase (PI3K) in bone marrow-derived MCs obtained from transgenic rats expressing green fluorescence protein. Myocardial infarction (MI) in rats was produced by ligature of the left coronary artery. One month after MI, rat hearts were injected with MCs in the presence or absence of 10 microg/ml IGF-1 with or without PI3K inhibitor, 5 microM LY294002. IGF-1 significantly increased engraftment of MCs between 6 h and 3 days after transplantation associated with the increase in stromal cell-derived factor-1alpha in the infracted LV. The transplanted MCs had disappeared 1 month after transplantation in all groups. MC transplantation with IGF-1 significantly increased neovascularization and inhibited cardiomyocyte apoptosis 3 days and 1 month after MC transplantation. This was associated with improved LV function 1 month after MC transplantation and eventually survival. LY294002 abrogated all of the beneficial effects of MC transplantation with IGF-1. IGF-1 alone had no effect on neovascularization and did not improve LV function and/or survival. These results suggest that IGF-1 improves engraftment of MCs at the time of transplantation via activation of PI3K and this improved engraftment of MCs may be attributed to an increased neovascularization and inhibition of cardiomyocyte death, leading to improvement of LV function and prolongation of survival despite the eventual loss of the transplanted MCs.

  14. High serum IGF-1 levels are associated with pregnancy loss following frozen-thawed euploid embryo transfer cycles.

    Science.gov (United States)

    Irani, Mohamad; Nasioudis, Dimitrios; Witkin, Steven S; Gunnala, Vinay; Spandorfer, Steven D

    2018-06-01

    An elevated level of insulin growth factor (IGF-1) in rat uterine fluid has been shown to exert detrimental effects of embryo development possibly leading to an increase in pregnancy loss. Interestingly, the administration of somatostatin to rats undergoing superovulation reduced IGF-1 levels in uterine luminal fluid and thus reversed its deleterious effects on embryo development and increased the number of normal embryos. Therefore, we investigated whether serum levels of IGF-1 correlate with the incidence of pregnancy loss following IVF. To account for aneuploidy and the effect of hormonal supplementation on serum IGF levels, we only included natural frozen-thawed euploid embryo transfer (N-FET) cycles. Sera collected in the follicular phase (cycle day 10) were tested for levels of IGF-1, IGF-2, and IGF-binding protein 1 (IGFBP-1) using quantitative ELISA. A total of 156 N-FET cycles were included: 120 resulted in a live birth whereas 36 led to a first trimester pregnancy loss. Women with a pregnancy loss had significantly higher serum IGF-1 levels compared to those who achieved a live birth (18.0 ± 1.1 vs. 14.6 ± 0.7 ng/mL, respectively). The two groups had comparable serum IGF-2 and IGFBP-1 levels. There was no significant difference in maternal age, body mass index, gravidity, parity, number of prior miscarriages, peak endometrial thickness, or infertility diagnosis between the two groups. In conclusion, women undergoing euploid blastocyst transfer with elevated serum IGF-1 concentrations may be at increased risk of pregnancy loss. This may constitute a novel molecular explanation of pregnancy loss of euploid conceptus. Copyright © 2018. Published by Elsevier B.V.

  15. BCL-2, in combination with MVP and IGF-1R expression, improves prediction of clinical outcome in complete response cervical carcinoma patients treated by radiochemotherapy.

    Science.gov (United States)

    Henríquez-Hernández, Luis Alberto; Lloret, Marta; Pinar, Beatriz; Bordón, Elisa; Rey, Agustín; Lubrano, Amina; Lara, Pedro Carlos

    2011-09-01

    To investigate whether BCL-2 expression would improve MVP/IGF-1R prediction of clinical outcome in cervix carcinoma patients treated by radiochemotherapy, and suggest possible mechanisms behind this effect. Fifty consecutive patients, who achieved complete response to treatment, from a whole series of 60 cases suffering from non-metastatic localized cervical carcinoma, were prospectively included in this study from July 1999 to December 2003. Follow-up was closed in January 2011. All patients received pelvic radiation (45-64.80 Gy in 1.8-2 Gy fractions) with concomitant cisplatin at 40 mg/m2/week doses followed by brachytherapy. Oncoprotein expression was studied by immunohistochemistry in paraffin-embedded tumour tissue. No relation was found between BCL-2 and clinicopathological variables. High MVP/IGF-1R/BCL-2 tumour expression was strongly related to poor local and regional disease-free survival (PMVP, and IGF-1R overexpression were related to poorer clinical outcome in cervical cancer patients who achieved clinical complete response to radiochemotherapy. The NHEJ repair protein Ku70/80 expression could be involved in the regulation of these oncoproteins. Copyright © 2011 Elsevier Inc. All rights reserved.

  16. Nutritional modulation of IGF-1 in relation to growth and body condition in Sceloporus lizards.

    Science.gov (United States)

    Duncan, Christine A; Jetzt, Amanda E; Cohick, Wendie S; John-Alder, Henry B

    2015-05-15

    Nutrition and energy balance are important regulators of growth and the growth hormone/insulin-like growth factor (GH/IGF) axis. However, our understanding of these functions does not extend uniformly to all classes of vertebrates and is mainly limited to controlled laboratory conditions. Lizards can be useful models to improve our understanding of the nutritional regulation of the GH/IGF-1 axis because many species are relatively easy to observe and manipulate both in the laboratory and in the field. In the present study, the effects of variation in food intake on growth, body condition, and hepatic IGF-1 mRNA levels were measured in (1) juveniles of Sceloporus jarrovii maintained on a full or 1/3 ration and (2) hatchlings of Sceloporus undulatus subjected to full or zero ration with or without re-feeding. These parameters plus plasma IGF-1 were measured in a third experiment using adults of S. undulatus subjected to full or zero ration with or without re-feeding. In all experiments, plasma corticosterone was measured as an anticipated indicator of nutritional stress. In S. jarrovii, growth and body condition were reduced but lizards remained in positive energy balance on 1/3 ration, and hepatic IGF-1 mRNA and plasma corticosterone were not affected in comparison to full ration. In S. undulatus, growth, body condition, hepatic IGF-1 mRNA, and plasma IGF-1 were all reduced by zero ration and restored by refeeding. Plasma corticosterone was increased in response to zero ration and restored by full ration in hatchlings but not adults of S. undulatus. These data indicate that lizards conform to the broader vertebrate model in which severe food deprivation and negative energy balance is required to attenuate systemic IGF-1 expression. However, when animals remain in positive energy balance, reduced food intake does not appear to affect systemic IGF-1. Consistent with other studies on lizards, the corticosterone response to reduced food intake is an unreliable indicator

  17. IGF-1 decreases collagen degradation in diabetic NOD mesangial cells: implications for diabetic nephropathy.

    Science.gov (United States)

    Lupia, E; Elliot, S J; Lenz, O; Zheng, F; Hattori, M; Striker, G E; Striker, L J

    1999-08-01

    Nonobese diabetic (NOD) mice develop glomerulosclerosis shortly after the onset of diabetes. We showed that mesangial cells (MCs) from diabetic mice exhibited a stable phenotypic switch, consisting of both increased IGF-1 synthesis and proliferation (Elliot SJ, Striker LJ, Hattori M, Yang CW, He CJ, Peten EP, Striker GE: Mesangial cells from diabetic NOD mice constitutively secrete increased amounts of insulin-like growth factor-I. Endocrinology 133:1783-1788, 1993). Because the extracellular matrix (ECM) accumulation in diabetic glomerulosclerosis may be partly due to decreased degradation, we examined the effect of excess IGF-1 on collagen turnover and the activity of metalloproteinases (MMPs) and tissue inhibitors of metalloproteinase (TIMPs) in diabetic and nondiabetic NOD-MC. Total collagen degradation was reduced by 58 +/- 18% in diabetic NOD-MCs, which correlated with a constitutive decrease in MMP-2 activity and mRNA levels, and nearly undetectable MMP-9 activity and mRNA. TIMP levels were slightly decreased in diabetic NOD-MC. The addition of recombinant IGF-1 to nondiabetic NOD-MC resulted in a decrease in MMP-2 and TIMP activity. Furthermore, treatment of diabetic NOD-MC with a neutralizing antibody against IGF-1 increased the latent form, and restored the active form, of MMP-2. In conclusion, the excessive production of IGF-1 contributes to the altered ECM turnover in diabetic NOD-MC, largely through a reduction of MMP-2 activity. These data suggest that IGF-1 could be a major contributor to the development of diabetic glomerulosclerosis.

  18. Predicting refeeding hypophosphataemia: insulin growth factor 1 (IGF-1) as a diagnostic biochemical marker for clinical practice.

    Science.gov (United States)

    Goyale, Atul; Ashley, Sarah L; Taylor, David R; Elnenaei, Manal O; Alaghband-Zadeh, Jamshid; Sherwood, Roy A; le Roux, Carel W; Vincent, Royce P

    2015-01-01

    Refeeding syndrome (RS) is a potentially fatal condition that can occur following the re-introduction of nutrition after a period of starvation. Hypophosphataemia following the reintroduction of nutrition is often the only reliable biochemical marker of RS. Refeeding index (RI) generated from baseline insulin-like growth factor-1 (IGF-1) and leptin has been proposed as a useful biochemical marker for the identification of patients at risk of developing refeeding hypophosphataemia (RH). A prospective study included 52 patients referred for parenteral nutrition (PN). The sensitivity and specificity of IGF-1 measured using a sensitive assay was compared to the RI in predicting the development of RH (a ≥ 30% drop in PO4 during the first 36-h of PN administration). Leptin and IGF-1 were analysed on baseline samples using a quantitative enzyme-linked immunoassay. Daily blood samples were collected from all patients for routine biochemistry for the full duration of PN administration. High sensitivity IGF-1 measurement alone was comparable with the RI, using receiver-operating characteristic (ROC) curve analysis, with areas under the curve being 0.79 and 0.80, respectively, and superior to leptin alone (0.72) for predicting ≥ 30% drop in PO4. The cut-off value for IGF-1 that gave best sensitivity (91% [95% CI 75-98%]) and specificity (65% [95% CI 41-85%]) was 63.7 µg/L, with a likelihood ratio of 2.59. Baseline IGF-1 is an objective, sensitive and specific biochemical marker in identifying patients who are at high risk of developing RH prior to PN administration and therefore may have a role in clinical practice. © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

  19. IGF-II receptors in luminal and basolateral membranes isolated from pars convoluta and pars recta of rabbit proximal tubule

    DEFF Research Database (Denmark)

    Jacobsen, Christian; Jessen, H; Flyvbjerg, A

    1995-01-01

    the inhibitory effect of beta-galactosidase. Analyses of 125I-IGF-II binding curves in the presence of beta-galactosidase or D-mannose 6-phosphate demonstrated that none of these compounds changed the binding affinity of 125I-IGF-II for the membrane vesicles. The IGF-II/M6P receptor content in the luminal...... membranes was in the range 0.21-0.34 pmol IGF-II/M6P receptor per mg protein and very low compared to 2.27-2.86 pmol IGF-II/M6P receptor per mg protein in basolateral membranes. Udgivelsesdato: 1995-Apr-12...

  20. G protein-coupled receptors (GPCRs) That Signal via Protein Kinase A (PKA) Cross-talk at Insulin Receptor Substrate 1 (IRS1) to Activate the phosphatidylinositol 3-kinase (PI3K)/AKT Pathway.

    Science.gov (United States)

    Law, Nathan C; White, Morris F; Hunzicker-Dunn, Mary E

    2016-12-30

    G protein-coupled receptors (GPCRs) activate PI3K/v-AKT thymoma viral oncoprotein (AKT) to regulate many cellular functions that promote cell survival, proliferation, and growth. However, the mechanism by which GPCRs activate PI3K/AKT remains poorly understood. We used ovarian preantral granulosa cells (GCs) to elucidate the mechanism by which the GPCR agonist FSH via PKA activates the PI3K/AKT cascade. Insulin-like growth factor 1 (IGF1) is secreted in an autocrine/paracrine manner by GCs and activates the IGF1 receptor (IGF1R) but, in the absence of FSH, fails to stimulate YXXM phosphorylation of IRS1 (insulin receptor substrate 1) required for PI3K/AKT activation. We show that PKA directly phosphorylates the protein phosphatase 1 (PP1) regulatory subunit myosin phosphatase targeting subunit 1 (MYPT1) to activate PP1 associated with the IGF1R-IRS1 complex. Activated PP1 is sufficient to dephosphorylate at least four IRS1 Ser residues, Ser 318 , Ser 346 , Ser 612 , and Ser 789 , and promotes IRS1 YXXM phosphorylation by the IGF1R to activate the PI3K/AKT cascade. Additional experiments indicate that this mechanism also occurs in breast cancer, thyroid, and preovulatory granulosa cells, suggesting that the PKA-dependent dephosphorylation of IRS1 Ser/Thr residues is a conserved mechanism by which GPCRs signal to activate the PI3K/AKT pathway downstream of the IGF1R. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  1. Diosgenin induces apoptosis in IGF-1-stimulated human thyrocytes through two caspase-dependent pathways

    Energy Technology Data Exchange (ETDEWEB)

    Mu, Shumin [Provincial Hospital Affiliated to Shandong University, Jinan 250021 (China); Hospital Affiliated to Shandong Traditional Chinese Medicine University, Jinan 250011 (China); Institute of Endocrinology, Shandong Academy of Clinical Medicine, Jinan 250021 (China); Tian, Xingsong; Ruan, Yongwei [Provincial Hospital Affiliated to Shandong University, Jinan 250021 (China); Liu, Yuantao [The Second Hospital of Shandong University, Jinan 250033 (China); Bian, Dezhi [Provincial Hospital Affiliated to Shandong University, Jinan 250021 (China); Jining Medical College, Jining 272013 (China); Ma, Chunyan [Provincial Hospital Affiliated to Shandong University, Jinan 250021 (China); Yu, Chunxiao [Provincial Hospital Affiliated to Shandong University, Jinan 250021 (China); Institute of Endocrinology, Shandong Academy of Clinical Medicine, Jinan 250021 (China); Feng, Mei [Provincial Hospital Affiliated to Shandong University, Jinan 250021 (China); Wang, Furong [Shandong University of Traditional Chinese Medicine, Jinan 250011 (China); Gao, Ling [Provincial Hospital Affiliated to Shandong University, Jinan 250021 (China); Institute of Endocrinology, Shandong Academy of Clinical Medicine, Jinan 250021 (China); Zhao, Jia-jun, E-mail: jjzhao@medmail.com.cn [Provincial Hospital Affiliated to Shandong University, Jinan 250021 (China); Institute of Endocrinology, Shandong Academy of Clinical Medicine, Jinan 250021 (China)

    2012-02-10

    Highlights: Black-Right-Pointing-Pointer Diosgenin induces apoptosis in IGF-1-treated thyrocytes through two caspase pathways. Black-Right-Pointing-Pointer Diosgenin inhibits FLIP and activates caspase-8 in FAS related-pathway. Black-Right-Pointing-Pointer Diosgenin increases ROS, regulates the ratio of Bax/Bcl-2 in mitochondrial pathway. -- Abstract: Insulin-like growth factor-1 (IGF-1) is a growth factor of the thyroid that has been shown in our previous study to possess proliferative and antiapoptotic effects in FRTL-5 cell lines through the upregulation of cyclin D and Fas-associated death domain-like interleukin-1-converting enzyme (FLICE)-inhibitory protein (FLIP). Diosgenin, a natural steroid sapogenin from plants, has been shown to induce apoptosis in many cell lines, with the exception of thyroid cells. In this report, we investigated the apoptotic effect and mechanism of diosgenin in IGF-1-stimulated primary human thyrocytes. Primary human thyrocytes were preincubated with or without IGF-1 for 24 h and subsequently exposed to varying concentrations of diosgenin for different times. We found that diosgenin induced apoptosis in human thyrocytes pretreated with IGF-1 in a dose-dependent manner through the activation of caspase cascades. Moreover, diosgenin inhibited FLIP and activated caspase-8 in the FAS-related apoptotic pathway. Diosgenin increased the production of ROS, regulated the balance of Bax and Bcl-2 and cleaved caspase-9 in the mitochondrial apoptotic pathway. These results indicate that diosgenin induces apoptosis in IGF-1-stimulated primary human thyrocytes through two caspase-dependent pathways.

  2. AKT signaling mediates IGF-I survival actions on otic neural progenitors.

    Directory of Open Access Journals (Sweden)

    Maria R Aburto

    Full Text Available BACKGROUND: Otic neurons and sensory cells derive from common progenitors whose transition into mature cells requires the coordination of cell survival, proliferation and differentiation programmes. Neurotrophic support and survival of post-mitotic otic neurons have been intensively studied, but the bases underlying the regulation of programmed cell death in immature proliferative otic neuroblasts remains poorly understood. The protein kinase AKT acts as a node, playing a critical role in controlling cell survival and cell cycle progression. AKT is activated by trophic factors, including insulin-like growth factor I (IGF-I, through the generation of the lipidic second messenger phosphatidylinositol 3-phosphate by phosphatidylinositol 3-kinase (PI3K. Here we have investigated the role of IGF-dependent activation of the PI3K-AKT pathway in maintenance of otic neuroblasts. METHODOLOGY/PRINCIPAL FINDINGS: By using a combination of organotypic cultures of chicken (Gallus gallus otic vesicles and acoustic-vestibular ganglia, Western blotting, immunohistochemistry and in situ hybridization, we show that IGF-I-activation of AKT protects neural progenitors from programmed cell death. IGF-I maintains otic neuroblasts in an undifferentiated and proliferative state, which is characterised by the upregulation of the forkhead box M1 (FoxM1 transcription factor. By contrast, our results indicate that post-mitotic p27(Kip-positive neurons become IGF-I independent as they extend their neuronal processes. Neurons gradually reduce their expression of the Igf1r, while they increase that of the neurotrophin receptor, TrkC. CONCLUSIONS/SIGNIFICANCE: Proliferative otic neuroblasts are dependent on the activation of the PI3K-AKT pathway by IGF-I for survival during the otic neuronal progenitor phase of early inner ear development.

  3. Identification of Insulin-Like Growth Factor-I Receptor (IGF-IR) Gene Promoter-Binding Proteins in Estrogen Receptor (ER)-Positive and ER-Depleted Breast Cancer Cells

    International Nuclear Information System (INIS)

    Sarfstein, Rive; Belfiore, Antonino; Werner, Haim

    2010-01-01

    The insulin-like growth factor I receptor (IGF-IR) has been implicated in the etiology of breast cancer. Overexpression of the IGF-IR gene is a typical feature of most primary breast cancers, whereas low IGF-IR levels are seen at advanced stages. Hence, evaluation of IGF-IR levels might be important for assessing prognosis. In the present study, we employed a proteomic approach based on DNA affinity chromatography followed either by mass spectroscopy (MS) or Western blot analysis to identify transcription factors that may associate with the IGF-IR promoter in estrogen receptor (ER)-positive and ER-depleted breast cancer cells. A biotinylated IGF-IR promoter fragment was bound to streptavidin magnetic beads and incubated with nuclear extracts of breast cancer cells. IGF-IR promoter-binding proteins were eluted with high salt and analyzed by MS and Western blots. Among the proteins that were found to bind to the IGF-IR promoter we identified zinc finger transcription factors Sp1 and KLF6, ER-α, p53, c-jun, and poly (ADP-ribosylation) polymerase. Furthermore, chromatin immune-precipitation (ChIP) analysis confirmed the direct in vivo binding of some of these transcription factors to IGF-IR promoter DNA. The functional relevance of binding data was assessed by cotransfection experiments with specific expression vectors along with an IGF-IR promoter reporter. In summary, we identified nuclear proteins that are potentially responsible for the differential expression of the IGF-IR gene in ER-positive and ER-depleted breast cancer cells

  4. Identification of Insulin-Like Growth Factor-I Receptor (IGF-IR) Gene Promoter-Binding Proteins in Estrogen Receptor (ER)-Positive and ER-Depleted Breast Cancer Cells

    Energy Technology Data Exchange (ETDEWEB)

    Sarfstein, Rive [Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978 (Israel); Belfiore, Antonino [Department of Clinical and Experimental Medicine, University Magna Graecia of Catanzaro, Catanzaro 88100 (Italy); Werner, Haim, E-mail: hwerner@post.tau.ac.il [Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978 (Israel)

    2010-03-25

    The insulin-like growth factor I receptor (IGF-IR) has been implicated in the etiology of breast cancer. Overexpression of the IGF-IR gene is a typical feature of most primary breast cancers, whereas low IGF-IR levels are seen at advanced stages. Hence, evaluation of IGF-IR levels might be important for assessing prognosis. In the present study, we employed a proteomic approach based on DNA affinity chromatography followed either by mass spectroscopy (MS) or Western blot analysis to identify transcription factors that may associate with the IGF-IR promoter in estrogen receptor (ER)-positive and ER-depleted breast cancer cells. A biotinylated IGF-IR promoter fragment was bound to streptavidin magnetic beads and incubated with nuclear extracts of breast cancer cells. IGF-IR promoter-binding proteins were eluted with high salt and analyzed by MS and Western blots. Among the proteins that were found to bind to the IGF-IR promoter we identified zinc finger transcription factors Sp1 and KLF6, ER-α, p53, c-jun, and poly (ADP-ribosylation) polymerase. Furthermore, chromatin immune-precipitation (ChIP) analysis confirmed the direct in vivo binding of some of these transcription factors to IGF-IR promoter DNA. The functional relevance of binding data was assessed by cotransfection experiments with specific expression vectors along with an IGF-IR promoter reporter. In summary, we identified nuclear proteins that are potentially responsible for the differential expression of the IGF-IR gene in ER-positive and ER-depleted breast cancer cells.

  5. EEN regulates the proliferation and survival of multiple myeloma cells by potentiating IGF-1 secretion

    International Nuclear Information System (INIS)

    Huang, Er-Wen; Xue, Sheng-Jiang; Li, Xiao-Yan; Xu, Suo-Wen; Cheng, Jian-Ding; Zheng, Jin-Xiang; Shi, He; Lv, Guo-Li; Li, Zhi-Gang; Li, Yue; Liu, Chang-Hui; Chen, Xiao-Hui; Liu, Hong; Li, Jie; Liu, Chao

    2014-01-01

    Highlights: • Levels of EEN expression paralleled with the rate of cell proliferation. • EEN was involved in the proliferation and survival of multiple myeloma (MM) cells. • EEN regulated the activity of IGF-1-Akt/mTOR pathway. • EEN regulated proliferation and survival of MM cells by enhancing IGF-1 secretion. - Abstract: The molecular mechanisms of multiple myeloma are not well defined. EEN is an endocytosis-regulating molecule. Here we report that EEN regulates the proliferation and survival of multiple myeloma cells, by regulating IGF-1 secretion. In the present study, we observed that EEN expression paralleled with cell proliferation, EEN accelerated cell proliferation, facilitated cell cycle transition from G1 to S phase by regulating cyclin-dependent kinases (CDKs) pathway, and delayed cell apoptosis via Bcl2/Bax-mitochondrial pathway. Mechanistically, we found that EEN was indispensable for insulin-like growth factor-1 (IGF-1) secretion and the activation of protein kinase B-mammalian target of rapamycin (Akt-mTOR) pathway. Exogenous IGF-1 overcame the phenotype of EEN depletion, while IGF-1 neutralization overcame that of EEN over-expression. Collectively, these data suggest that EEN may play a pivotal role in excessive cell proliferation and insufficient cell apoptosis of bone marrow plasma cells in multiple myeloma. Therefore, EEN may represent a potential diagnostic marker or therapeutic target for multiple myeloma

  6. EEN regulates the proliferation and survival of multiple myeloma cells by potentiating IGF-1 secretion

    Energy Technology Data Exchange (ETDEWEB)

    Huang, Er-Wen [Guangzhou Institute of Forensic Science, Guangzhou (China); Department of Forensic Pathology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou (China); Xue, Sheng-Jiang [Department of Forensic Pathology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou (China); Li, Xiao-Yan [Department of Pharmacy, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou (China); Xu, Suo-Wen [Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou (China); Cheng, Jian-Ding; Zheng, Jin-Xiang [Department of Forensic Pathology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou (China); Shi, He; Lv, Guo-Li; Li, Zhi-Gang; Li, Yue; Liu, Chang-Hui; Chen, Xiao-Hui; Liu, Hong [Guangzhou Institute of Forensic Science, Guangzhou (China); Li, Jie, E-mail: mdlijie@sina.com [Department of Anaesthesiology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou (China); Liu, Chao, E-mail: liuchaogaj@21cn.com [Guangzhou Institute of Forensic Science, Guangzhou (China)

    2014-05-02

    Highlights: • Levels of EEN expression paralleled with the rate of cell proliferation. • EEN was involved in the proliferation and survival of multiple myeloma (MM) cells. • EEN regulated the activity of IGF-1-Akt/mTOR pathway. • EEN regulated proliferation and survival of MM cells by enhancing IGF-1 secretion. - Abstract: The molecular mechanisms of multiple myeloma are not well defined. EEN is an endocytosis-regulating molecule. Here we report that EEN regulates the proliferation and survival of multiple myeloma cells, by regulating IGF-1 secretion. In the present study, we observed that EEN expression paralleled with cell proliferation, EEN accelerated cell proliferation, facilitated cell cycle transition from G1 to S phase by regulating cyclin-dependent kinases (CDKs) pathway, and delayed cell apoptosis via Bcl2/Bax-mitochondrial pathway. Mechanistically, we found that EEN was indispensable for insulin-like growth factor-1 (IGF-1) secretion and the activation of protein kinase B-mammalian target of rapamycin (Akt-mTOR) pathway. Exogenous IGF-1 overcame the phenotype of EEN depletion, while IGF-1 neutralization overcame that of EEN over-expression. Collectively, these data suggest that EEN may play a pivotal role in excessive cell proliferation and insufficient cell apoptosis of bone marrow plasma cells in multiple myeloma. Therefore, EEN may represent a potential diagnostic marker or therapeutic target for multiple myeloma.

  7. IGF-1 release kinetics from chitosan microparticles fabricated using environmentally benign conditions

    Energy Technology Data Exchange (ETDEWEB)

    Mantripragada, Venkata P. [Biomedical Engineering Program, The University of Toledo, Toledo, OH 43614-5807 (United States); Jayasuriya, Ambalangodage C., E-mail: a.jayasuriya@utoledo.edu [Biomedical Engineering Program, The University of Toledo, Toledo, OH 43614-5807 (United States); Department of Orthopaedic Surgery, The University of Toledo, Toledo, OH 43614-5807 (United States)

    2014-09-01

    The main objective of this study is to maximize growth factor encapsulation efficiency into microparticles. The novelty of this study is to maximize the encapsulated growth factors into microparticles by minimizing the use of organic solvents and using relatively low temperatures. The microparticles were fabricated using chitosan biopolymer as a base polymer and cross-linked with tripolyphosphate (TPP). Insulin like-growth factor-1 (IGF-1) was encapsulated into microparticles to study release kinetics and bioactivity. In order to authenticate the harms of using organic solvents like hexane and acetone during microparticle preparation, IGF-1 encapsulated microparticles prepared by the emulsification and coacervation methods were compared. The microparticles fabricated by emulsification method have shown a significant decrease (p < 0.05) in IGF-1 encapsulation efficiency, and cumulative release during the two-week period. The biocompatibility of chitosan microparticles and the bioactivity of the released IGF-1 were determined in vitro by live/dead viability assay. The mineralization data observed with von Kossa assay, was supported by mRNA expression levels of osterix and runx2, which are transcription factors necessary for osteoblasts differentiation. Real time RT-PCR data showed an increased expression of runx2 and a decreased expression of osterix over time, indicating differentiating osteoblasts. Chitosan microparticles prepared in optimum environmental conditions are a promising controlled delivery system for cells to attach, proliferate, differentiate and mineralize, thereby acting as a suitable bone repairing material. - Highlights: • Coacervation chitosan microparticles were biocompatible and biodegradable. • IGF-1 encapsulation efficiency increased with coacervation chitosan microparticles. • Coacervation chitosan microparticles support osteoblast attachment and differentiation. • Coacervation chitosan microparticles support osteoblast mineralization.

  8. IGF-1 release kinetics from chitosan microparticles fabricated using environmentally benign conditions

    International Nuclear Information System (INIS)

    Mantripragada, Venkata P.; Jayasuriya, Ambalangodage C.

    2014-01-01

    The main objective of this study is to maximize growth factor encapsulation efficiency into microparticles. The novelty of this study is to maximize the encapsulated growth factors into microparticles by minimizing the use of organic solvents and using relatively low temperatures. The microparticles were fabricated using chitosan biopolymer as a base polymer and cross-linked with tripolyphosphate (TPP). Insulin like-growth factor-1 (IGF-1) was encapsulated into microparticles to study release kinetics and bioactivity. In order to authenticate the harms of using organic solvents like hexane and acetone during microparticle preparation, IGF-1 encapsulated microparticles prepared by the emulsification and coacervation methods were compared. The microparticles fabricated by emulsification method have shown a significant decrease (p < 0.05) in IGF-1 encapsulation efficiency, and cumulative release during the two-week period. The biocompatibility of chitosan microparticles and the bioactivity of the released IGF-1 were determined in vitro by live/dead viability assay. The mineralization data observed with von Kossa assay, was supported by mRNA expression levels of osterix and runx2, which are transcription factors necessary for osteoblasts differentiation. Real time RT-PCR data showed an increased expression of runx2 and a decreased expression of osterix over time, indicating differentiating osteoblasts. Chitosan microparticles prepared in optimum environmental conditions are a promising controlled delivery system for cells to attach, proliferate, differentiate and mineralize, thereby acting as a suitable bone repairing material. - Highlights: • Coacervation chitosan microparticles were biocompatible and biodegradable. • IGF-1 encapsulation efficiency increased with coacervation chitosan microparticles. • Coacervation chitosan microparticles support osteoblast attachment and differentiation. • Coacervation chitosan microparticles support osteoblast mineralization

  9. Targeted mass spectrometry analysis of the proteins IGF1, IGF2, IBP2, IBP3 and A2GL by blood protein precipitation

    DEFF Research Database (Denmark)

    Such-Sanmartín, Gerard; Bache, Nicolai; Callesen, Anne K

    2015-01-01

    aggravated when using fast high-throughput methods, which are necessary for analysis of hundreds and thousands of samples in clinical laboratories. The blood proteins IGF1, IGF2, IBP2, IBP3 and A2GL have been proposed as indirect biomarkers for detection of GH administration and as putative biomarkers...

  10. Simvastatin inhibits the proliferation of human prostate cancer PC-3 cells via down-regulation of the insulin-like growth factor 1 receptor

    International Nuclear Information System (INIS)

    Sekine, Yoshitaka; Furuya, Yosuke; Nishii, Masahiro; Koike, Hidekazu; Matsui, Hiroshi; Suzuki, Kazuhiro

    2008-01-01

    Recently, statins have been being studied for their proapoptic and antimetastatic effects. However, the exact mechanisms of their anticancer action are still unclear. Dolichyl phosphate is a nonsterol isoprenoid derivative in the mevalonate pathway that affects the expression of the Insulin-like growth factor 1 receptor (IGF-1R). IGF-1R activation is required for prostate cell proliferation; therefore, IGF-1R inhibitory agents may be of preventive and/or therapeutic value. In this study, the effects of simvastatin on IGF-1R signaling in prostate cancer PC-3 cells were examined. Simvastatin suppressed proliferation and induced apoptosis of PC-3, and the expression of IGF-1R was suppressed by simvastatin. Knockdown of IGF-1R by siRNA led to inhibition of proliferation of PC-3. Simvastatin also inhibited IGF-1-induced activation of both ERK and Akt signaling and IGF-1-induced PC-3 cell proliferation. Our results suggest statins are potent inhibitors of the IGF-1/IGF-1R system in prostate cancer cells and may be beneficial in prostate cancer treatment

  11. Insulin-like growth factor-1 receptor in mature osteoblasts is required for periosteal bone formation induced by reloading

    Science.gov (United States)

    Kubota, Takuo; Elalieh, Hashem Z.; Saless, Neema; Fong, Chak; Wang, Yongmei; Babey, Muriel; Cheng, Zhiqiang; Bikle, Daniel D.

    2013-11-01

    Skeletal loading and unloading has a pronounced impact on bone remodeling, a process also regulated by insulin-like growth factor-1 (IGF-1) signaling. Skeletal unloading leads to resistance to the anabolic effect of IGF-1, while reloading after unloading restores responsiveness to IGF-1. However, a direct study of the importance of IGF-1 signaling in the skeletal response to mechanical loading remains to be tested. In this study, we assessed the skeletal response of osteoblast-specific Igf-1 receptor deficient (Igf-1r-/-) mice to unloading and reloading. The mice were hindlimb unloaded for 14 days and then reloaded for 16 days. Igf-1r-/- mice displayed smaller cortical bone and diminished periosteal and endosteal bone formation at baseline. Periosteal and endosteal bone formation decreased with unloading in Igf-1r+/+ mice. However, the recovery of periosteal bone formation with reloading was completely inhibited in Igf-1r-/- mice, although reloading-induced endosteal bone formation was not hampered. These changes in bone formation resulted in the abolishment of the expected increase in total cross-sectional area with reloading in Igf-1r-/- mice compared to the control mice. These results suggest that the Igf-1r in mature osteoblasts has a critical role in periosteal bone formation in the skeletal response to mechanical loading.

  12. IGF-1 prevents ANG II-induced skeletal muscle atrophy via Akt- and Foxo-dependent inhibition of the ubiquitin ligase atrogin-1 expression

    Science.gov (United States)

    Yoshida, Tadashi; Semprun-Prieto, Laura; Sukhanov, Sergiy

    2010-01-01

    Congestive heart failure is associated with activation of the renin-angiotensin system and skeletal muscle wasting. Angiotensin II (ANG II) has been shown to increase muscle proteolysis and decrease circulating and skeletal muscle IGF-1. We have shown previously that skeletal muscle-specific overexpression of IGF-1 prevents proteolysis and apoptosis induced by ANG II. These findings indicated that downregulation of IGF-1 signaling in skeletal muscle played an important role in the wasting effect of ANG II. However, the signaling pathways and mechanisms whereby IGF-1 prevents ANG II-induced skeletal muscle atrophy are unknown. Here we show ANG II-induced transcriptional regulation of two ubiquitin ligases atrogin-1 and muscle ring finger-1 (MuRF-1) that precedes the reduction of skeletal muscle IGF-1 expression, suggesting that activation of atrogin-1 and MuRF-1 is an initial mechanism leading to skeletal muscle atrophy in response to ANG II. IGF-1 overexpression in skeletal muscle prevented ANG II-induced skeletal muscle wasting and the expression of atrogin-1, but not MuRF-1. Dominant-negative Akt and constitutively active Foxo-1 blocked the ability of IGF-1 to prevent ANG II-mediated upregulation of atrogin-1 and skeletal muscle wasting. Our findings demonstrate that the ability of IGF-1 to prevent ANG II-induced skeletal muscle wasting is mediated via an Akt- and Foxo-1-dependent signaling pathway that results in inhibition of atrogin-1 but not MuRF-1 expression. These data suggest strongly that atrogin-1 plays a critical role in mechanisms of ANG II-induced wasting in vivo. PMID:20228261

  13. Zcchc11 Uridylates Mature miRNAs to Enhance Neonatal IGF-1 Expression, Growth, and Survival

    Science.gov (United States)

    Kozlowski, Elyse; Matsuura, Kori Y.; Ferrari, Joseph D.; Morris, Samantha A.; Powers, John T.; Daley, George Q.; Quinton, Lee J.; Mizgerd, Joseph P.

    2012-01-01

    The Zcchc11 enzyme is implicated in microRNA (miRNA) regulation. It can uridylate let-7 precursors to decrease quantities of the mature miRNA in embryonic stem cell lines, suggested to mediate stem cell maintenance. It can uridylate mature miR-26 to relieve silencing activity without impacting miRNA content in cancer cell lines, suggested to mediate cytokine and growth factor expression. Broader roles of Zcchc11 in shaping or remodeling the miRNome or in directing biological or physiological processes remain entirely speculative. We generated Zcchc11-deficient mice to address these knowledge gaps. Zcchc11 deficiency had no impact on embryogenesis or fetal development, but it significantly decreased survival and growth immediately following birth, indicating a role for this enzyme in early postnatal fitness. Deep sequencing of small RNAs from neonatal livers revealed roles of this enzyme in miRNA sequence diversity. Zcchc11 deficiency diminished the lengths and terminal uridine frequencies for diverse mature miRNAs, but it had no influence on the quantities of any miRNAs. The expression of IGF-1, a liver-derived protein essential to early growth and survival, was enhanced by Zcchc11 expression in vitro, and miRNA silencing of IGF-1 was alleviated by uridylation events observed to be Zcchc11-dependent in the neonatal liver. In neonatal mice, Zcchc11 deficiency significantly decreased IGF-1 mRNA in the liver and IGF-1 protein in the blood. We conclude that the Zcchc11-mediated terminal uridylation of mature miRNAs is pervasive and physiologically significant, especially important in the neonatal period for fostering IGF-1 expression and enhancing postnatal growth and survival. We propose that the miRNA 3′ terminus is a regulatory node upon which multiple enzymes converge to direct silencing activity and tune gene expression. PMID:23209448

  14. Zcchc11 uridylates mature miRNAs to enhance neonatal IGF-1 expression, growth, and survival.

    Directory of Open Access Journals (Sweden)

    Matthew R Jones

    Full Text Available The Zcchc11 enzyme is implicated in microRNA (miRNA regulation. It can uridylate let-7 precursors to decrease quantities of the mature miRNA in embryonic stem cell lines, suggested to mediate stem cell maintenance. It can uridylate mature miR-26 to relieve silencing activity without impacting miRNA content in cancer cell lines, suggested to mediate cytokine and growth factor expression. Broader roles of Zcchc11 in shaping or remodeling the miRNome or in directing biological or physiological processes remain entirely speculative. We generated Zcchc11-deficient mice to address these knowledge gaps. Zcchc11 deficiency had no impact on embryogenesis or fetal development, but it significantly decreased survival and growth immediately following birth, indicating a role for this enzyme in early postnatal fitness. Deep sequencing of small RNAs from neonatal livers revealed roles of this enzyme in miRNA sequence diversity. Zcchc11 deficiency diminished the lengths and terminal uridine frequencies for diverse mature miRNAs, but it had no influence on the quantities of any miRNAs. The expression of IGF-1, a liver-derived protein essential to early growth and survival, was enhanced by Zcchc11 expression in vitro, and miRNA silencing of IGF-1 was alleviated by uridylation events observed to be Zcchc11-dependent in the neonatal liver. In neonatal mice, Zcchc11 deficiency significantly decreased IGF-1 mRNA in the liver and IGF-1 protein in the blood. We conclude that the Zcchc11-mediated terminal uridylation of mature miRNAs is pervasive and physiologically significant, especially important in the neonatal period for fostering IGF-1 expression and enhancing postnatal growth and survival. We propose that the miRNA 3' terminus is a regulatory node upon which multiple enzymes converge to direct silencing activity and tune gene expression.

  15. Effect of microRNA-135a on Cell Proliferation, Migration, Invasion, Apoptosis and Tumor Angiogenesis Through the IGF-1/PI3K/Akt Signaling Pathway in Non-Small Cell Lung Cancer.

    Science.gov (United States)

    Zhou, Yufei; Li, Shaoxia; Li, Jiangtao; Wang, Dongfeng; Li, Quanxing

    2017-01-01

    This study explored the ability of microRNA-135a (miR-135a) to influence cell proliferation, migration, invasion, apoptosis and tumor angiogenesis through the IGF-1/PI3K/Akt signaling pathway in non-small cell lung cancer (NSCLC). NSCLC tissues and adjacent normal tissues were collected from 138 NSCLC patients. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the expression levels of miR-135a and IGF-1, PI3K, Akt, VEGF, bFGF and IL-8 mRNA; western blotting was used to determine the expression levels of IGF-1, PI3K and Akt protein; and enzyme-linked immunosorbent assay (ELISA) was used to analyze the expression levels of VEGF, bFGF and IL-8 protein. Human NSCLC cell lines (A549, H460, and H1299) and the human bronchial epithelial cell line (HBE) were selected. A549 cells were assigned to blank, negative control (NC), miR-135a mimics, miR-135a inhibitors, IGF-1 siRNA and miR-135a inhibitors + IGF-1 siRNA groups. The following were performed: an MTT assay to assess cell proliferation, a scratch test to detect cell migration, a Transwell assay to measure cell invasion, and a flow cytometry to analyze cell apoptosis. The expression level of miR-135a was lower while those of IGF-1, PI3K and Akt mRNA were higher in NSCLC tissues than in the adjacent normal tissues. Dual-luciferase reporter assay indicated IGF-1 as a target of miR-135a. The in vitro results showed that compared with the blank group, cell proliferation, migration and invasion were suppressed, mRNA and protein levels of IGF-1, PI3K, Akt, VEGF, bFGF and IL-8 were reduced, and cell apoptosis was enhanced in the miR-135a mimics and IGF-1 siRNA groups. Compared with the IGF-1 siRNA group, cells in the miR-135a inhibitors + IGF-1 siRNA group demonstrated increased cell proliferation, migration and invasion, elevated mRNA and protein levels of IGF-1, PI3K, Akt, VEGF, bFGF and IL-8 and reduced cell apoptosis. These findings indicated that miR-135a promotes cell apoptosis and inhibits

  16. Metformin inhibits the proliferation of human prostate cancer PC-3 cells via the downregulation of insulin-like growth factor 1 receptor

    International Nuclear Information System (INIS)

    Kato, Haruo; Sekine, Yoshitaka; Furuya, Yosuke; Miyazawa, Yoshiyuki; Koike, Hidekazu; Suzuki, Kazuhiro

    2015-01-01

    Metformin is a biguanide drug that is widely used for the treatment of type 2 diabetes. Recent studies have shown that metformin inhibits cancer cell proliferation and tumor growth both in vitro and in vivo. The anti-tumor mechanisms of metformin include activation of the AMP-activated protein kinase/mTOR pathway and direct inhibition of insulin/insulin-like growth factor (IGF)-mediated cellular proliferation. However, the anti-tumor mechanism in prostate cancer remains unclear. Because activation of the IGF-1 receptor (IGF-1R) is required for prostate cell proliferation, IGF-1R inhibitors may be of therapeutic value. Accordingly, we examined the effects of metformin on IGF-1R signaling in prostate cancer cells. Metformin significantly inhibited PC-3 cell proliferation, migration, and invasion. IGF-1R mRNA expression decreased significantly after 48 h of treatment, and IGF-1R protein expression decreased in a similar manner. IGF-1R knockdown by siRNA transfection led to inhibited proliferation, migration and invasion of PC-3 cells. IGF-1 activated both ERK1/2 and Akt, but these effects were attenuated by metformin treatment. In addition, intraperitoneal treatment with metformin significantly reduced tumor growth and IGF-1R mRNA expression in PC-3 xenografts. Our results suggest that metformin is a potent inhibitor of the IGF-1/IGF-1R system and may be beneficial in prostate cancer treatment. - Highlights: • Metformin inhibited PC-3 cell proliferation, migration, and invasion. • Metformin decreased IGF-1R mRNA and protein expressions in PC-3 cells. • Metformin inhibited IGF-1 induced ERK and Akt phosphorylations in PC-3 cells. • Metformin treatment inhibited PC-3 cell growth and IGF-1R expression in vivo. • Metformin may be a potent inhibitor of the IGF-1/IGF-1R signaling

  17. Metformin inhibits the proliferation of human prostate cancer PC-3 cells via the downregulation of insulin-like growth factor 1 receptor

    Energy Technology Data Exchange (ETDEWEB)

    Kato, Haruo, E-mail: hal.kato@gunma-u.ac.jp; Sekine, Yoshitaka; Furuya, Yosuke; Miyazawa, Yoshiyuki; Koike, Hidekazu; Suzuki, Kazuhiro

    2015-05-22

    Metformin is a biguanide drug that is widely used for the treatment of type 2 diabetes. Recent studies have shown that metformin inhibits cancer cell proliferation and tumor growth both in vitro and in vivo. The anti-tumor mechanisms of metformin include activation of the AMP-activated protein kinase/mTOR pathway and direct inhibition of insulin/insulin-like growth factor (IGF)-mediated cellular proliferation. However, the anti-tumor mechanism in prostate cancer remains unclear. Because activation of the IGF-1 receptor (IGF-1R) is required for prostate cell proliferation, IGF-1R inhibitors may be of therapeutic value. Accordingly, we examined the effects of metformin on IGF-1R signaling in prostate cancer cells. Metformin significantly inhibited PC-3 cell proliferation, migration, and invasion. IGF-1R mRNA expression decreased significantly after 48 h of treatment, and IGF-1R protein expression decreased in a similar manner. IGF-1R knockdown by siRNA transfection led to inhibited proliferation, migration and invasion of PC-3 cells. IGF-1 activated both ERK1/2 and Akt, but these effects were attenuated by metformin treatment. In addition, intraperitoneal treatment with metformin significantly reduced tumor growth and IGF-1R mRNA expression in PC-3 xenografts. Our results suggest that metformin is a potent inhibitor of the IGF-1/IGF-1R system and may be beneficial in prostate cancer treatment. - Highlights: • Metformin inhibited PC-3 cell proliferation, migration, and invasion. • Metformin decreased IGF-1R mRNA and protein expressions in PC-3 cells. • Metformin inhibited IGF-1 induced ERK and Akt phosphorylations in PC-3 cells. • Metformin treatment inhibited PC-3 cell growth and IGF-1R expression in vivo. • Metformin may be a potent inhibitor of the IGF-1/IGF-1R signaling.

  18. Insulin-like growth factor I (IGF-1) Ec/Mechano Growth factor--a splice variant of IGF-1 within the growth plate.

    Science.gov (United States)

    Schlegel, Werner; Raimann, Adalbert; Halbauer, Daniel; Scharmer, Daniela; Sagmeister, Susanne; Wessner, Barbara; Helmreich, Magdalena; Haeusler, Gabriele; Egerbacher, Monika

    2013-01-01

    Human insulin-like growth factor 1 Ec (IGF-1Ec), also called mechano growth factor (MGF), is a splice variant of insulin-like growth factor 1 (IGF-1), which has been shown in vitro as well as in vivo to induce growth and hypertrophy in mechanically stimulated or damaged muscle. Growth, hypertrophy and responses to mechanical stimulation are important reactions of cartilaginous tissues, especially those in growth plates. Therefore, we wanted to ascertain if MGF is expressed in growth plate cartilage and if it influences proliferation of chondrocytes, as it does in musculoskeletal tissues. MGF expression was analyzed in growth plate and control tissue samples from piglets aged 3 to 6 weeks. Furthermore, growth plate chondrocyte cell culture was used to evaluate the effects of the MGF peptide on proliferation. We showed that MGF is expressed in considerable amounts in the tissues evaluated. We found the MGF peptide to be primarily located in the cytoplasm, and in some instances, it was also found in the nucleus of the cells. Addition of MGF peptides was not associated with growth plate chondrocyte proliferation.

  19. The Insulin-like Growth Factor (IGF)-I E-Peptides Modulate Cell Entry of the Mature IGF-I Protein

    OpenAIRE

    Pfeffer, Lindsay A.; Brisson, Becky K.; Lei, Hanqin; Barton, Elisabeth R.

    2009-01-01

    Insulin-like growth factor (IGF)-I is a critical protein for cell development and growth. Alternative splicing of the igf1 gene gives rise to multiple isoforms. In rodents, proIGF-IA and proIGF-IB have different carboxy-terminal extensions called the E-peptides (EA and EB) and upon further posttranslational processing, produce the identical mature IGF-I protein. Rodent EB has been reported to have mitogenic and motogenic effects independent of IGF-I. However, effects of EA or EB on mature IGF...

  20. Serum IGF-1 concentrations change with soy and seaweed supplements in healthy postmenopausal American women.

    Science.gov (United States)

    Teas, Jane; Irhimeh, Mohammad R; Druker, Susan; Hurley, Thomas G; Hébert, James R; Savarese, Todd M; Kurzer, Mindy S

    2011-01-01

    Insulin-like growth factor 1 (IGF-1) is an anabolic hormone important for growth and development. However, high-circulating serum concentrations in adults are associated with increased risk of postmenopausal breast cancer. Nutritional status and specific foods influence serum IGF-1 concentrations. Breast cancer incidence is typically low in Asian countries where soy is commonly consumed. Paradoxically, soy supplement trials in American women have reported significant increases in IGF-1. Seaweed also is consumed regularly in Asian countries where breast cancer risk is low. We investigated the possibility that seaweed could modify soy-associated increases in IGF-1 in American women. Thirty healthy postmenopausal women (mean age 58 yr) participated in this 14-wk double-blinded, randomized, placebo-controlled crossover clinical trial. Participants consumed 5 g/day placebo or seaweed (Alaria esculenta) in capsules for 7 wk. During the 7th wk, a high-soy protein isolate powder was added (2 mg/kg body weight aglycone equivalent isoflavones). Overnight fasting blood samples were collected after each intervention period. Soy significantly increased serum IGF-1 concentrations compared to the placebo (21.2 nmol/L for soy vs. 16.9 nmol/L for placebo; P = 0.0001). The combination of seaweed and soy significantly reduced this increase by about 40% (21.2 nmol/L for soy alone vs. 19.4 nmol/L; P = 0.01). Concurrent seaweed and soy consumption may be important in modifying the effect of soy on IGF-1 serum concentrations.