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Sample records for axis regulates prostate

  1. A Targetable GATA2-IGF2 Axis Confers Aggressiveness in Lethal Prostate Cancer

    Science.gov (United States)

    Vidal, Samuel J.; Rodriguez-Bravo, Veronica; Quinn, S. Aidan; Rodriguez-Barrueco, Ruth; Lujambio, Amaia; Williams, Estrelania; Sun, Xiaochen; de la Iglesia-Vicente, Janis; Lee, Albert; Readhead, Ben; Chen, Xintong; Galsky, Matthew; Esteve, Berta; Petrylak, Daniel P.; Dudley, Joel T.; Rabadan, Raul; Silva, Jose M.; Hoshida, Yujin; Lowe, Scott W.; Cordon-Cardo, Carlos; Domingo-Domenech, Josep

    2015-01-01

    SUMMARY Elucidating the determinants of aggressiveness in lethal prostate cancer may stimulate therapeutic strategies that improve clinical outcomes. We used experimental models and clinical databases to identify GATA2 as a regulator of chemotherapy resistance and tumorigenicity in this context. Mechanistically, direct upregulation of the growth hormone IGF2 emerged as a mediator of the aggressive properties regulated by GATA2. IGF2 in turn activated IGF1R and INSR as well as a downstream polykinase program. The characterization of this axis prompted a combination strategy whereby dual IGF1R/INSR inhibition restored the efficacy of chemotherapy and improved survival in preclinical models. These studies reveal a GATA2-IGF2 aggressiveness axis in lethal prostate cancer and identify a therapeutic opportunity in this challenging disease. PMID:25670080

  2. CXCL12/CXCR4 Axis Activation Mediates Prostate Myofibroblast Phenoconversion through Non-Canonical EGFR/MEK/ERK Signaling

    Science.gov (United States)

    Rodríguez-Nieves, José A.; Patalano, Susan C.; Almanza, Diego; Gharaee-Kermani, Mehrnaz; Macoska, Jill A.

    2016-01-01

    Benign prostate hyperplasia (BPH), an enlargement of the prostate common in aging in men, is associated with urinary voiding dysfunction manifest as Lower Urinary Tract Symptoms (LUTS). Although inflammation and abnormal smooth muscle contractions are known to play key roles in the development of LUTS, tissue fibrosis may also be an important and previously unrecognized contributing factor. Tissue fibrosis arises from the unregulated differentiation of fibroblasts or other precursor cell types into myofibroblasts, which is usually accomplished by activation of the TGFβ/TGFβR axis. Previously we reported that the CXC-type chemokines, CXCL5, CXCL8 and CXCL12, which are up-regulated in the aging in the prostate, can drive this differentiation process as well in the absence of TGFβ. Based on this data we sought to elucidate the molecular mechanisms employed by CXCL12, and its receptor CXCR4, during prostate myofibroblast phenoconversion. The results of these studies suggest that CXCL12/CXCR4-mediated signaling events in prostate myofibroblast phenoconversion may proceed through non-canonical pathways that do not depend on TGFβ/TGFβR axis activation or Smad signaling. Here we report that CXCL12/CXCR4 axis activation promotes signaling through the EGFR and downstream MEK/ERK and PI3K/Akt pathways during myofibroblast phenoconversion, but not through TGFβ/TGFβR and downstream Smad signaling, in prostate fibroblasts undergoing myofibroblast phenoconversion. We document that EGFR transactivation is required for CXCL12-mediated signaling and expression of genes associate with myofibroblast phenoconversion (α-SMA, COL1a1). Our study successfully identified TGFβ/TGFβR-independent molecular mechanisms that promote CXCL12/CXCR4-induced myofibroblast phenoconversion. This information may be crucial for the development of novel therapies and potential biomarkers for prostatic fibrosis. PMID:27434301

  3. Copper signaling axis as a target for prostate cancer therapeutics.

    Science.gov (United States)

    Safi, Rachid; Nelson, Erik R; Chitneni, Satish K; Franz, Katherine J; George, Daniel J; Zalutsky, Michael R; McDonnell, Donald P

    2014-10-15

    Previously published reports indicate that serum copper levels are elevated in patients with prostate cancer and that increased copper uptake can be used as a means to image prostate tumors. It is unclear, however, to what extent copper is required for prostate cancer cell function as we observed only modest effects of chelation strategies on the growth of these cells in vitro. With the goal of exploiting prostate cancer cell proclivity for copper uptake, we developed a "conditional lethal" screen to identify compounds whose cytotoxic actions were manifested in a copper-dependent manner. Emerging from this screen was a series of dithiocarbamates, which, when complexed with copper, induced reactive oxygen species-dependent apoptosis of malignant, but not normal, prostate cells. One of the dithiocarbamates identified, disulfiram (DSF), is an FDA-approved drug that has previously yielded disappointing results in clinical trials in patients with recurrent prostate cancer. Similarly, in our studies, DSF alone had a minimal effect on the growth of prostate cancer tumors when propagated as xenografts. However, when DSF was coadministered with copper, a very dramatic inhibition of tumor growth in models of hormone-sensitive and of castrate-resistant disease was observed. Furthermore, we determined that prostate cancer cells express high levels of CTR1, the primary copper transporter, and additional chaperones that are required to maintain intracellular copper homeostasis. The expression levels of most of these proteins are increased further upon treatment of androgen receptor (AR)-positive prostate cancer cell lines with androgens. Not surprisingly, robust CTR1-dependent uptake of copper into prostate cancer cells was observed, an activity that was accentuated by activation of AR. Given these data linking AR to intracellular copper uptake, we believe that dithiocarbamate/copper complexes are likely to be effective for the treatment of patients with prostate cancer whose

  4. Pten Regulates Epithelial Cytodifferentiation during Prostate Development.

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    Isabel B Lokody

    Full Text Available Gene expression and functional studies have indicated that the molecular programmes involved in prostate development are also active in prostate cancer. PTEN has been implicated in human prostate cancer and is frequently mutated in this disease. Here, using the Nkx3.1:Cre mouse strain and a genetic deletion approach, we investigate the role of Pten specifically in the developing mouse prostate epithelia. In contrast to its role in other developing organs, this gene is dispensable for the initial developmental processes such as budding and branching. However, as cytodifferentiation progresses, abnormal luminal cells fill the ductal lumens together with augmented epithelial proliferation. This phenotype resembles the hyperplasia seen in postnatal Pten deletion models that develop neoplasia at later stages. Consistent with this, gene expression analysis showed a number of genes affected that are shared with Pten mutant prostate cancer models, including a decrease in androgen receptor regulated genes. In depth analysis of the phenotype of these mice during development revealed that loss of Pten leads to the precocious differentiation of epithelial cells towards a luminal cell fate. This study provides novel insight into the role of Pten in prostate development as part of the process of coordinating the differentiation and proliferation of cell types in time and space to form a functional organ.

  5. Pten Regulates Epithelial Cytodifferentiation during Prostate Development

    DEFF Research Database (Denmark)

    Lokody, Isabel B; Francis, Jeffrey C; Gardiner, Jennifer R;

    2015-01-01

    that are shared with Pten mutant prostate cancer models, including a decrease in androgen receptor regulated genes. In depth analysis of the phenotype of these mice during development revealed that loss of Pten leads to the precocious differentiation of epithelial cells towards a luminal cell fate. This study...

  6. SLUG promotes prostate cancer cell migration and invasion via CXCR4/CXCL12 axis

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    Uygur Berna

    2011-11-01

    Full Text Available Abstract Background SLUG is a zinc-finger transcription factor of the Snail/Slug zinc-finger family that plays a role in migration and invasion of tumor cells. Mechanisms by which SLUG promotes migration and invasion in prostate cancers remain elusive. Methods Expression level of CXCR4 and CXCL12 was examined by Western blot, RT-PCR, and qPCR analyses. Forced expression of SLUG was mediated by retroviruses, and SLUG and CXCL12 was downregulated by shRNAs-expressing lentiviruses. Migration and invasion of prostate cancer were measured by scratch-wound assay and invasion assay, respectively. Research We demonstrated that forced expression of SLUG elevated CXCR4 and CXCL12 expression in human prostate cancer cell lines PC3, DU145, 22RV1, and LNCaP; conversely, reduced expression of SLUG by shRNA downregulated CXCR4 and CXCL12 expression at RNA and protein levels in prostate cancer cells. Furthermore, ectopic expression of SLUG increased MMP9 expression and activity in PC3, 22RV1, and DU-145 cells, and SLUG knockdown by shRNA downregulated MMP9 expression. We showed that CXCL12 is required for SLUG-mediated MMP9 expression in prostate cancer cells. Moreover, we found that migration and invasion of prostate cancer cells was increased by ectopic expression of SLUG and decreased by SLUG knockdown. Notably, knockdown of CXCL12 by shRNA impaired SLUG-mediated migration and invasion in prostate cancer cells. Lastly, our data suggest that CXCL12 and SLUG regulate migration and invasion of prostate cancer cells independent of cell growth. Conclusion We provide the first compelling evidence that upregulation of autocrine CXCL12 is a major mechanism underlying SLUG-mediated migration and invasion of prostate cancer cells. Our findings suggest that CXCL12 is a therapeutic target for prostate cancer metastasis.

  7. Targeting Met and VEGFR Axis in Metastatic Castration-Resistant Prostate Cancer: 'Game Over'?

    Science.gov (United States)

    Modena, Alessandra; Massari, Francesco; Ciccarese, Chiara; Brunelli, Matteo; Santoni, Matteo; Montironi, Rodolfo; Martignoni, Guido; Tortora, Giampaolo

    2016-08-01

    Despite recent advances that have been made in the therapeutic landscape of metastatic castration-resistant prostate cancer (mCRPC), effective management of bone metastases remains a key goal not yet reached. The receptor tyrosine kinase MET and the vascular endothelial growth factor receptor (VEGFR) seem to play an important role in prostate cancer progression and pathological bone turnover, representing potential targets for improving clinical outcomes in mCRPC. Studies evaluating agents that target one or both these pathways have demonstrated modest activity but no improvement in overall survival. Nevertheless, this therapeutic strategy seems to still be a promising and engaging area of prostate cancer research and the interest in better understanding the MET/VEGFR axis and the mechanism of action of these inhibitors is growing. This review describes the rationale for targeting MET and VEGFR pathway in mCRPC and provides the clinical data available to date and an update on ongoing trials.

  8. Genes regulated by androgen in the rat ventral prostate

    OpenAIRE

    Wang, Zhou; Tufts, Rachel; Haleem, Riffat; Cai, Xiaoyan

    1997-01-01

    Genes that are regulated by androgen in the prostate were studied in the rat. Four of the less than 10 genes that are down-regulated by androgen in the ventral prostate of a 7-day castrated rat were identified; their mRNAs decayed with identical kinetics. Twenty-five of the estimated 56 genes that are up-regulated by androgen in the castrated prostate have been isolated. The up-regulated genes fall into two kinetic types. Early genes are significantly up-regulated by 6.5 hr whereas the delaye...

  9. Androgen regulated genes in human prostate xenografts in mice: relation to BPH and prostate cancer.

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    Harold D Love

    Full Text Available Benign prostatic hyperplasia (BPH and prostate carcinoma (CaP are linked to aging and the presence of androgens, suggesting that androgen regulated genes play a major role in these common diseases. Androgen regulation of prostate growth and development depends on the presence of intact epithelial-stromal interactions. Further, the prostatic stroma is implicated in BPH. This suggests that epithelial cell lines are inadequate to identify androgen regulated genes that could contribute to BPH and CaP and which could serve as potential clinical biomarkers. In this study, we used a human prostate xenograft model to define a profile of genes regulated in vivo by androgens, with an emphasis on identifying candidate biomarkers. Benign transition zone (TZ human prostate tissue from radical prostatectomies was grafted to the sub-renal capsule site of intact or castrated male immunodeficient mice, followed by the removal or addition of androgens, respectively. Microarray analysis of RNA from these tissues was used to identify genes that were; 1 highly expressed in prostate, 2 had significant expression changes in response to androgens, and, 3 encode extracellular proteins. A total of 95 genes meeting these criteria were selected for analysis and validation of expression in patient prostate tissues using quantitative real-time PCR. Expression levels of these genes were measured in pooled RNAs from human prostate tissues with varying severity of BPH pathologic changes and CaP of varying Gleason score. A number of androgen regulated genes were identified. Additionally, a subset of these genes were over-expressed in RNA from clinical BPH tissues, and the levels of many were found to correlate with disease status. Our results demonstrate the feasibility, and some of the problems, of using a mouse xenograft model to characterize the androgen regulated expression profiles of intact human prostate tissues.

  10. Three-axis MR-conditional robot for high-intensity focused ultrasound for treating prostate diseases transrectally

    OpenAIRE

    Yiallouras, Christos; Ioannides, Kleanthis; Dadakova, Tetiana; Pavlina, Matt; Bock, Michael; Damianou, Christakis

    2015-01-01

    Background A prototype magnetic resonance image (MRI)-conditional robot was developed for navigating a high-intensity focused ultrasound (HIFU) system in order to treat prostate cancer transrectally. Materials and methods The developed robotic device utilizes three PC-controlled axes: a linear axis for motion along the rectum, an angular axis for rotation in the rectum, and a linear axis to lift the robot up and down. Experiments with the system were performed in a 1.5-T MRI system using gel ...

  11. Prostate cancer characteristics associated with response to pre-receptor targeting of the androgen axis.

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    Elahe A Mostaghel

    Full Text Available Factors influencing differential responses of prostate tumors to androgen receptor (AR axis-directed therapeutics are poorly understood, and predictors of treatment efficacy are needed. We hypothesized that the efficacy of inhibiting DHT ligand synthesis would associate with intra-tumoral androgen ratios indicative of relative dependence on DHT-mediated growth.We characterized two androgen-sensitive prostate cancer xenograft models after androgen suppression by castration in combination with the SRD5A inhibitor, dutasteride, as well as a panel of castration resistant metastases obtained via rapid autopsy.In LuCaP35 tumors (intra-tumoral T:DHT ratio 2:1 dutasteride suppressed DHT to 0.02 ng/gm and prolonged survival vs. castration alone (337 vs.152 days, HR 2.8, p = 0.0015. In LuCaP96 tumors (T:DHT 10:1, survival was not improved despite similar DHT reduction (0.02 ng/gm. LuCaP35 demonstrated higher expression of steroid biosynthetic enzymes maintaining DHT levels (5-fold higher SRD5A1, 41 fold higher, 99-fold higher RL-HSD, p<0.0001 for both, reconstitution of intra-tumoral DHT (to ∼30% of untreated tumors, and ∼2 fold increased expression of full length AR. In contrast, LuCaP96 demonstrated higher levels of steroid catabolizing enzymes (6.9-fold higher AKR1C2, 3000-fold higher UGT2B15, p = 0.002 and p<0.0001 respectively, persistent suppression of intra-tumoral DHT, and 6-8 fold induction of full length AR and the ligand independent V7 AR splice variant. Human metastases demonstrated bio-active androgen levels and AR full length and AR splice-variant expression consistent with the range observed in xenografts.Intrinsic differences in basal steroidogenesis, as well as variable expression of full length and splice-variant AR, associate with response and resistance to pre-receptor AR ligand suppression. Expression of steroidogenic enzymes and AR isoforms may serve as potential biomarkers of sensitivity to potent AR-axis inhibition and

  12. The diet-microbiota-metabolite axis regulates the host physiology.

    Science.gov (United States)

    Yamada, Takahiro; Takahashi, Daisuke; Hase, Koji

    2016-07-01

    The intestinal microbiota has been implicated in a wide range of diseases, including inflammatory bowel disease, obesity and cancer. Food ingredients are considered a major determinant of gut microbial composition, as exemplified by high-fat diet-induced dysbiosis that can affect host physiology. Accumulating studies show that microbial metabolites are key regulators of the intestinal epithelial barrier and gut immunity. In particular, short-chain fatty acids produced by bacterial fermentation of indigestible polysaccharides have profound impacts on host physiology beyond the gut. In this review, we describe the influences of the diet-microbiota-metabolite axis on host physiology, and especially on the immune and metabolic systems. PMID:26970281

  13. Periostin is up-regulated in high grade and high stage prostate cancer

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    Schraml Peter

    2010-06-01

    Full Text Available Abstract Background Expression of periostin is an indicator of epithelial-mesenchymal transition in cancer but a detailed analysis of periostin expression in prostate cancer has not been conducted so far. Methods Here, we evaluated periostin expression in prostate cancer cells and peritumoural stroma immunohistochemically in two independent prostate cancer cohorts, including a training cohort (n = 93 and a test cohort (n = 325. Metastatic prostate cancers (n = 20, hormone refractory prostate cancers (n = 19 and benign prostatic tissues (n = 38 were also analyzed. Results In total, strong epithelial periostin expression was detectable in 142 of 418 (34.0% of prostate carcinomas and in 11 of 38 benign prostate glands (28.9%. Increased periostin expression in carcinoma cells was significantly associated with high Gleason score (p Conclusions Our data indicate that periostin up-regulation is related to increased tumour aggressiveness in prostate cancer and might be a promising target for therapeutical interventions in primary and metastatic prostate cancer.

  14. Hydrogen Sulfide Signaling Axis as a Target for Prostate Cancer Therapeutics

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    Mingzhe Liu

    2016-01-01

    Full Text Available Hydrogen sulfide (H2S was originally considered toxic at elevated levels; however just in the past decade H2S has been proposed to be an important gasotransmitter with various physiological and pathophysiological roles in the body. H2S can be generated endogenously from L-cysteine by multiple enzymes, including cystathionine gamma-lyase, cystathionine beta-synthase, and 3-mercaptopyruvate sulfurtransferase in combination with cysteine aminotransferase. Prostate cancer is a major health concern and no effective treatment for prostate cancers is available. H2S has been shown to inhibit cell survival of androgen-independent, androgen-dependent, and antiandrogen-resistant prostate cancer cells through different mechanisms. Various H2S-releasing compounds, including sulfide salts, diallyl disulfide, diallyl trisulfide, sulforaphane, and other polysulfides, also have been shown to inhibit prostate cancer growth and metastasis. The expression of H2S-producing enzyme was reduced in both human prostate cancer tissues and prostate cancer cells. Androgen receptor (AR signaling is indispensable for the development of castration resistant prostate cancer, and H2S was shown to inhibit AR transactivation and contributes to antiandrogen-resistant status. In this review, we summarized the current knowledge of H2S signaling in prostate cancer and described the molecular alterations, which may bring this gasotransmitter into the clinic in the near future for developing novel pharmacological and therapeutic interventions for prostate cancer.

  15. Hydrogen Sulfide Signaling Axis as a Target for Prostate Cancer Therapeutics

    Science.gov (United States)

    Liu, Mingzhe; Wu, Lingyun; Montaut, Sabine; Yang, Guangdong

    2016-01-01

    Hydrogen sulfide (H2S) was originally considered toxic at elevated levels; however just in the past decade H2S has been proposed to be an important gasotransmitter with various physiological and pathophysiological roles in the body. H2S can be generated endogenously from L-cysteine by multiple enzymes, including cystathionine gamma-lyase, cystathionine beta-synthase, and 3-mercaptopyruvate sulfurtransferase in combination with cysteine aminotransferase. Prostate cancer is a major health concern and no effective treatment for prostate cancers is available. H2S has been shown to inhibit cell survival of androgen-independent, androgen-dependent, and antiandrogen-resistant prostate cancer cells through different mechanisms. Various H2S-releasing compounds, including sulfide salts, diallyl disulfide, diallyl trisulfide, sulforaphane, and other polysulfides, also have been shown to inhibit prostate cancer growth and metastasis. The expression of H2S-producing enzyme was reduced in both human prostate cancer tissues and prostate cancer cells. Androgen receptor (AR) signaling is indispensable for the development of castration resistant prostate cancer, and H2S was shown to inhibit AR transactivation and contributes to antiandrogen-resistant status. In this review, we summarized the current knowledge of H2S signaling in prostate cancer and described the molecular alterations, which may bring this gasotransmitter into the clinic in the near future for developing novel pharmacological and therapeutic interventions for prostate cancer. PMID:27019751

  16. Daxx regulates mitotic progression and prostate cancer predisposition.

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    Kwan, Pak Shing; Lau, Chi Chiu; Chiu, Yung Tuen; Man, Cornelia; Liu, Ji; Tang, Kai Dun; Wong, Yong Chuan; Ling, Ming-Tat

    2013-04-01

    Mitotic progression of mammalian cells is tightly regulated by the E3 ubiquitin ligase anaphase promoting complex (APC)/C. Deregulation of APC/C is frequently observed in cancer cells and is suggested to contribute to chromosome instability and cancer predisposition. In this study, we identified Daxx as a novel APC/C inhibitor frequently overexpressed in prostate cancer. Daxx interacts with the APC/C coactivators Cdc20 and Cdh1 in vivo, with the binding of Cdc20 dependent on the consensus destruction boxes near the N-terminal of the Daxx protein. Ectopic expression of Daxx, but not the D-box deleted mutant (DaxxΔD-box), inhibited the degradation of APC/Cdc20 and APC/Cdh1 substrates, leading to a transient delay in mitotic progression. Daxx is frequently upregulated in prostate cancer tissues; the expression level positively correlated with the Gleason score and disease metastasis (P = 0.027 and 0.032, respectively). Furthermore, ectopic expression of Daxx in a non-malignant prostate epithelial cell line induced polyploidy under mitotic stress. Our data suggest that Daxx may function as a novel APC/C inhibitor, which promotes chromosome instability during prostate cancer development.

  17. Regulation of the transcriptional coactivator FHL2 licenses activation of the androgen receptor in castrate-resistant prostate cancer.

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    McGrath, Meagan J; Binge, Lauren C; Sriratana, Absorn; Wang, Hong; Robinson, Paul A; Pook, David; Fedele, Clare G; Brown, Susan; Dyson, Jennifer M; Cottle, Denny L; Cowling, Belinda S; Niranjan, Birunthi; Risbridger, Gail P; Mitchell, Christina A

    2013-08-15

    It is now clear that progression from localized prostate cancer to incurable castrate-resistant prostate cancer (CRPC) is driven by continued androgen receptor (AR), signaling independently of androgen. Thus, there remains a strong rationale to suppress AR activity as the single most important therapeutic goal in CRPC treatment. Although the expression of ligand-independent AR splice variants confers resistance to AR-targeted therapy and progression to lethal castrate-resistant cancer, the molecular regulators of AR activity in CRPC remain unclear, in particular those pathways that potentiate the function of mutant AR in CRPC. Here, we identify FHL2 as a novel coactivator of ligand-independent AR variants that are important in CRPC. We show that the nuclear localization of FHL2 and coactivation of the AR is driven by calpain cleavage of the cytoskeletal protein filamin, a pathway that shows differential activation in prostate epithelial versus prostate cancer cell lines. We further identify a novel FHL2-AR-filamin transcription complex, revealing how deregulation of this axis promotes the constitutive, ligand-independent activation of AR variants, which are present in CRPC. Critically, the calpain-cleaved filamin fragment and FHL2 are present in the nucleus only in CRPC and not benign prostate tissue or localized prostate cancer. Thus, our work provides mechanistic insight into the enhanced AR activation, most notably of the recently identified AR variants, including AR-V7 that drives CRPC progression. Furthermore, our results identify the first disease-specific mechanism for deregulation of FHL2 nuclear localization during cancer progression. These results offer general import beyond prostate cancer, given that nuclear FHL2 is characteristic of other human cancers where oncogenic transcription factors that drive disease are activated like the AR in prostate cancer.

  18. An FGF3-BMP Signaling Axis Regulates Caudal Neural Tube Closure, Neural Crest Specification and Anterior-Posterior Axis Extension.

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    Matthew J Anderson

    2016-05-01

    Full Text Available During vertebrate axis extension, adjacent tissue layers undergo profound morphological changes: within the neuroepithelium, neural tube closure and neural crest formation are occurring, while within the paraxial mesoderm somites are segmenting from the presomitic mesoderm (PSM. Little is known about the signals between these tissues that regulate their coordinated morphogenesis. Here, we analyze the posterior axis truncation of mouse Fgf3 null homozygotes and demonstrate that the earliest role of PSM-derived FGF3 is to regulate BMP signals in the adjacent neuroepithelium. FGF3 loss causes elevated BMP signals leading to increased neuroepithelium proliferation, delay in neural tube closure and premature neural crest specification. We demonstrate that elevated BMP4 depletes PSM progenitors in vitro, phenocopying the Fgf3 mutant, suggesting that excessive BMP signals cause the Fgf3 axis defect. To test this in vivo we increased BMP signaling in Fgf3 mutants by removing one copy of Noggin, which encodes a BMP antagonist. In such mutants, all parameters of the Fgf3 phenotype were exacerbated: neural tube closure delay, premature neural crest specification, and premature axis termination. Conversely, genetically decreasing BMP signaling in Fgf3 mutants, via loss of BMP receptor activity, alleviates morphological defects. Aberrant apoptosis is observed in the Fgf3 mutant tailbud. However, we demonstrate that cell death does not cause the Fgf3 phenotype: blocking apoptosis via deletion of pro-apoptotic genes surprisingly increases all Fgf3 defects including causing spina bifida. We demonstrate that this counterintuitive consequence of blocking apoptosis is caused by the increased survival of BMP-producing cells in the neuroepithelium. Thus, we show that FGF3 in the caudal vertebrate embryo regulates BMP signaling in the neuroepithelium, which in turn regulates neural tube closure, neural crest specification and axis termination. Uncovering this FGF3

  19. REGULATION OF THE THYROID AXIS IN DEVELOPING XENOPUS LAEVIS

    Science.gov (United States)

    The focus of the research presented here is the development of an in vitro pituitary gland culture system to test the effect of chemicals directly on the gland without influence of other parts of the HPT axis.

  20. LEF1 in androgen-independent prostate cancer: regulation of androgen receptor expression, prostate cancer growth and invasion

    OpenAIRE

    Li, Yirong; Wang, Longgui; Zhang, Miao; Melamed, Jonathan; Liu, Xiaomei; Reiter, Robert; Wei, Jianjun; Peng, Yi; Zou, Xuanyi; Pellicer, Angel; Garabedian, Michael J.; Ferrari, Anna; Lee, Peng

    2009-01-01

    A major obstacle in treating prostate cancer is the development of androgen-independent disease. In this study, we examined LEF1 expression in androgen-independent cancer as well as its regulation of androgen receptor (AR) expression, prostate cancer growth and invasion in androgen-independent prostate cancer cells. Affymetrix microarray analysis of LNCaP and LNCaP-AI (androgen-independent variant LNCaP) cells revealed 100-fold increases in LEF1 expression in LNCaP-AI cells. We showed that LE...

  1. Periostin is up-regulated in high grade and high stage prostate cancer

    International Nuclear Information System (INIS)

    Expression of periostin is an indicator of epithelial-mesenchymal transition in cancer but a detailed analysis of periostin expression in prostate cancer has not been conducted so far. Here, we evaluated periostin expression in prostate cancer cells and peritumoural stroma immunohistochemically in two independent prostate cancer cohorts, including a training cohort (n = 93) and a test cohort (n = 325). Metastatic prostate cancers (n = 20), hormone refractory prostate cancers (n = 19) and benign prostatic tissues (n = 38) were also analyzed. In total, strong epithelial periostin expression was detectable in 142 of 418 (34.0%) of prostate carcinomas and in 11 of 38 benign prostate glands (28.9%). Increased periostin expression in carcinoma cells was significantly associated with high Gleason score (p < 0.01) and advanced tumour stage (p < 0.05) in the test cohort. Whereas periostin expression was weak or absent in the stroma around normal prostate glands, strong periostin expression in tumour stroma was found in most primary and metastatic prostate cancers. High stromal periostin expression was associated with higher Gleason scores (p < 0.001). There was a relationship between stromal periostin expression and shortened PSA relapse free survival times in the training cohort (p < 0.05). Our data indicate that periostin up-regulation is related to increased tumour aggressiveness in prostate cancer and might be a promising target for therapeutical interventions in primary and metastatic prostate cancer

  2. Regulation of Androgen Receptor and Prostate Cancer Growth by Cyclin-dependent Kinase 5*

    OpenAIRE

    Hsu, Fu-Ning; Chen, Mei-Chih; Chiang, Ming-Ching; Lin, Eugene; Lee, Yueh-Tsung; Huang, Pao-Hsuan; Lee, Guan-Shun; Lin, Ho

    2011-01-01

    Prostate cancer is the most frequently diagnosed male malignancy. The normal prostate development and prostate cancer progression are mediated by androgen receptor (AR). Recently, the roles of cyclin-dependent kinase 5 (Cdk5) and its activator, p35, in cancer biology are explored one after another. We have previously demonstrated that Cdk5 may regulate proliferation of thyroid cancer cells. In addition, we also identify that Cdk5 overactivation can be triggered by drug treatments and leads to...

  3. Regulation of Prostate Development and Benign Prostatic Hyperplasia by Autocrine Cholinergic Signaling via Maintaining the Epithelial Progenitor Cells in Proliferating Status

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    Naitao Wang

    2016-05-01

    Full Text Available Regulation of prostate epithelial progenitor cells is important in prostate development and prostate diseases. Our previous study demonstrated a function of autocrine cholinergic signaling (ACS in promoting prostate cancer growth and castration resistance. However, whether or not such ACS also plays a role in prostate development is unknown. Here, we report that ACS promoted the proliferation and inhibited the differentiation of prostate epithelial progenitor cells in organotypic cultures. These results were confirmed by ex vivo lineage tracing assays and in vivo renal capsule recombination assays. Moreover, we found that M3 cholinergic receptor (CHRM3 was upregulated in a large subset of benign prostatic hyperplasia (BPH tissues compared with normal tissues. Activation of CHRM3 also promoted the proliferation of BPH cells. Together, our findings identify a role of ACS in maintaining prostate epithelial progenitor cells in the proliferating state, and blockade of ACS may have clinical implications for the management of BPH.

  4. Stress and serial adult metamorphosis: multiple roles for the stress axis in socially regulated sex change

    OpenAIRE

    Solomon-Lane, Tessa K.; Crespi, Erica J.; Matthew Scott Grober

    2013-01-01

    Socially regulated sex change in teleost fishes is a striking example of social status information regulating biological function in the service of reproductive success. The establishment of social dominance in sex changing species is translated into a cascade of changes in behavior, physiology, neuroendocrine function, and morphology that transforms a female into a male, or vice versa. The hypothalamic-pituitary-interrenal axis (HPI, homologous to HP-adrenal axis in mammals and birds) has ...

  5. TCTP is an androgen-regulated gene implicated in prostate cancer.

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    Mari Kaarbø

    Full Text Available TCTP has been implicated in a plethora of important cellular processes related to cell growth, cell cycle progression, malignant transformation and inhibition of apoptosis. In addition to these intracellular functions, TCTP has extracellular functions and plays an important role in immune cells. TCTP expression was previously shown to be deregulated in prostate cancer, but its function in prostate cancer cells is largely unknown. Here we show that TCTP expression is regulated by androgens in LNCaP prostate cancer cells in vitro as well as human prostate cancer xenografts in vivo. Knockdown of TCTP reduced colony formation and increased apoptosis in LNCaP cells, implicating it as an important factor for prostate cancer cell growth. Global gene expression profiling in TCTP knockdown LNCaP cells showed that several interferon regulated genes are regulated by TCTP, suggesting that it may have a role in regulating immune function in prostate cancer. In addition, recombinant TCTP treatment increased colony formation in LNCaP cells suggesting that secreted TCTP may function as a proliferative factor in prostate cancer. These results suggest that TCTP may have a role in prostate cancer development.

  6. The Lin28/let-7 Axis Regulates Glucose Metabolism

    NARCIS (Netherlands)

    Zhu, Hao; Shyh-Chang, Ng; Segre, Ayellet V.; Shinoda, Gen; Shah, Samar P.; Einhorn, William S.; Takeuchi, Ayumu; Engreitz, Jesse M.; Hagan, John P.; Kharas, Michael G.; Urbach, Achia; Thornton, James E.; Triboulet, Robinson; Gregory, Richard I.; Altshuler, David; Daley, George Q.

    2011-01-01

    The let-7 tumor suppressor microRNAs are known for their regulation of oncogenes, while the RNA-binding proteins Lin28a/b promote malignancy by inhibiting let-7 biogenesis. We have uncovered unexpected roles for the Lin28/let-7 pathway in regulating-metabolism. When overexpressed in mice, both Lin28

  7. Liver-gut axis in the regulation of iron homeostasis

    Institute of Scientific and Technical Information of China (English)

    Deepak Darshan; Gregory J Anderson

    2007-01-01

    The human body requires about 1-2 mg of iron per day for its normal functioning, and dietary iron is the only source for this essential metal. Since humans do not possess a mechanism for the active excretion of iron,the amount of iron in the body is determined by the amount absorbed across the proximal small intestine and, consequently, intestinal iron absorption is a highly regulated process. In recent years, the liver has emerged as a central regulator of both iron absorption and iron release from other tissues. It achieves this by secreting a peptide hormone called hepcidin that acts on the small intestinal epithelium and other cells to limit iron delivery to the plasma. Hepcidin itself is regulated in response to various systemic stimuli including variations in body iron stores, the rate of erythropoiesis, inflammation and hypoxia, the same stimuli that have been known for many years to modulate iron absorption. This review will summarize recent findings on the role played by the liver and hepcidin in the regulation of body iron absorption.

  8. Androgenic regulation of hedgehog signaling pathway components in prostate cancer cells

    OpenAIRE

    Chen, Mengqian; Tanner, Matthew; Levine, Alice C.; Levina, Elina; Ohouo, Patrice; Buttyan, Ralph

    2009-01-01

    Hedgehog signaling is thought to play a role in several human cancers including prostate cancer. Although prostate cancer cells express many of the gene products involved in hedgehog signaling, these cells are refractory to the canonical signaling effects of exogenous hedgehog ligands or to activated Smoothened, the hedgehog-regulated mediator of Gli transcriptional activation. Here, we show that the expression of hedgehog ligands and some hedgehog target genes are regulated by androgen in th...

  9. ANDROGEN REGULATION OF PROSTATIC STEROID BINDING PROTEIN GENE TRANSCRIPTION

    Institute of Scientific and Technical Information of China (English)

    ZHANGYong-Lian; ZHOUZong-Xun; ZHANGYou-Duan; PARKERMalcolmG

    1989-01-01

    Prostatic steroid binding protein (PSBP) is a major protein secreted in the rat ventral prostate (V.P.) and also one of the components in seminal fluid, The potential importance of this protein in male fertility emerged from its ability of binding cholesterol which might modulate the proportion of phospholipids and cholesterol in sperm making it suitable

  10. Loss of PDEF, a prostate-derived Ets factor is associated with aggressive phenotype of prostate cancer: Regulation of MMP 9 by PDEF

    Directory of Open Access Journals (Sweden)

    Meacham Randall B

    2010-06-01

    and increased MMP9 expression during the transition to aggressive prostate cancer. Conclusions These studies demonstrate for the first time negative regulation of MMP9 expression by PDEF, and that PDEF expression was lost in aggressive prostate cancer and was inversely associated with MMP9 expression in clinical samples of prostate cancer. Based on these exciting results, we propose that loss of PDEF along with increased MMP9 expression should serve as novel markers for early detection of aggressive prostate cancer.

  11. Neuromedins U and S involvement in the regulation of the hypothalamo - pituitary - adrenal axis.

    Directory of Open Access Journals (Sweden)

    Ludwik K. Malendowicz

    2012-12-01

    Full Text Available Abstract: We reviewed neuromedin U (NMU and neuromedin S (NMS involvement in the regulation of the hypothalamo - pituitary - adrenal (HPA axis function. NMU and NMS are structurally related and highly conserved neuropeptides. They exert biological effects via two GPCR receptors designated as NMUR1 and NMUR2 which show differential expression. NMUR1 is expressed predominantly at the periphery, while NMUR2 in the central nervous system. Elements of the NMU/NMS and their receptors network are also expressed in the HPA axis and progress in molecular biology techniques provided new information on their actions within this system. Several lines of evidence suggest that within the HPA axis NMU and NMS act at both hypothalamic and adrenal levels. Moreover, new data suggest that NMU and NMS are involved in central and peripheral control of the stress response.

  12. Cloning of a novel insulin-regulated ghrelin transcript in prostate cancer.

    Science.gov (United States)

    Seim, Inge; Lubik, Amy A; Lehman, Melanie L; Tomlinson, Nadine; Whiteside, Eliza J; Herington, Adrian C; Nelson, Colleen C; Chopin, Lisa K

    2013-04-01

    Ghrelin is a multifunctional hormone, with roles in stimulating appetite and regulating energy balance, insulin secretion and glucose homoeostasis. The ghrelin gene locus (GHRL) is highly complex and gives rise to a range of novel transcripts derived from alternative first exons and internally spliced exons. The wild-type transcript encodes a 117 amino acid preprohormone that is processed to yield the 28 amino acid peptide ghrelin. Here, we identified insulin-responsive transcription corresponding to cryptic exons in intron 2 of the human ghrelin gene. A transcript, termed in2c-ghrelin (intron 2-cryptic), was cloned from the testis and the LNCaP prostate cancer cell line. This transcript may encode an 83 amino acid preproghrelin isoform that codes for ghrelin, but not obestatin. It is expressed in a limited number of normal tissues and in tumours of the prostate, testis, breast and ovary. Finally, we confirmed that in2c-ghrelin transcript expression, as well as the recently described in1-ghrelin transcript, is significantly upregulated by insulin in cultured prostate cancer cells. Metabolic syndrome and hyperinsulinaemia have been associated with prostate cancer risk and progression. This may be particularly significant after androgen deprivation therapy for prostate cancer, which induces hyperinsulinaemia, and this could contribute to castrate-resistant prostate cancer growth. We have previously demonstrated that ghrelin stimulates prostate cancer cell line proliferation in vitro. This study is the first description of insulin regulation of a ghrelin transcript in cancer and should provide further impetus for studies into the expression, regulation and function of ghrelin gene products.

  13. Regulation of Autophagy of Prostate Cancer Cells by β-Catenin Signaling

    Directory of Open Access Journals (Sweden)

    Rongkai Lin

    2015-01-01

    Full Text Available Background/Aims: Autophagy is a cellular degradation process for the recycling of damaged or superfluous intracellular compartments to provide an alternative energy source during periods of metabolic stress for maintaining cell homeostasis and viability. Although autophagy in different contexts have been shown to use similar signaling pathways, the exact molecular regulation of autophagy has been found to be cell-type dependent. Methods: We used rapamycin to trigger autophagy and used nitric oxide (NO to inhibit autophagy in prostate cancer cells. IWP-2 was used to inhibit β-catenin signaling. Autophagy-associated proteins were examined by Western blot. Results: We found that nitric oxide (NO, a potent cellular messenger, impaired rapamycin-induced autophagy in prostate cancer cells. Further analyses showed that NO induced nuclear accumulation of β-catenin, a key factor of Wnt signaling pathway, to inhibit autophagy in prostate cancer cells. Conclusions: We demonstrate involvement of β-catenin signaling in the regulation of autophagy of prostate cancer cells. Our results shed light on a previously unappreciated β-catenin signaling pathway for regulating autophagy in prostate cancer.

  14. Glucocorticoid receptor gene methylation and HPA-axis regulation in adolescents. The TRAILS study.

    Science.gov (United States)

    van der Knaap, Lisette J; Oldehinkel, Albertine J; Verhulst, Frank C; van Oort, Floor V A; Riese, Harriëtte

    2015-08-01

    Early life adversity and psychopathology are thought to be linked through HPA-axis deregulation. Changes in methylation levels of stress reactivity genes such as the glucocorticoid receptor gene (NR3C1) can be induced by adversity. Higher NR3C1 methylation levels have been associated with a reduced NR3C1 expression, possibly leading to impaired negative feedback regulation of the HPA-axis. In this study we tested whether methylation levels of NR3C1 were associated with HPA-axis regulation, operationalized as cortisol responses. In 361 adolescents (mean age 16.1, SD=0.6), salivary cortisol samples were collected before, during, and after a social stress task, from which response measures (cortisol activation and recovery) were calculated. Higher NR3C1 methylation levels were associated with a flattened cortisol recovery slope, indicating a delayed recovery time. Cortisol response activation was not associated with NR3C1 methylation. These results suggest that methylation of NR3C1 may impair negative feedback of the HPA-axis in adolescents.

  15. Neuromedins U and S involvement in the regulation of the hypothalamo - pituitary - adrenal axis.

    OpenAIRE

    Ludwik K Malendowicz; Agnieszka eZiolkowska; Marcin eRucinski

    2012-01-01

    Abstract: We reviewed neuromedin U (NMU) and neuromedin S (NMS) involvement in the regulation of the hypothalamo - pituitary - adrenal (HPA) axis function. NMU and NMS are structurally related and highly conserved neuropeptides. They exert biological effects via two GPCR receptors designated as NMUR1 and NMUR2 which show differential expression. NMUR1 is expressed predominantly at the periphery, while NMUR2 in the central nervous system. Elements of the NMU/NMS and their receptors network are...

  16. Neuromedins U and S involvement in the regulation of the hypothalamo–pituitary–adrenal axis

    OpenAIRE

    Ludwik K Malendowicz; Ziolkowska, Agnieszka; Rucinski, Marcin

    2012-01-01

    We reviewed neuromedin U (NMU) and neuromedin S (NMS) involvement in the regulation of the hypothalamo–pituitary–adrenal (HPA) axis function. NMU and NMS are structurally related and highly conserved neuropeptides. They exert biological effects via two GPCR receptors designated as NMUR1 and NMUR2 which show differential expression. NMUR1 is expressed predominantly at the periphery, while NMUR2 in the central nervous system. Elements of the NMU/NMS and their receptors network are also expresse...

  17. The Akt-mTOR axis is a pivotal regulator of eccentric hypertrophy during volume overload

    OpenAIRE

    Masataka Ikeda; Tomomi Ide; Takeo Fujino; Yuka Matsuo; Shinobu Arai; Keita Saku; Takamori Kakino; Yasuhiro Oga; Akiko Nishizaki; Kenji Sunagawa

    2015-01-01

    The heart has two major modalities of hypertrophy in response to hemodynamic loads: concentric and eccentric hypertrophy caused by pressure and volume overload (VO), respectively. However, the molecular mechanism of eccentric hypertrophy remains poorly understood. Here we demonstrate that the Akt-mammalian target of rapamycin (mTOR) axis is a pivotal regulator of eccentric hypertrophy during VO. While mTOR in the heart was activated in a left ventricular end-diastolic pressure (LVEDP)-depende...

  18. The Androgen Receptor Regulates PPARγ Expression and Activity in Human Prostate Cancer Cells.

    Science.gov (United States)

    Olokpa, Emuejevoke; Bolden, Adrienne; Stewart, LaMonica V

    2016-12-01

    The peroxisome proliferator activated receptor gamma (PPARγ) is a ligand-activated transcription factor that regulates growth and differentiation within normal prostate and prostate cancers. However the factors that control PPARγ within the prostate cancers have not been characterized. The goal of this study was to examine whether the androgen receptor (AR) regulates PPARγ expression and function within human prostate cancer cells. qRT-PCR and Western blot analyses revealed nanomolar concentrations of the AR agonist dihydrotestosterone (DHT) decrease PPARγ mRNA and protein within the castration-resistant, AR-positive C4-2 and VCaP human prostate cancer cell lines. The AR antagonists bicalutamide and enzalutamide blocked the ability of DHT to reduce PPARγ levels. In addition, siRNA mediated knockdown of AR increased PPARγ protein levels and ligand-induced PPARγ transcriptional activity within the C4-2 cell line. Furthermore, proteasome inhibitors that interfere with AR function increased the level of basal PPARγ and prevented the DHT-mediated suppression of PPARγ. These data suggest that AR normally functions to suppress PPARγ expression within AR-positive prostate cancer cells. To determine whether increases in AR protein would influence PPARγ expression and activity, we used lipofectamine-based transfections to overexpress AR within the AR-null PC-3 cells. The addition of AR to PC-3 cells did not significantly alter PPARγ protein levels. However, the ability of the PPARγ ligand rosiglitazone to induce activation of a PPARγ-driven luciferase reporter and induce expression of FABP4 was suppressed in AR-positive PC-3 cells. Together, these data indicate AR serves as a key modulator of PPARγ expression and function within prostate tumors. J. Cell. Physiol. 231: 2664-2672, 2016. © 2016 Wiley Periodicals, Inc. PMID:26945682

  19. Epigenetic Regulation of Vitamin D 24-Hydroxylase/CYP24A1 in Human Prostate Cancer

    Science.gov (United States)

    Luo, Wei; Karpf, Adam R.; Deeb, Kristin K.; Muindi, Josephia R.; Morrison, Carl D.; Johnson, Candace S.; Trump, Donald L.

    2010-01-01

    Calcitriol, a regulator of calcium homeostasis with antitumor properties, is degraded by the product of the CYP24A1 gene which is downregulated in human prostate cancer by unknown mechanisms. We found that CYP24A1 expression is inversely correlated with promoter DNA methylation in prostate cancer cell lines. Treatment with the DNA methyltransferase inhibitor 5-aza-2′-deoxycytidine (DAC) activates CYP24A1 expression in prostate cancer cells. In vitro methylation of the CYP24A1 promoter represses its promoter activity. Furthermore, inhibition of histone deacetylases by trichostatin A (TSA) enhances the expression of CYP24A1 in prostate cancer cells. ChIP-qPCR reveals that specific histone modifications are associated with the CYP24A1 promoter region. Treatment with TSA increases H3K9ac and H3K4me2 and simultaneously decreases H3K9me2 at the CYP24A1 promoter. ChIP-qPCR assay reveals that treatment with DAC and TSA increases the recruitment of VDR to the CYP24A1 promoter. RT-PCR analysis of paired human prostate samples reveals that CYP24A1 expression is down-regulated in prostate malignant lesions compared to adjacent histologically benign lesions. Bisulfite pyrosequencing shows that CYP24A1 gene is hypermethylated in malignant lesions compared to matched benign lesions. Our findings indicate that repression of CYP24A1 gene expression in human prostate cancer cells is mediated in part by promoter DNA methylation and repressive histone modifications. PMID:20587525

  20. Regulation of prostate cancer progression by the tumor microenvironment.

    Science.gov (United States)

    Shiao, Stephen L; Chu, Gina Chia-Yi; Chung, Leland W K

    2016-09-28

    Prostate cancer remains the most frequently diagnosed cancer in men in North America, and despite recent advances in treatment patients with metastatic disease continue to have poor five-year survival rates. Recent studies in prostate cancer have revealed the critical role of the tumor microenvironment in the initiation and progression to advanced disease. Experimental data have uncovered a reciprocal relationship between the cells in the microenvironment and malignant tumor cells in which early changes in normal tissue microenvironment can promote tumorigenesis and in turn tumor cells can promote further pro-tumor changes in the microenvironment. In the tumor microenvironment, the presence of persistent immune infiltrates contributes to the recruitment and reprogramming of other non-immune stromal cells including cancer-associated fibroblasts and a unique recently identified population of metastasis-initiating cells (MICs). These MICs, which can also be found as part of the circulating tumor cell (CTC) population in PC patients, promote cancer cell transformation, enhance metastatic potential and confer therapeutic resistance. MICs act can on other cells within the tumor microenvironment in part by secreting exosomes that reprogram adjacent stromal cells to create a more favorable tumor microenvironment to support continued cancer growth and progression. We review here the current data on the intricate relationship between inflammation, reactive stroma, tumor cells and disease progression in prostate cancer. PMID:26828013

  1. Differential environmental regulation of neurogenesis along the septo-temporal axis of the hippocampus.

    Science.gov (United States)

    Tanti, Arnaud; Rainer, Quentin; Minier, Frederic; Surget, Alexandre; Belzung, Catherine

    2012-09-01

    The hippocampus is involved in both cognitive and emotional processing; these different functions are topographically distributed along its septo-temporal axis, the dorsal (septal) hippocampus being preferentially involved in cognitive processes such as learning and memory while the ventral (temporal) hippocampus participates in emotional regulation and anxiety-related behaviors. Newborn hippocampal neurons become functionally integrated into hippocampal networks and are likely to contribute to hippocampal functions, but whether their regulation and function are homogenous throughout this axis is not clear. Here we investigate changes in cell proliferation and neurogenesis along the septo-temporal axis of the hippocampus induced by the Unpredictable Chronic Mild Stress model of depression (UCMS), chronic fluoxetine treatment and enriched environment. Mice were either subjected to UCMS, standard housing or enriched environment. Stress-exposed mice were treated daily with fluoxetine (10 mg/kg) or vehicle. Effects of UCMS regimen, fluoxetine treatment and enrichment were assessed by physical measures and behavioral testing. Quantitative changes in cell proliferation and neurogenesis were assessed by immunohistochemistry using BrdU labeling. Results indicate that UCMS decreased cell proliferation and neurogenesis preferentially in the ventral hippocampus, an effect that was reversed by fluoxetine treatment. Environmental enrichment on the other hand increased cell proliferation in both divisions but promoted neurogenesis only in the dorsal hippocampus. These results indicate that environmental factors can differentially regulate neurogenesis in a region-specific manner. This may possibly underlie heterogeneous function of newborn neurons along the septo-temporal axis of the hippocampus and have functional significance as to their implication in stress related disorders and memory processes. PMID:22561281

  2. Primary cilia function regulates the length of the embryonic trunk axis and urogenital field in mice

    DEFF Research Database (Denmark)

    Wainwright, Elanor N.; Svingen, Terje; Ting Ng, Ee;

    2014-01-01

    assembly, result in a range of embryo patterning defects, affecting the limbs, skeleton and neural system. Here, we show that embryos of the mouse mutant Ift144twt develop gonads that are larger than wild-type. Investigation of the early patterning of the urogenital ridge revealed that the anterior......–posterior domain of the gonad/mesonephros was extended at 10.5 dpc, with no change in the length of the metanephros. In XY embryos, this extension resulted in an increase in testis cord number. Moreover, we observed a concomitant extension of the trunk axis in both sexes, with no change in the length of the tail...... domain or somite number. Our findings support a model in which: (1) primary cilia regulate embryonic trunk elongation; (2) the length of the trunk axis determines the size of the urogenital ridges; and (3) the gonad domain is partitioned into a number of testis cords that depends on the available space...

  3. Reciprocal positive regulation between TRPV6 and NUMB in PTEN-deficient prostate cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Sung-Young; Hong, Chansik; Wie, Jinhong [Department of Physiology, Seoul National University College of Medicine, Seoul 110-799 (Korea, Republic of); Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799 (Korea, Republic of); Kim, Euiyong [Department of Physiology, College of Medicine, Inje University, Busan 614-735 (Korea, Republic of); Kim, Byung Joo [Division of Longevity and Biofunctional Medicine, Pusan National University School of Korean Medicine, Yangsan 626-870 (Korea, Republic of); Ha, Kotdaji [Department of Physiology, Seoul National University College of Medicine, Seoul 110-799 (Korea, Republic of); Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799 (Korea, Republic of); Cho, Nam-Hyuk; Kim, In-Gyu [Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799 (Korea, Republic of); Jeon, Ju-Hong [Department of Physiology, Seoul National University College of Medicine, Seoul 110-799 (Korea, Republic of); Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799 (Korea, Republic of); So, Insuk, E-mail: insuk@snu.ac.kr [Department of Physiology, Seoul National University College of Medicine, Seoul 110-799 (Korea, Republic of); Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799 (Korea, Republic of)

    2014-04-25

    Highlights: • TRPV6 interacts with tumor suppressor proteins. • Numb has a selective effect on TRPV6, depending on the prostate cancer cell line. • PTEN is a novel regulator of TRPV6–Numb complex. - Abstract: Calcium acts as a second messenger and plays a crucial role in signaling pathways involved in cell proliferation. Recently, calcium channels related to calcium influx into the cytosol of epithelial cells have attracted attention as a cancer therapy target. Of these calcium channels, TRPV6 is overexpressed in prostate cancer and is considered an important molecule in the process of metastasis. However, its exact role and mechanism is unclear. NUMB, well-known tumor suppressor gene, is a novel interacting partner of TRPV6. We show that NUMB and TRPV6 have a reciprocal positive regulatory relationship in PC-3 cells. We repeated this experiment in two other prostate cancer cell lines, DU145 and LNCaP. Interestingly, there were no significant changes in TRPV6 expression following NUMB knockdown in DU145. We revealed that the presence or absence of PTEN was the cause of NUMB–TRPV6 function. Loss of PTEN caused a positive correlation of TRPV6–NUMB expression. Collectively, we determined that PTEN is a novel interacting partner of TRPV6 and NUMB. These results demonstrated a novel relationship of NUMB–TRPV6 in prostate cancer cells, and show that PTEN is a novel regulator of this complex.

  4. ERG Cooperates with Androgen Receptor in Regulating Trefoil Factor 3 in Prostate Cancer Disease Progression

    Directory of Open Access Journals (Sweden)

    David S. Rickman

    2010-12-01

    Full Text Available To elucidate the role of ETS gene fusions in castration-resistant prostate cancer (CRPC, we characterized the transcriptome of 54 CRPC tumor samples from men with locally advanced or metastatic disease. Trefoil factor 3 (TFF3 emerged as the most highly differentially regulated gene with respect to ERG rearrangement status and resistance to hormone ablation therapy. Conventional chromatin immunoprecipitation (ChIP-polymerase chain reaction and ChIP followed by DNA sequencing (ChIP-seq revealed direct binding of ERG to ETS binding sites in the TFF3 promoter in ERG-rearranged prostate cancer cell lines. These results were confirmed in ERG-rearranged hormone-naive prostate cancer (HNPC and CRPC tissue samples. Functional studies demonstrated that ERG has an inhibitory effect on TFF3 expression in hormone-naive cancer but not in the castration-resistant state. In addition, we provide evidence suggesting an effect of androgen receptor signaling on ERG-regulated TFF3 expression. Furthermore, TFF3 overexpression enhances ERG-mediated cell invasion in CRPC prostate cancer cells. Taken together, our findings reveal a novel mechanism for enhanced tumor cell aggressiveness resulting from ERG rearrangement in the castration-resistant setting through TFF3 gene expression.

  5. ERG cooperates with androgen receptor in regulating trefoil factor 3 in prostate cancer disease progression.

    Science.gov (United States)

    Rickman, David S; Chen, Ying-Bei; Banerjee, Samprit; Pan, Yihang; Yu, Jindan; Vuong, Terry; Perner, Sven; Lafargue, Christopher J; Mertz, Kirsten D; Setlur, Sunita R; Sircar, Kanishka; Chinnaiyan, Arul M; Bismar, Tarek A; Rubin, Mark A; Demichelis, Francesca

    2010-12-01

    To elucidate the role of ETS gene fusions in castration-resistant prostate cancer (CRPC), we characterized the transcriptome of 54 CRPC tumor samples from men with locally advanced or metastatic disease. Trefoil factor 3 (TFF3) emerged as the most highly differentially regulated gene with respect to ERG rearrangement status and resistance to hormone ablation therapy. Conventional chromatin immunoprecipitation (ChIP)-polymerase chain reaction and ChIP followed by DNA sequencing (ChIP-seq) revealed direct binding of ERG to ETS binding sites in the TFF3 promoter in ERG-rearranged prostate cancer cell lines. These results were confirmed in ERG-rearranged hormone-naive prostate cancer (HNPC) and CRPC tissue samples. Functional studies demonstrated that ERG has an inhibitory effect on TFF3 expression in hormone-naive cancer but not in the castration-resistant state. In addition, we provide evidence suggesting an effect of androgen receptor signaling on ERG-regulated TFF3 expression. Furthermore, TFF3 overexpression enhances ERG-mediated cell invasion in CRPC prostate cancer cells. Taken together, our findings reveal a novel mechanism for enhanced tumor cell aggressiveness resulting from ERG rearrangement in the castration-resistant setting through TFF3 gene expression.

  6. Syndecan-1 responsive microRNA-126 and 149 regulate cell proliferation in prostate cancer

    Energy Technology Data Exchange (ETDEWEB)

    Fujii, Tomomi; Shimada, Keiji [Department of Pathology, Nara Medical University School of Medicine, Nara (Japan); Tatsumi, Yoshihiro [Department of Pathology, Nara Medical University School of Medicine, Nara (Japan); Department of Urology, Nara Medical University School of Medicine, Nara (Japan); Fujimoto, Kiyohide [Department of Urology, Nara Medical University School of Medicine, Nara (Japan); Konishi, Noboru, E-mail: nkonishi@naramed-u.ac.jp [Department of Pathology, Nara Medical University School of Medicine, Nara (Japan)

    2015-01-02

    Highlights: • Syndecan-1 is highly expressed in androgen independent prostate cancer cells, PC3. • Syndecan-1 regulates the expression of miR-126 and -149 in prostate cancer cells. • MiR-126 and 149 control cell growth via p21 induction and senescence mechanism. • MiR-126 and 149 promote cell proliferation by suppressing SOX2, NANOG, and Oct4. - Abstract: MicroRNAs (miRNAs) are short (19–24 nt), low molecular weight RNAs that play important roles in the regulation of target genes associated with cell proliferation, differentiation, and development, by binding to the 3′-untranslated region of the target mRNAs. In this study, we examined the expression of miRNA-126 (miR-126) and miR-149 in prostate cancer, and investigated the molecular mechanisms by which they affect syndecan-1 in prostate cancer. Functional analysis of miR-126 and miR-149 was conducted in the prostate cancer cell lines, PC3, Du145, and LNCaP. The expression levels of SOX2, NANOG, Oct4, miR-126 and miR-149 were evaluated by quantitative RT-PCR. After silencing syndecan-1, miR-126, and/or miR-149 in the PC3 cells, cell proliferation, senescence, and p21 induction were assessed using the MTS assay, senescence-associated β-galactosidase (SA-β-Gal) assay, and immunocytochemistry, respectively. Compared to the Du145 and LNCaP cells, PC3 cells exhibited higher expression of syndecan-1. When syndecan-1 was silenced, the PC3 cells showed reduced expression of miR-126 and miR-149 most effectively. Suppression of miR-126 and/or miR-149 significantly inhibited cell growth via p21 induction and subsequently, induced senescence. The mRNA expression levels of SOX2, NANOG, and Oct4 were significantly increased in response to the silencing of miR-126 and/or miR-149. Our results suggest that miR-126 and miR-149 are associated with the expression of syndecan-1 in prostate cancer cells. These miRNAs promote cell proliferation by suppressing SOX2, NANOG, and Oct4. The regulation of these factors by mi

  7. Post-transcriptional regulation of wnt8a is essential to zebrafish axis development.

    Science.gov (United States)

    Wylie, Annika D; Fleming, Jo-Ann G W; Whitener, Amy E; Lekven, Arne C

    2014-02-01

    wnt8a Is essential for normal patterning during vertebrate embryonic development, and either gain or loss-of-function gene dysregulation results in severe axis malformations. The zebrafish wnt8a locus is structured such that transcripts may possess two regulatory 3' untranslated regions (UTRs), raising the possibility of post-transcriptional regulation as an important mode of wnt8a signaling control. To determine whether both UTRs contribute to post-transcriptional wnt8a gene regulation, each UTR (UTR1 and UTR2) was tested in transient and transgenic reporter assays. Both UTRs suppress EGFP reporter expression in cis, with UTR2 exhibiting a more pronounced effect. UTR2 contains a 6 base sequence necessary for UTR2 regulatory function that is complementary to the seed of the microRNA, miR-430. A target protector morpholino that overlaps the seed complement stabilizes both reporter mRNAs and wnt8a mRNAs, and produces phenotypic abnormalities consistent with wnt8a gain-of-function. In rescue assays, specific functions can be attributed to each of the two wnt8a proteins encoded by the locus. An interplay of wnt8a.1 and wnt8a.2 regulates neural and mesodermal patterning and morphogenesis as well as patterning between brain subdivisions. Thus, post-transcriptional control of wnt8a is essential to fine tune the balance of the signaling outputs of the complex wnt8a locus.

  8. Curcumin down-regulates AR gene expression and activation in prostate cancer cell lines.

    Science.gov (United States)

    Nakamura, Keiichiro; Yasunaga, Yutaka; Segawa, Takehiko; Ko, Daejin; Moul, Judd W; Srivastava, Shiv; Rhim, Johng S

    2002-10-01

    Curcumin, traditionally used as a seasoning spice in Indian cuisine, has been reported to decrease the proliferation potential of prostate cancer cells, by a mechanism that is not fully understood. In the current study, we have evaluated the effects of curcumin in cell growth, activation of signal transduction, and transforming activities of both androgen-dependent and independent cell lines. Prostate cancer cell lines, LNCaP and PC-3, were treated with curcumin and its effects were further analyzed on signal transduction and expression of androgen receptor (AR) and AR-related cofactors using transient transfection assay and Western blotting. Our results show that curcumin down-regulates transactivation and expression of AR, activator protein-1 (AP-1), nuclear factor-kappaB (NF-kappaB), and CREB (cAMP response element-binding protein)-binding protein (CBP). Curcumin also inhibited the transforming activities of both cell lines as evidenced by the reduced colony forming ability in soft agar. The results obtained here demonstrate that curcumin has a potential therapeutic effect on prostate cancer cells through down-regulation of AR and AR-related cofactors (AP-1, NF-kappaB and CBP). PMID:12239622

  9. Sphingosine kinase-1 is central to androgen-regulated prostate cancer growth and survival.

    Directory of Open Access Journals (Sweden)

    Audrey Dayon

    Full Text Available BACKGROUND: Sphingosine kinase-1 (SphK1 is an oncogenic lipid kinase notably involved in response to anticancer therapies in prostate cancer. Androgens regulate prostate cancer cell proliferation, and androgen deprivation therapy is the standard of care in the management of patients with advanced disease. Here, we explored the role of SphK1 in the regulation of androgen-dependent prostate cancer cell growth and survival. METHODOLOGY/PRINCIPAL FINDINGS: Short-term androgen removal induced a rapid and transient SphK1 inhibition associated with a reduced cell growth in vitro and in vivo, an event that was not observed in the hormono-insensitive PC-3 cells. Supporting the critical role of SphK1 inhibition in the rapid effect of androgen depletion, its overexpression could impair the cell growth decrease. Similarly, the addition of dihydrotestosterone (DHT to androgen-deprived LNCaP cells re-established cell proliferation, through an androgen receptor/PI3K/Akt dependent stimulation of SphK1, and inhibition of SphK1 could markedly impede the effects of DHT. Conversely, long-term removal of androgen support in LNCaP and C4-2B cells resulted in a progressive increase in SphK1 expression and activity throughout the progression to androgen-independence state, which was characterized by the acquisition of a neuroendocrine (NE-like cell phenotype. Importantly, inhibition of the PI3K/Akt pathway--by negatively impacting SphK1 activity--could prevent NE differentiation in both cell models, an event that could be mimicked by SphK1 inhibitors. Fascinatingly, the reversability of the NE phenotype by exposure to normal medium was linked with a pronounced inhibition of SphK1 activity. CONCLUSIONS/SIGNIFICANCE: We report the first evidence that androgen deprivation induces a differential effect on SphK1 activity in hormone-sensitive prostate cancer cell models. These results also suggest that SphK1 activation upon chronic androgen deprivation may serve as a

  10. Exosomes from the tumor microenvironment as reciprocal regulators that enhance prostate cancer progression.

    Science.gov (United States)

    Liu, Che-Ming; Hsieh, Chia-Ling; Shen, Chia-Ning; Lin, Cheng-Chieh; Shigemura, Katsumi; Sung, Shian-Ying

    2016-09-01

    Distant organ metastasis of prostate cancer is a puzzle, and various theories have successively arisen to explain the mechanism of lethal cancer progression. While perhaps agreeable to many cancer biologists, the very statement of "seed and soil" proposed by Stephan Paget in 1881 is arguably still the major statement for organ-specific cancer metastasis. Since recent studies showed important correlations of regulation of cancer cells and the microenvironment, exosomes from cancer and stromal cells seem to create another important niche for metastasis. Stromal cells pretreated with exosomes from metastatic cancer cells increase the potential of change stromal cells. The poorly metastatic cancer cells could also enhance malignancy through transfer of proteins, microribonucleic acid and messenger ribonucleic acid to recipient cancer cells. Herein, we reviewed extracellular exosomes as a factor involved in cross-talk between stromal and prostate cancer epithelial cells. PMID:27397852

  11. A novel KLF6-Rho GTPase axis regulates hepatocellular carcinoma cell migration and dissemination

    Science.gov (United States)

    Ahronian, Leanne G.; Zhu, Lihua Julie; Chen, Ya-Wen; Chu, Hsiao-Chien; Klimstra, David S.; Lewis, Brian C.

    2016-01-01

    The presence of invasion into the extra-hepatic portion of the portal vein or the development of distant metastases renders hepatocellular carcinoma (HCC) patients ineligible for the only potential curative options for this malignancy - tumor resection or organ transplantation. Gene expression profiling of murine HCC cell lines identified KLF6 as a potential regulator of HCC cell migration. KLF6 knockdown increases cell migration, consistent with the correlation between decreased KLF6 mRNA levels and the presence of vascular invasion in human HCC. Concordantly, single-copy deletion of Klf6 in a HCC mouse model results in increased tumor formation, increased metastasis to the lungs, and decreased survival, indicating that KLF6 suppresses both HCC development and metastasis. By combining gene expression profiling and chromatin immunoprecipitation coupled to deep sequencing, we identified novel transcriptional targets of KLF6 in HCC cells including VAV3, a known activator of the RAC1 small GTPase. Indeed, RAC1 activity is increased in KLF6 knockdown cells in a VAV3-dependent manner, and knockdown of either RAC1 or VAV3 impairs HCC cell migration. Together, our data demonstrate a novel function for KLF6 in constraining HCC dissemination through the regulation of a VAV3-RAC1 signaling axis. PMID:26876204

  12. Evidence for a Role of Adolescent Endocannabinoid Signaling in Regulating HPA Axis Stress Responsivity and Emotional Behavior Development.

    Science.gov (United States)

    Lee, Tiffany T-Y; Gorzalka, Boris B

    2015-01-01

    Adolescence is a period characterized by many distinct physical, behavioral, and neural changes during the transition from child- to adulthood. In particular, adolescent neural changes often confer greater plasticity and flexibility, yet with this comes the potential for heightened vulnerability to external perturbations such as stress exposure or recreational drug use. There is substantial evidence to suggest that factors such as adolescent stress exposure have longer lasting and sometimes more deleterious effects on an organism than stress exposure during adulthood. Moreover, the adolescent neuroendocrine response to stress exposure is different from that of adults, suggesting that further maturation of the adolescent hypothalamic-pituitary-adrenal (HPA) axis is required. The endocannabinoid (eCB) system is a potential candidate underlying these age-dependent differences given that it is an important regulator of the adult HPA axis and neuronal development. Therefore, this review will focus on (1) the functionality of the adolescent HPA axis, (2) eCB regulation of the adult HPA axis, (3) dynamic changes in eCB signaling during the adolescent period, (4) the effects of adolescent stress exposure on the eCB system, and (5) modulation of HPA axis activity and emotional behavior by adolescent cannabinoid treatment. Collectively, the emerging picture suggests that the eCB system mediates interactions between HPA axis stress responsivity, emotionality, and maturational stage. These findings may be particularly relevant to our understanding of the development of affective disorders and the risks of adolescent cannabis consumption on emotional health and stress responsivity.

  13. Expression of apoptosis-regulating genes in the rat prostate following botulinum toxin type a injection

    Directory of Open Access Journals (Sweden)

    Gorgal Tiago

    2012-01-01

    Full Text Available Abstract Background Onabotulinumtoxin A (OnabotA injection has been investigated as a novel treatment for benign prostatic enlargement caused by benign prostatic hyperplasia. An OnabotA - induced volume reduction caused by sympathetic fibers impairment has been proposed as a potential mechanism of action. Our aim was to investigate the expression of apoptosis-regulating proteins in the rat prostate following OnabotA intraprostatic injection. Methods Adult Wistar rats were injected in the ventral lobes of the prostate with 10 U of OnabotA or saline. A set of OnabotA-injected animals was further treated with 0.5 mg/kg of phenylephrine (PHE subcutaneously daily. All animals were sacrificed after 1 week and had their prostates harvested. Immunohistochemical staining was performed for Bax, Bcl-xL and caspase-3 proteins and visualized by the avidin-biotin method. The optical density of the glandular cells was also determined, with measurement of differences between average optical densities for each group. Results Saline-treated animals showed intense epithelial staining for Bcl-xL and a faint labelling for both Bax and Caspase-3. OnabotA-treated rats showed a reduced epithelial staining of Bcl-xL and a consistently increased Bax and Caspase-3 staining when compared with saline-treated animals. PHE-treated animals showed a stronger Bcl-xL staining and reduced staining of both Bax and Caspase-3 when compared to the OnabotA group. Mean signal intensity measurements for each immunoreaction confirmed a significant decrease of the signal intensity for Bcl-xL and a significant increase of the signal intensity for Bax and Caspase 3 in OnabotA-injected animals when compared with the control group. In OnabotA+PHE treated animals mean signal intensity for Bcl-xL, Bax and Caspase 3 immunoreactions was identical to that of the control animals. Conclusions These results support the hypothesis that OnabotA activates apoptotic pathways in the rat prostate through a

  14. Molecular signatures of prostate stem cells reveal novel signaling pathways and provide insights into prostate cancer.

    Directory of Open Access Journals (Sweden)

    Roy Blum

    Full Text Available BACKGROUND: The global gene expression profiles of adult and fetal murine prostate stem cells were determined to define common and unique regulators whose misexpression might play a role in the development of prostate cancer. METHODOLOGY/PRINCIPAL FINDINGS: A distinctive core of transcriptional regulators common to both fetal and adult primitive prostate cells was identified as well as molecules that are exclusive to each population. Elements common to fetal and adult prostate stem cells include expression profiles of Wnt, Shh and other pathways identified in stem cells of other organs, signatures of the aryl-hydrocarbon receptor, and up-regulation of components of the aldehyde dehydrogenase/retinoic acid receptor axis. There is also a significant lipid metabolism signature, marked by overexpression of lipid metabolizing enzymes and the presence of the binding motif for Srebp1. The fetal stem cell population, characterized by more rapid proliferation and self-renewal, expresses regulators of the cell cycle, such as E2f, Nfy, Tead2 and Ap2, at elevated levels, while adult stem cells show a signature in which TGF-beta has a prominent role. Finally, comparison of the signatures of primitive prostate cells with previously described profiles of human prostate tumors identified stem cell molecules and pathways with deregulated expression in prostate tumors including chromatin modifiers and the oncogene, Erg. CONCLUSIONS/SIGNIFICANCE: Our data indicate that adult prostate stem or progenitor cells may acquire characteristics of self-renewing primitive fetal prostate cells during oncogenesis and suggest that aberrant activation of components of prostate stem cell pathways may contribute to the development of prostate tumors.

  15. Androgen mediated translational and postranslational regulation of IGFBP-2 in androgen-sensitive LNCaP human prostate cancer cells

    OpenAIRE

    David J. DeGraff; Aguiar, Adam A.; Chen, Qian; Adams, Lisa K.; Williams, B. Jill; Sikes, Robert A.

    2010-01-01

    The insulin-like growth factor (IGF) axis is associated intimately with prostate cancer (PCa) development, growth, survival and metastasis. In particular, increased levels of IGFBP-2 expression are associated with advanced PCa, bone metastasis, and the development of castrate resistant PCa. Previously, we reported that androgen treatment decreased intracellular and extracellular IGFBP-2 in the androgen sensitive (AS) PCa cell line, LNCaP. Nonetheless, the mechanism by which androgen treatment...

  16. Avian prostatic acid phosphatase: estrogen regulation in the oviduct and epithelial cell-derived ovarian carcinomas.

    Science.gov (United States)

    Bae, Hyocheol; Lim, Whasun; Bae, Seung-Min; Bazer, Fuller W; Choi, Youngsok; Song, Gwonhwa

    2014-07-01

    Prostatic acid phosphatase (ACPP) is a glycoprotein that is mainly synthesized and secreted by glandular epithelial cells (GE) of the prostate, and it is well known as a biomarker for prostate cancer. Although ACPP was used as prognostic/diagnostic indicator and studied to elucidate regulatory mechanism(s) during several decades in humans, its role is not clearly understood. Gene profiling data using a chicken DNA microarray revealed that ACPP increased significantly during remodeling and recrudescence of the oviduct in response to estrogen. Thus, in this study, we investigated the expression and hormonal regulation of ACPP gene in the reproductive tracts of chickens. ACPP was specifically detected in the luminal cells (LE) and GE of chicken oviduct, and diethylstilbestrol (a synthetic nonsteroidal estrogen) stimulated its expression during development of the oviduct. In addition, ACPP mRNA and protein were localized to LE and GE during the regeneration phase of the oviduct of laying hens during induced molting. Furthermore, ACPP mRNA and protein were abundant in GE of ovarian carcinoma, but not in normal ovaries. Moreover, strong expression of ACPP protein was detected in epithelial cells of cancerous ovaries from women. Collectively, results of the present study are the first to show that ACPP is a novel estrogen-stimulated gene in the oviductal epithelial cells of the chicken and that its expression increases significantly in epithelial cells of ovarian carcinoma, which indicates that it may be a candidate biomarker for diagnosis of epithelia-derived ovarian cancer in women. PMID:24829029

  17. WNT signaling regulates self-renewal and differentiation of prostate cancer cells with stem cell characteristics

    Institute of Scientific and Technical Information of China (English)

    Isabelle Bisson; David M Prowse

    2009-01-01

    Prostate cancer cells with stem cell characteristics were identified in human prostate cancer cell lines by their abil-ity to form from single cells self-renewing prostaspheres in non-adherent cultures. Prostaspheres exhibited heteroge-neous expression of proliferation, differentiation and stem cell-associated makers CD44, ABCG2 and CD133. Treat-ment with WNT inhibitors reduced both prostasphere size and self-renewal, In contrast, addition of Wnt3a caused increased prostasphere size and self-renewal, which was associated with a significant increase in nuclear β-catenin, keratin 18, CD133 and CD44 expression. As a high proportion of LNCaP and C4-2B cancer cells express androgen receptor we determined the effect of the androgen receptor antagonist bicalutamide. Androgen receptor inhibition reduced prostasphere size and expression of PSA, but did not inhibit prostasphere formation. These effects are con-sistent with the androgen-independent self-renewal of cells with stem cell characteristics and the androgen-dependent proliferation of transit amplifying cells. As the canonical WNT signaling effector β-catenin can also associate with the androgen receptor, we propose a model for tumour propagation involving a balance between WNT and androgen re-ceptor activity. That would affect the self-renewal of a cancer cell with stem cell characteristics and drive transit am-plifying cell proliferation and differentiation. In conclusion, we provide evidence that WNT activity regulates the self-renewal of prostate cancer cells with stem cell characteristics independently of androgen receptor activity. Inhibition of WNT signaling therefore has the potential to reduce the self-renewal of prostate cancer cells with stem cell charac-teristics and improve the therapeutic outcome.

  18. The hippo pathway effector YAP regulates motility, invasion, and castration-resistant growth of prostate cancer cells.

    Science.gov (United States)

    Zhang, Lin; Yang, Shuping; Chen, Xingcheng; Stauffer, Seth; Yu, Fang; Lele, Subodh M; Fu, Kai; Datta, Kaustubh; Palermo, Nicholas; Chen, Yuanhong; Dong, Jixin

    2015-04-01

    Yes-associated protein (YAP) is an effector of the Hippo tumor suppressor pathway. The functional significance of YAP in prostate cancer has remained elusive. In this study, we first show that enhanced expression of YAP is able to transform immortalized prostate epithelial cells and promote migration and invasion in both immortalized and cancerous prostate cells. We found that YAP mRNA was upregulated in androgen-insensitive prostate cancer cells (LNCaP-C81 and LNCaP-C4-2 cells) compared to the level in androgen-sensitive LNCaP cells. Importantly, ectopic expression of YAP activated androgen receptor signaling and was sufficient to promote LNCaP cells from an androgen-sensitive state to an androgen-insensitive state in vitro, and YAP conferred castration resistance in vivo. Accordingly, YAP knockdown greatly reduced the rates of migration and invasion of LNCaP-C4-2 cells and under androgen deprivation conditions largely blocked cell division in LNCaP-C4-2 cells. Mechanistically, we found that extracellular signal-regulated kinase-ribosomal s6 kinase signaling was downstream of YAP for cell survival, migration, and invasion in androgen-insensitive cells. Finally, immunohistochemistry showed significant upregulation and hyperactivation of YAP in castration-resistant prostate tumors compared to their levels in hormone-responsive prostate tumors. Together, our results identify YAP to be a novel regulator in prostate cancer cell motility, invasion, and castration-resistant growth and as a potential therapeutic target for metastatic castration-resistant prostate cancer (CRPC). PMID:25645929

  19. miR-708/LSD1 axis regulates the proliferation and invasion of breast cancer cells.

    Science.gov (United States)

    Ma, Lin; Ma, Shan; Zhao, Guimei; Yang, Longqiu; Zhang, Peng; Yi, Qingting; Cheng, Shuguang

    2016-04-01

    Breast cancer is one of the most common malignant tumors in women worldwide. The microRNAs (miRNAs) are small, noncoding RNAs that regulate various biological processes, including breast cancer. miR-708 played an important role in a variety of cancers. However, its involvement in breast cancer remains largely unclear. In this study, we found that forced the expression of miR-708 in breast cancer cell lines decreased cell proliferation and invasion, whereas inhibition of miR-708 increased cell growth and invasion. miR-708 could directly target the LSD1 3'UTR to downregulate the expression. Further studies suggested that inhibition of LSD1 could phenocopied function of the miR-708 overexpression in MDA-MB-231 cells .Overexpression of LSD1 could counteract the effects of miR-708 on the proliferation and invasion. Taken together, the results indicate that miR-708 may function as a tumor suppressor gene in breast cancer development, and miR-708/LSD1 axis may be a therapeutic intervention in breast cancer in the future. PMID:26833707

  20. PPARγ isoforms differentially regulate metabolic networks to mediate mouse prostatic epithelial differentiation

    OpenAIRE

    Strand, D.W.; Jiang, M; Murphy, T A; Yi, Y.; Konvinse, K C; Franco, O E; Wang, Y.; Young, J D; Hayward, S.W.

    2012-01-01

    Recent observations indicate prostatic diseases are comorbidities of systemic metabolic dysfunction. These discoveries revealed fundamental questions regarding the nature of prostate metabolism. We previously showed that prostate-specific ablation of PPARγ in mice resulted in tumorigenesis and active autophagy. Here, we demonstrate control of overlapping and distinct aspects of prostate epithelial metabolism by ectopic expression of individual PPARγ isoforms in PPARγ knockout prostate epithel...

  1. Sex and stress steroids in adolescence: Gonadal regulation of the hypothalamic-pituitary-adrenal axis in the rat.

    Science.gov (United States)

    Green, Matthew R; McCormick, Cheryl M

    2016-08-01

    This review provides an overview of the current understanding of the role of the hypothalamic-pituitary-gonadal (HPG) axis in regulating the hypothalamic-pituitary-adrenal (HPA) axis response to stressors. HPA function is influenced by both organizational (programming) and activational effects of gonadal hormones. Typically, in adult rats, estradiol increases and androgens decrease the HPA response to stressors, thereby contributing to sex differences in HPA function, and sensitivity of the HPA axis to gonadal steroids is in part determined by exposure to these hormones in early development. Although developmental differences in HPA function are well characterized, the extent to which gonadal steroids contribute to age differences in HPA function is not well understood. Deficits in the understanding of the relationships between the HPA and HPG axes are greatest for the adolescent period of development. The critical outstanding questions are, when do gonadal hormones begin to regulate HPA function in adolescence, and what mechanisms precipitate change in sensitivity of the HPA axis to the HPG axis at this stage of life. PMID:26851306

  2. CACUL1 functions as a negative regulator of androgen receptor in prostate cancer cells.

    Science.gov (United States)

    Choi, Hanbyeul; Lee, Sang Hyup; Um, Soo-Jong; Kim, Eun-Joo

    2016-07-01

    The androgen receptor (AR) plays a critical role in the initiation and progression of prostate cancer (PCa), and thus its regulation is an important tool in PCa therapy. Here, we report that CDK2-associated cullin 1 (CACUL1) directly associates with AR and suppresses AR transcriptional activity. In addition, CACUL1 represses histone demethylase LSD1-mediated AR transactivation by competing with LSD1 for AR binding. Depletion of CACUL1 enhances the LSD1 occupancy of the AR-target promoter, accompanied by decreased accumulation of H3K9me2, a repressive transcriptional marker. CACUL1 and LSD1 oppositely regulate CDX-induced cell death in AR-positive LNCaP and metastatic castrate-resistant LNCaP-LN3 cells. These data suggest that CACUL1 impairs LSD1-mediated activation of AR, thereby implicating it as a potential antitumor target in PCa. PMID:27085459

  3. Prostate; Prostate

    Energy Technology Data Exchange (ETDEWEB)

    Rouviere, O.; Valette, O.; Grivolat, S.; Colin-Pangaud, C.; Bouvier, R.; Chapelon, J.Y.; Gelet, A.; Lyonnet, D.; Rouviere, O.; Mege-Lechevallier, F.; Chapelon, J.Y.; Gelet, A.; Bouvier, R.; Boutitie, F.; Lyonnet, D. [69 - Lyon (France)

    2005-10-15

    Two methods to detect recurrence of prostate cancer are presented. Dynamic magnetic resonance imaging after radiotherapy and color doppler after high intensity focused ultrasounds (but with patients that have not received a hormones therapy). These two methods presents an useful contribution. (N.C.)

  4. miRNA Regulation Network Analysis in Qianliening Capsule Treatment of Benign Prostatic Hyperplasia

    Directory of Open Access Journals (Sweden)

    Liya Liu

    2015-01-01

    Full Text Available Objective. The objective of this study was to evaluate the molecular mechanism by which Qianliening capsule (QC treats benign prostatic hyperplasia (BPH. Methods. Benign prostatic hyperplasia epithelial cell line BPH-1 was treated with 0, 1.25, 2.5, and 5 mg/mL QC for 48 h, respectively. Evaluation of cell viability and observation of morphologic changes of BPH-1 cell gene expression and miRNA expression profiles were analyzed. Real-time quantitative PCR was used to confirm changes in miRNA and gene expression. GO and KEGG pathway-based approaches were used to investigate biological functions and signaling pathways affected by differentially expressed mRNAs. Results. QC inhibited BPH-1 cell proliferation. Differential expression of 19 upregulated and 2 downregulated miRNAs was observed in QC-treated BPH-1 cells compared to untreated control cells. 107 upregulated and 71 downregulated genes were identified between the two groups. Significantly enriched signaling pathways based on deregulated mRNAs were mainly involved in regulation of cell proliferation, apoptosis, and so on. Additionally, miRNA-mRNA network analysis integrated these miRNAs and genes by outlining interactions of miRNA and related genes. Conclusion. The study was the first report of differentially expressed miRNA and mRNA in QC-treated BPH-1 cells.

  5. Cosuppression of Sprouty and Sprouty-Related Negative Regulators of FGF Signalling in Prostate Cancer: A Working Hypothesis

    Directory of Open Access Journals (Sweden)

    Stephen J. Assinder

    2015-01-01

    Full Text Available Deregulation of FGF receptor tyrosine kinase (RTK signalling is common in prostate cancer. Normally, to moderate RTK signalling, induction of Sprouty (SPRY and Sprouty-related (SPRED antagonists occurs. Whilst decreased SPRY and SPRED has been described in some cancers, their role in prostate cancer is poorly understood. Therefore, we hypothesise that due to the need for tight regulation of RTK signalling, SPRY and SPRED negative regulators provide a degree of redundancy which ensures that a suppression of one or more family member does not lead to disease. Contrary to this, our analyses of prostates from 24-week-old Spry1- or Spry2-deficientmice, either hemizygous (+/− or homozygous (−/− for the null allele, revealed a significantly greater incidence of PIN compared to wild-type littermates. We further investigated redundancy of negative regulators in the clinical setting in a preliminary analysis of Gene Expression Omnibus and Oncomine human prostate cancer datasets. Consistent with our hypothesis, in two datasets analysed a significant cosuppression of SPRYs and SPREDs is evident. These findings demonstrate the importance of negative regulators of receptor tyrosine signalling, such as Spry, in the clinical setting, and highlight their importance for future pharmacopeia.

  6. Regulation of Gene Expression and Inhibition of Experimental Prostate Cancer Bone Metastasis by Dietary Genistein

    OpenAIRE

    Yiwei Li; Mingxin Che; Sunita Bhagat; Kerrie-Lynn Ellis; Omer Kucuk; Doerge, Daniel R.; Judith Abrams; Cher, Michael L.; Sarkar, Fazlul H

    2004-01-01

    Prostate cancer frequently metastasizes to the bone, and the treatment outcome for metastatic prostate cancer has been disappointing so far. Dietary genistein, derived primarily from soy product, has been proposed to be partly responsible for the low rate of prostate cancer in Asians. Our previous studies have shown that genistein elicits pleiotropic effects on prostate cancer cells, but there are no studies documenting comprehensive gene expression profiles and antitumor effects of dietary g...

  7. Regulation of Gene Expression and Inhibition of Experimental Prostate Cancer Bone Metastasis by Dietary Genistein1

    OpenAIRE

    Li, Yiwei; Che, Mingxin; Bhagat, Sunita; Ellis, Kerrie-Lynn; KUCUK, Omer; Doerge, Daniel R.; Abrams, Judith; Cher, Michael L.; Sarkar, Fazlul H

    2004-01-01

    Prostate cancer frequently metastasizes to the bone, and the treatment outcome for metastatic prostate cancer has been disappointing so far. Dietary genistein, derived primarily from soy product, has been proposed to be partly responsible for the low rate of prostate cancer in Asians. Our previous studies have shown that genistein elicits pleiotropic effects on prostate cancer cells, but there are no studies documenting comprehensive gene expression profiles and antitumor effects of dietary g...

  8. Nrf1 and Nrf2 transcription factors regulate androgen receptor transactivation in prostate cancer cells.

    Directory of Open Access Journals (Sweden)

    Michelle A Schultz

    Full Text Available Despite androgen deprivation therapy (ADT, persistent androgen receptor (AR signaling enables outgrowth of castration resistant prostate cancer (CRPC. In prostate cancer (PCa cells, ADT may enhance AR activity through induction of oxidative stress. Herein, we investigated the roles of Nrf1 and Nrf2, transcription factors that regulate antioxidant gene expression, on hormone-mediated AR transactivation using a syngeneic in vitro model of androgen dependent (LNCaP and castration resistant (C4-2B PCa cells. Dihydrotestosterone (DHT stimulated transactivation of the androgen response element (ARE was significantly greater in C4-2B cells than in LNCaP cells. DHT-induced AR transactivation was coupled with higher nuclear translocation of p65-Nrf1 in C4-2B cells, as compared to LNCaP cells. Conversely, DHT stimulation suppressed total Nrf2 levels in C4-2B cells but elevated total Nrf2 levels in LNCaP cells. Interestingly, siRNA mediated silencing of Nrf1 attenuated AR transactivation while p65-Nrf1 overexpression enhanced AR transactivation. Subsequent studies showed that Nrf1 physically interacts with AR and enhances AR's DNA-binding activity, suggesting that the p65-Nrf1 isoform is a potential AR coactivator. In contrast, Nrf2 suppressed AR-mediated transactivation by stimulating the nuclear accumulation of the p120-Nrf1 which suppressed AR transactivation. Quantitative RT-PCR studies further validated the inductive effects of p65-Nrf1 isoform on the androgen regulated genes, PSA and TMPRSS2. Therefore, our findings implicate differential roles of Nrf1 and Nrf2 in regulating AR transactivation in PCa cells. Our findings also indicate that the DHT-stimulated increase in p65-Nrf1 and the simultaneous suppression of both Nrf2 and p120-Nrf1 ultimately facilitates AR transactivation in CRPC cells.

  9. PI3K/AKT pathway regulates E-cadherin and Desmoglein 2 in aggressive prostate cancer

    International Nuclear Information System (INIS)

    Reduced expression of both classical and desmosomal cadherins has been associated with different types of carcinomas, including prostate cancer. This study aims to provide a comprehensive view of the role and regulation of cell–cell adhesion in prostate cancer aggressiveness by examining the functional implications of both E-cadherin and Desmoglein 2 (DSG2). E-cadherin expression was first examined using immunofluorescence in 50 normal prostate tissues and in a cohort of 414 prostate cancer patients. Correlation and survival analyses were performed to assess its clinical significance. In primary prostate cancer patients, reduced expression of both E-cadherin and DSG2 is significantly associated with an earlier biochemical recurrence. Transgenic DU145 E-cadherin knockdown and constitutively active AKT overexpression lines were generated. Functional implications of such genetic alterations were analyzed in vitro and in vivo, the latter by using tumorigenesis as well as extravasation and metastatic tumor formation assays. We observed that loss of E-cadherin leads to impaired primary and metastatic tumor formation in vivo, suggesting a tumor promoter role for E-cadherin in addition to its known role as a tumor suppressor. Activation of AKT leads to a significant reduction in E-cadherin expression and nuclear localization of Snail, suggesting a role for the PI3K/AKT signaling pathway in the transient repression of E-cadherin. This reduced expression may be regulated by separate mechanisms as neither the loss of E-cadherin nor activation of AKT significantly affected DSG2 expression. In conclusion, these findings illustrate the critical role of cell–cell adhesion in the progression to aggressive prostate cancer, through regulation by the PI3K pathway

  10. CXCR4 expression in prostate cancer progenitor cells.

    Directory of Open Access Journals (Sweden)

    Anna Dubrovska

    Full Text Available Tumor progenitor cells represent a population of drug-resistant cells that can survive conventional chemotherapy and lead to tumor relapse. However, little is known of the role of tumor progenitors in prostate cancer metastasis. The studies reported herein show that the CXCR4/CXCL12 axis, a key regulator of tumor dissemination, plays a role in the maintenance of prostate cancer stem-like cells. The CXCL4/CXCR12 pathway is activated in the CD44(+/CD133(+ prostate progenitor population and affects differentiation potential, cell adhesion, clonal growth and tumorigenicity. Furthermore, prostate tumor xenograft studies in mice showed that a combination of the CXCR4 receptor antagonist AMD3100, which targets prostate cancer stem-like cells, and the conventional chemotherapeutic drug Taxotere, which targets the bulk tumor, is significantly more effective in eradicating tumors as compared to monotherapy.

  11. FSH and TSH in the Regulation of Bone Mass: The Pituitary/Immune/Bone Axis

    OpenAIRE

    Graziana Colaianni; Concetta Cuscito; Silvia Colucci

    2013-01-01

    Recent evidences have highlighted that the pituitary hormones have profound effects on bone, so that the pituitary-bone axis is now becoming an important issue in the skeletal biology. Here, we discuss the topical evidence about the dysfunction of the pituitary-bone axis that leads to osteoporotic bone loss. We will explore the context of FSH and TSH hormones arguing their direct or indirect role in bone loss. In addition, we will focus on the knowledge that both FSH and TSH have influence on...

  12. Androgens regulate Hedgehog signalling and proliferation in androgen-dependent prostate cells.

    Science.gov (United States)

    Sirab, Nanor; Terry, Stéphane; Giton, Frank; Caradec, Josselin; Chimingqi, Mihelaiti; Moutereau, Stéphane; Vacherot, Francis; de la Taille, Alexandre; Kouyoumdjian, Jean-Claude; Loric, Sylvain

    2012-09-15

    Prostate cancer (PCa) is androgen sensitive in its development and progression to metastatic disease. Hedgehog (Hh) pathway activation is important in the initiation and growth of various carcinomas including PCa. We and others have observed aberrations of Hh pathway during the progression of PCa to the castration-resistant state. The involvement of androgen signalling in Hh pathway activation, however, remains largely elusive. Here we investigate the direct role of androgen signalling on Hh pathway. We examined the effect of Dihydrosterone (DHT), antiandrogen, bicalutamide, and Hh pathway inhibitor, KAAD-cyclopamine in four human prostate cell lines (two cancerous: LNCaP, VCaP, and two normal: PNT2 and PNT2-ARm which harbours a mutant version of androgen receptor (AR) that is commonly found in LNCaP). Cell proliferation as well as Hh pathway members (SHH, IHH, DHH, GLI, PTCH) mRNA expression levels were assessed. We showed that KAAD-cyclopamine decreased cell proliferation of DHT-stimulated LNCaP, VCaP and PNT2-ARm cells. SHH expression was found to be downregulated by DHT in all AR posititve cells. The negative effect of DHT on SHH expression was counteracted when cells were treated by bicalutamide. Importantly, KAAD-cyclopamine treatment seemed to inhibit AR activity. Moreover, bicalutamide as well as KAAD-cyclopamine treatments induced GLI and PTCH expression in VCaP and PNT2-ARm. Our results suggest that Hh pathway activity can be regulated by androgen signalling. Specifically, we show that the DHT-induced inhibition of Hh pathway is AR dependent. The mutual interaction between these two pathways might be important in the regulation of cell proliferation in PCa.

  13. Specific changes in the expression of imprinted genes in prostate cancer-implications for cancer progression and epigenetic regulation

    Institute of Scientific and Technical Information of China (English)

    Teodora Ribarska; Klaus-Marius Bastian; Annemarie Koch; Wolfgang A Schulz

    2012-01-01

    Epigenetic dysregulation comprising DNA hypermethylation and hypomethylation,enhancer of zeste homologue 2 (EZH2)overexpression and altered patterns of histone modifications is associated with the progression of prostate cancer.DNA methylation,EZH2 and histone modifications also ensure the parental-specific monoallelic expression of at least 62 imprinted genes.Although it is therefore tempting to speculate that epigenetic dysregulation may extend to imprinted genes,expression changes in cancerous prostates are only well documented for insulin-like growth factor 2 (IGF2).A literature and database survey on imprinted genes in prostate cancer suggests that the expression of most imprinted genes remains unchanged despite global disturbances in epigenetic mechanisms.Instead,selective genetic and epigenetic changes appear to lead to the inactivation of a sub-network of imprinted genes,which might function in the prostate to limit cell growth induced viathe PI3K/Akt pathway,modulate androgen responses and regulate differentiation.Whereas dysregulation of IG F2 may constitute an early change in prostate carcinogenesis,inactivation of this imprinted gene network is rather associated with cancer progression.

  14. Up-regulation of eEF1A2 promotes proliferation and inhibits apoptosis in prostate cancer

    Energy Technology Data Exchange (ETDEWEB)

    Sun, Yue [Department of Pathology, The First Affiliated Hospital, Zhejiang University Medical College, Hangzhou (China); Du, Chengli [Department of Hepatobiliary Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou (China); Wang, Bo; Zhang, Yanling; Liu, Xiaoyan [Department of Pathology, The First Affiliated Hospital, Zhejiang University Medical College, Hangzhou (China); Ren, Guoping, E-mail: renguoping12345@163.com [Department of Pathology, The First Affiliated Hospital, Zhejiang University Medical College, Hangzhou (China)

    2014-07-18

    Highlights: • The expression of eEF1A2 is up-regulated in prostate cancer tissues. • Suppression of eEF1A2 inhibits the proliferation and promotes apoptosis. • Inhibition of eEF1A2 enhances the expression of apoptotic relevant proteins. • The expressions of eEF1A2 and cleavage-caspase3 are inversely correlated. - Abstract: Background: eEF1A2 is a protein translation factor involved in protein synthesis, which possesses important function roles in cancer development. This study aims at investigating the expression pattern of eEF1A2 in prostate cancer and its potential role in prostate cancer development. Methods: We examined the expression level of eEF1A2 in 30 pairs of prostate cancer tissues by using RT-PCR and immunohistochemical staining (IHC). Then we applied siRNA specifically targeting eEF1A2 to down-regulate its expression in DU-145 and PC-3 cells. Flow cytometer was used to explore apoptosis and Western-blot was used to detect the pathway proteins of apoptosis. Results: Our results showed that the expression level of eEF1A2 in prostate cancer tissues was significantly higher compared to their corresponding normal tissues. Reduction of eEF1A2 expression in DU-145 and PC-3 cells led to a dramatic inhibition of proliferation accompanied with enhanced apoptosis rate. Western blot revealed that apoptosis pathway proteins (caspase3, BAD, BAX, PUMA) were significantly up-regulated after suppression of eEF1A2. More importantly, the levels of eEF1A2 and caspase3 were inversely correlated in prostate cancer tissues. Conclusion: Our data suggests that eEF1A2 plays an important role in prostate cancer development, especially in inhibiting apoptosis. So eEF1A2 might serve as a potential therapeutic target in prostate cancer.

  15. Epigenetic regulation of CpG promoter methylation in invasive prostate cancer cells

    Directory of Open Access Journals (Sweden)

    Farrar William L

    2010-10-01

    Full Text Available Abstract Background Recently, much attention has been focused on gaining a better understanding of the different populations of cells within a tumor and their contribution to cancer progression. One of the most commonly used methods to isolate a more aggressive sub-population of cells utilizes cell sorting based on expression of certain cell adhesion molecules. A recently established method we developed is to isolate these more aggressive cells based on their properties of increased invasive ability. These more invasive cells have been previously characterized as tumor initiating cells (TICs that have a stem-like genomic signature and express a number of stem cell genes including Oct3/4 and Nanog and are more tumorigenic compared to their 'non-invasive' counterpart. They also have a profile reminiscent of cells undergoing a classic pattern of epithelial to mesenchymal transition or EMT. Using this model of invasion, we sought to investigate which genes are under epigenetic control in this rare population of cells. Epigenetic modifications, specifically DNA methylation, are key events regulating the process of normal human development. To determine the specific methylation pattern in these invasive prostate cells, and if any developmental genes were being differentially regulated, we analyzed differences in global CpG promoter methylation. Results Differentially methylated genes were determined and select genes were chosen for additional analyses. The non-receptor tyrosine kinase BMX and transcription factor SOX1 were found to play a significant role in invasion. Ingenuity pathway analysis revealed the methylated gene list frequently displayed genes from the IL-6/STAT3 pathway. Cells which have decreased levels of the targets BMX and SOX1 also display loss of STAT3 activity. Finally, using Oncomine, it was determined that more aggressive metastatic prostate cancers in humans also have higher levels of both Stat3 and Sox1. Conclusions Using this

  16. Andrographolide inhibits prostate cancer by targeting cell cycle regulators, CXCR3 and CXCR7 chemokine receptors.

    Science.gov (United States)

    Mir, Hina; Kapur, Neeraj; Singh, Rajesh; Sonpavde, Guru; Lillard, James W; Singh, Shailesh

    2016-01-01

    Despite state of the art cancer diagnostics and therapies offered in clinic, prostate cancer (PCa) remains the second leading cause of cancer-related deaths. Hence, more robust therapeutic/preventive regimes are required to combat this lethal disease. In the current study, we have tested the efficacy of Andrographolide (AG), a bioactive diterpenoid isolated from Andrographis paniculata, against PCa. This natural agent selectively affects PCa cell viability in a dose and time-dependent manner, without affecting primary prostate epithelial cells. Furthermore, AG showed differential effect on cell cycle phases in LNCaP, C4-2b and PC3 cells compared to retinoblastoma protein (RB(-/-)) and CDKN2A lacking DU-145 cells. G2/M transition was blocked in LNCaP, C4-2b and PC3 after AG treatment whereas DU-145 cells failed to transit G1/S phase. This difference was primarily due to differential activation of cell cycle regulators in these cell lines. Levels of cyclin A2 after AG treatment increased in all PCa cells line. Cyclin B1 levels increased in LNCaP and PC3, decreased in C4-2b and showed no difference in DU-145 cells after AG treatment. AG decreased cyclin E2 levels only in PC3 and DU-145 cells. It also altered Rb, H3, Wee1 and CDC2 phosphorylation in PCa cells. Intriguingly, AG reduced cell viability and the ability of PCa cells to migrate via modulating CXCL11 and CXCR3 and CXCR7 expression. The significant impact of AG on cellular and molecular processes involved in PCa progression suggests its potential use as a therapeutic and/or preventive agent for PCa. PMID:27029529

  17. Regulation of DU145 prostate cancer cell growth by Scm-like with four mbt domains 2

    Indian Academy of Sciences (India)

    Kwanghyun Lee; Wonho Na; Je-Heon Maeng; Hongjin Wu; Bong-Gun Ju

    2013-03-01

    Mammalian SFMBTs have been considered to be polycomb group repressors. However, molecular mechanisms underlying mammalian SFMBTs-mediated gene regulation and their biological function have not been characterized. In the present study, we identified YY1 and methylated histones as interacting proteins of human SFMBT2. We also found that human SFMBT2 binds preferentially to methylated histone H3 and H4 that are associated with transcriptional repression. Using DU145 prostate cancer cells as a model, we showed that SFMBT2 has a transcriptional repression activity on HOXB13 gene expression. In addition, occupancy of SFMBT2 coincided with enrichment of diand tri-methylated H3K9 and H4K20 as well as tri-methylated H3K27 at the HOXB13 gene promoter. When SFMBT2 was depleted by siRNA in DU145 prostate cancer cells, significant up-regulation of HOXB13 gene expression and decreased cell growth were observed. Collectively, our findings indicate that human SFMBT2 may regulate cell growth via epigenetic regulation of HOXB13 gene expression in DU145 prostate cancer cells.

  18. Met-Independent Hepatocyte Growth Factor-mediated regulation of cell adhesion in human prostate cancer cells

    Directory of Open Access Journals (Sweden)

    Davis Rodney

    2006-07-01

    Full Text Available Abstract Background Prostate cancer cells communicate reciprocally with the stromal cells surrounding them, inside the prostate, and after metastasis, within the bone. Each tissue secretes factors for interpretation by the other. One stromally-derived factor, Hepatocyte Growth Factor (HGF, was found twenty years ago to regulate invasion and growth of carcinoma cells. Working with the LNCaP prostate cancer progression model, we found that these cells could respond to HGF stimulation, even in the absence of Met, the only known HGF receptor. The new HGF binding partner we find on the cell surface may help to clarify conflicts in the past literature about Met expression and HGF response in cancer cells. Methods We searched for Met or any HGF binding partner on the cells of the PC3 and LNCaP prostate cancer cell models, using HGF immobilized on agarose beads. By using mass spectrometry analyses and sequencing we have identified nucleolin protein as a novel HGF binding partner. Antibodies against nucleolin (or HGF were able to ameliorate the stimulatory effects of HGF on met-negative prostate cancer cells. Western blots, RT-PCR, and immunohistochemistry were used to assess nucleolin levels during prostate cancer progression in both LNCaP and PC3 models. Results We have identified HGF as a major signaling component of prostate stromal-conditioned media (SCM and have implicated the protein nucleolin in HGF signal reception by the LNCaP model prostate cancer cells. Antibodies that silence either HGF (in SCM or nucleolin (on the cell surfaces eliminate the adhesion-stimulatory effects of the SCM. Likewise, addition of purified HGF to control media mimics the action of SCM. C4-2, an LNCaP lineage-derived, androgen-independent human prostate cancer cell line, responds to HGF in a concentration-dependent manner by increasing its adhesion and reducing its migration on laminin substratum. These HGF effects are not due to shifts in the expression levels of

  19. Role of the hypothalamic–pituitary–thyroid axis in metabolic regulation by JNK1

    OpenAIRE

    Sabio, Guadalupe; Cavanagh-Kyros, Julie; Barrett, Tamera; Jung, Dae Young; Ko, Hwi Jin; Ong, Helena; Morel, Caroline; Mora, Alfonso; Reilly, Judith; Kim, Jason K.; Davis, Roger J

    2010-01-01

    The cJun N-terminal kinase 1 (JNK1) is implicated in diet-induced obesity. Indeed, germline ablation of the murine Jnk1 gene prevents diet-induced obesity. Here we demonstrate that selective deficiency of JNK1 in the murine nervous system is sufficient to suppress diet-induced obesity. The failure to increase body mass is mediated, in part, by increased energy expenditure that is associated with activation of the hypothalamic–pituitary–thyroid axis. Disruption of thyroid hormone function prev...

  20. The Zfhx3-Mediated Axis Regulates Sleep and Interval Timing in Mice

    Directory of Open Access Journals (Sweden)

    Edoardo Balzani

    2016-07-01

    Full Text Available An AT motif-dependent axis, modulated by the transcription factor Zfhx3, influences the circadian clock in mice. In particular, gain of function of Zfhx3 significantly shortens circadian rhythms and alters the transcriptional activity of an important class of neuropeptides that controls intercellular signaling in the suprachiasmatic nucleus (SCN of the hypothalamus. The ZFHX3/AT axis revealed an important, largely cell-nonautonomous control of the circadian clock. Here, by studying the recently identified circadian mouse mutant Zfhx3Sci/+, we identify significant effects on sleep homeostasis, a phenomenon that is outside the canonical circadian clock system and that is modulated by the activity of those neuropeptides at a circuit level. We show that the Zfhx3Sci/+ mutation accelerates the circadian clock at both the hourly scale (i.e., advancing circadian rhythms and the seconds-to-minutes scale (i.e., anticipating behavioral responses in mice. The in vivo results are accompanied by a significant presence of sleep targets among protein-protein interactions of the Zfhx3Sci/+-dependent network.

  1. p300 Acetyltransferase Regulates Androgen Receptor Degradation and PTEN-Deficient Prostate Tumorigenesis

    NARCIS (Netherlands)

    Zhong, J.; Ding, L.; Bohrer, L.R.; Pan, Y.; Liu, P.; Zhang, Jun; Sebo, T.J.; Karnes, R.J.; Tindall, D.J.; Deursen, J.M. van; Huang, H.

    2014-01-01

    Overexpression of the histone acetyltransferase p300 is implicated in the proliferation and progression of prostate cancer, but evidence of a causal role is lacking. In this study, we provide genetic evidence that this generic transcriptional coactivator functions as a positive modifier of prostate

  2. Cinnamomi Cortex (Cinnamomum verum) Suppresses Testosterone-induced Benign Prostatic Hyperplasia by Regulating 5α-reductase.

    Science.gov (United States)

    Choi, Hyun-Myung; Jung, Yunu; Park, Jinbong; Kim, Hye-Lin; Youn, Dong-Hyun; Kang, JongWook; Jeong, Mi-Young; Lee, Jong-Hyun; Yang, Woong Mo; Lee, Seok-Geun; Ahn, Kwang Seok; Um, Jae-Young

    2016-01-01

    Cinnamomi cortex (dried bark of Cinnamomum verum) is an important drug in Traditional Korean Medicine used to improve blood circulation and Yang Qi. Benign prostatic hyperplasia (BPH) is a common chronic disease in aging men. This study was conducted to determine the effect of Cinnamomi cortex water extract (CC) on BPH. BPH was induced by a pre-4-week daily injection of testosterone propionate (TP). Six weeks of further injection with (a) vehicle, (b) TP, (c) TP + CC, (d) TP + finasteride (Fi) was carried on. As a result, the prostate weight and prostatic index of the CC treatment group were reduced. Histological changes including epithelial thickness and lumen area were recovered as normal by CC treatment. The protein expressions of prostate specific antigen, estrogen receptor α (ERα), androgen receptor (AR), 5α-reductase (5AR), and steroid receptor coactivator 1 were suppressed by treatment of CC. Immunohistochemical assays supported the western blot results, as the expressions of AR and ERα were down-regulated by CC treatment as well. Further in vitro experiments showed CC was able to inhibit proliferation of RWPE-1 cells by suppressing 5AR and AR. These results all together suggest CC as a potential treatment for BPH. PMID:27549514

  3. Construction of Smac gene-containing and human prostate specific antigen promoter-regulated vector and its expression

    Institute of Scientific and Technical Information of China (English)

    Yu Wu; Fuqing Zeng; Liang Wang; Yanbo Wang; Guiyi Liao

    2007-01-01

    Objective: To construct an eukaryotic expression vector containing Smac gene and study the expression efficiency and specificity of prostate specific antigen(PSA) enhancer/promoter in a possible targeted gene therapy scheme for prostate cancer. Methods: PSA enhancer (PSAE) and promoter (PSAP) sequences were amplified using PCR method. CMV and T7 promoters were deleted from pcDNA3.1-Smac and replaced by the two specific fragments to generate pPSAE-PSAP-Smac. After transfection into different cell lines, the status of cells was observed. And then, we determined the relative concentration of Smac mRNA in RT-PCR. Results: The recombinant plasmid of pPSAE-PSAP-Smac was successfully constructed. And only the prostate cancer cell line PC-3 was suppressed after transfection with pPSAE-PSAP-Smac. However, other nonprostate lines were not. Moreover,the concentration of Smac mRNA regulated by PSA promoter and enhancer was higher in comparison to the CMV promoter-driven control vectors. Conclusion: An expression vector containing the Smac gene (based on elements of the PSA gene regulatory sequences) has been developed and shown to function in prostate cancer cell lines which provides a solid platform for launching clinical studies.

  4. Skip Regulates TGF-β1-Induced Extracellular Matrix Degrading Proteases Expression in Human PC-3 Prostate Cancer Cells

    Directory of Open Access Journals (Sweden)

    Victor Villar

    2013-01-01

    Full Text Available Purpose. To determine whether Ski-interacting protein (SKIP regulates TGF-β1-stimulated expression of urokinase-type plasminogen activator (uPA, matrix metalloproteinase-9 (MMP-9, and uPA Inhibitor (PAI-1 in the androgen-independent human prostate cancer cell model. Materials and Methods. PC-3 prostate cancer cell line was used. The role of SKIP was evaluated using synthetic small interference RNA (siRNA compounds. The expression of uPA, MMP-9, and PAI-1 was evaluated by zymography assays, RT-PCR, and promoter transactivation analysis. Results. In PC-3 cells TGF-β1 treatment stimulated uPA, PAI-1, and MMP-9 expressions. The knockdown of SKIP in PC-3 cells enhanced the basal level of uPA, and TGF-β1 treatment inhibited uPA production. Both PAI-1 and MMP-9 production levels were increased in response to TGF-β1. The ectopic expression of SKIP inhibited both TGF-β1-induced uPA and MMP-9 promoter transactivation, while PAI-1 promoter response to the factor was unaffected. Conclusions. SKIP regulates the expression of uPA, PAI-1, and MMP-9 stimulated by TGF-β1 in PC-3 cells. Thus, SKIP is implicated in the regulation of extracellular matrix degradation and can therefore be suggested as a novel therapeutic target in prostate cancer treatment.

  5. Development of a small-molecule serum- and glucocorticoid-regulated kinase-1 antagonist and its evaluation as a prostate cancer therapeutic.

    Science.gov (United States)

    Sherk, Andrea B; Frigo, Daniel E; Schnackenberg, Christine G; Bray, Jeffrey D; Laping, Nicholas J; Trizna, Walter; Hammond, Marlys; Patterson, Jaclyn R; Thompson, Scott K; Kazmin, Dmitri; Norris, John D; McDonnell, Donald P

    2008-09-15

    Androgens, through their actions on the androgen receptor (AR), are required for the development of the prostate and contribute to the pathologic growth dysregulation observed in prostate cancers. Consequently, androgen ablation has become an essential component of the pharmacotherapy of prostate cancer. In this study, we explored the utility of targeting processes downstream of AR as an alternate approach for therapy. Specifically, we show that the serum and glucocorticoid-regulated kinase 1 (SGK1) gene is an androgen-regulated target gene in cellular models of prostate cancer. Furthermore, functional serum- and glucocorticoid-regulated kinase 1 (SGK1) protein, as determined by the phosphorylation of its target Nedd4-2, was also increased with androgen treatment. Importantly, we determined that RNA interference-mediated knockdown of SGK1 expression attenuates the androgen-mediated growth of the prostate cancer cell line LNCaP. Given these findings, we explored the utility of SGK1 as a therapeutic target in prostate cancer by developing and evaluating a small-molecule inhibitor of this enzyme. From these studies emerged GSK650394, a competitive inhibitor that quantitatively blocks the effect of androgens on LNCaP cell growth. Thus, in addition to androgen ablation, inhibition of pathways downstream of AR is likely to have therapeutic utility in prostate cancer.

  6. Weight loss by calorie restriction versus bariatric surgery differentially regulates the HPA axis in male rats

    Science.gov (United States)

    Grayson, Bernadette E.; Hakala-Finch, Andrew P.; Kekulawala, Melani; Laub, Holly; Egan, Ann E.; Ressler, Ilana B.; Woods, Stephen C.; Herman, James P.; Seeley, Randy J.; Benoit, Stephen C.; Ulrich-Lai, Yvonne M.

    2015-01-01

    Behavioral modifications for the treatment of obesity, including caloric restriction, have notoriously low long-term success rates relative to bariatric weight-loss surgery. The reasons for the difference in sustained weight loss are not clear. One possibility is that caloric restriction alone activates the stress-responsive hypothalamo-pituitary-adrenocortical (HPA) axis, undermining the long-term maintenance of weight loss, and that this is abrogated after bariatric surgery. Accordingly, we compared the HPA response to weight loss in 5 groups of male rats: (1) high-fat diet-induced obese (DIO) rats treated with Roux-en-Y gastric bypass surgery (RYGB, n=7), (2) DIO rats treated with vertical sleeve gastrectomy (VSG, n=11), (3) DIO rats given sham surgery and subsequently restricted to the food intake of the VSG/RYGB groups (Pair-fed, n=11), (4) ad libitum-fed DIO rats given sham surgery (Obese, n=11) and (5) ad libitum chow-fed rats given sham surgery (Lean, n=12). Compared to Lean controls, food-restricted rats exhibited elevated morning (nadir) non-stress plasma corticosterone concentrations and increased hypothalamic corticotropin releasing hormone and vasopressin mRNA expression, indicative of basal HPA activation. This was largely prevented when weight loss was achieved by bariatric surgery. DIO increased HPA activation by acute (novel environment) stress and this was diminished by bariatric surgery-, but not pair-feeding-, induced weight loss. These results suggest that the HPA axis is differentially affected by weight loss from caloric restriction versus bariatric surgery, and this may contribute to the differing long-term effectiveness of these two weight-loss approaches. PMID:25238021

  7. Nesfatin-1 regulates the hypothalamo-pituitary-ovarian axis of fish.

    Science.gov (United States)

    Gonzalez, Ronald; Shepperd, Erin; Thiruppugazh, Vetri; Lohan, Sneha; Grey, Caleb L; Chang, John P; Unniappan, Suraj

    2012-10-01

    Nesfatin-1 is an anorexigen in goldfish. In the present study, we provide novel data indicating the presence and regulatory effects of nesfatin-1 on the hypothalamo-pituitary-ovarian (HPO) axis of goldfish. Nucleobindin-2 (NUCB2)/nesfatin-1-like immunoreactive (ir) cells are present in the hypothalamus and in the pituitary, suggesting a hypophysiotropic role for nesfatin-1. NUCB2/nesfatin-1-like ir cells colocalize gonadotropin-releasing hormone (GnRH) in the nucleus lateralis tuberis posterioris and the nucleus anterior tuberis of the goldfish hypothalamus. The presence of nesfatin-1 with GnRH in these two nuclei implicated in pituitary hormone release suggests a role for nesfatin-1 on gonadotropin secretion. A single i.p. injection of synthetic goldfish nesfatin-1 (50 ng/g body wt) resulted in an acute decrease (∼75%) in the expression of hypothalamic chicken GnRH-II and salmon GnRH mRNAs at 15 min postinjection in goldfish. Meanwhile, pituitary luteinizing hormone (LH) beta and follicle-stimulating hormone beta mRNAs were also inhibited (∼80%), but only at 60 min postinjection. Nesfatin-1 administration also resulted in a significant reduction (∼60%) in serum LH levels at 60 min postadministration. Nesfatin-1-like immunoreactivity was also found in the follicle cells, but not the oocytes, in zebrafish and goldfish ovaries. Incubation of zebrafish follicles with nesfatin-1 resulted in a significant reduction in basal germinal vesicle breakdown (∼50%) during the oocyte maturation. In addition, nesfatin-1 also attenuated the stimulatory effects of maturation-inducing hormone on germinal vesicle breakdown. Together, the current results indicate that nesfatin-1 is a metabolic hormone with an inhibitory tone on fish reproduction. Nesfatin-1 appears to elicit this suppressive effect through actions on all three tissues in the fish HPO axis. PMID:22895855

  8. A protein in rat prostatic chromatin interacting with androgen regulated gene

    Institute of Scientific and Technical Information of China (English)

    XUYOUHAI; RONGCHANG; 等

    1992-01-01

    2M NaCl-insoluble fraction of rat ventral Prostate chromatin(residual proteins)contain proteins able to interact specifically with androgen-receptor complex and is ,therefore,a part of the aceptor complex.Among residual proteins a 98 KDa protein has been found which binds significantly to a genomic fiagment containing an androgen-regulated gene coding for a 22 KDa protein The biological significance of this binding in androgen action need to be further studied.A mini-plasmid clone containing 22 KDa protein coding sequence was cloned into charon 4A genomic library from which a 5.7 Kb genomic fragment was isolated,identified by hybridization with a 5' and a 3' cDNA probes,and shown to contain the 3' flanking sequence.Restriction enzyme treatment of this fragment yielded a 4.7 Kb restriction fragmwent representing the 5' upstream region and a 1.0 Kb containing part of the coding sequence.Deletion studies indicated that the 97 KDa protein bound only to a subclone of about 300 bp segment .Furthermore,gel shifting experiment supported its DNA-protein binding.

  9. Gold nanoparticle sensitize radiotherapy of prostate cancer cells by regulation of the cell cycle

    Energy Technology Data Exchange (ETDEWEB)

    Roa, Wilson; Zhang Xiaojing; Guo Linghong; Patel, Samir; Xing, James Z [Department of Radiation Oncology, Cross Cancer Institute, Edmonton, AB (Canada); Shaw, Andrew; Hu Xiuying; Sun Xuejun [Department of Experimental Oncology, Cross Cancer Institute, Edmonton, AB (Canada); Xiong Yeping; Chen Jie [Department of Electrical and Computer Engineering, University of Alberta, Edmonton, AB (Canada); Gulavita, Sunil [Thunder Bay Regional Health Science Center, Thunder Bay, ON (Canada); Moore, Ronald, E-mail: wilsonro@cancerboard.ab.c, E-mail: jxing@ualberta.c [Department of Surgery, Cross Cancer Institute, Edmonton, AB (Canada)

    2009-09-16

    Glucose-capped gold nanoparticles (Glu-GNPs) have been used to improve cellular targeting and radio-sensitization. In this study, we explored the mechanism of Glu-GNP enhanced radiation sensitivity in radiation-resistant human prostate cancer cells. Cell survival and proliferation were measured using MTT and clonogenic assay. Flow cytometry with staining by propidium iodide (PI) was performed to study the cell cycle changes induced by Glu-GNPs, and western blotting was used to determine the expression of p53 and cyclin proteins that correlated to cell cycle regulation. With 2 Gy of ortho-voltage irradiation, Glu-GNP showed a 1.5-2.0 fold enhancement in growth inhibition when compared to x-rays alone. Comparing the cell cycle change, Glu-GNPs induced acceleration in the G0/G1 phase and accumulation of cells in the G2/M phase at 29.8% versus 18.4% for controls at 24 h. G2/M arrest was accompanied by decreased expression of p53 and cyclin A, and increased expression of cyclin B1 and cyclin E. In conclusion, Glu-GNPs trigger activation of the CDK kinases leading to cell cycle acceleration in the G0/G1 phase and accumulation in the G2/M phase. This activation is accompanied by a striking sensitization to ionizing radiation, which may have clinical implications.

  10. Gold nanoparticle sensitize radiotherapy of prostate cancer cells by regulation of the cell cycle

    Science.gov (United States)

    Roa, Wilson; Zhang, Xiaojing; Guo, Linghong; Shaw, Andrew; Hu, Xiuying; Xiong, Yeping; Gulavita, Sunil; Patel, Samir; Sun, Xuejun; Chen, Jie; Moore, Ronald; Xing, James Z.

    2009-09-01

    Glucose-capped gold nanoparticles (Glu-GNPs) have been used to improve cellular targeting and radio-sensitization. In this study, we explored the mechanism of Glu-GNP enhanced radiation sensitivity in radiation-resistant human prostate cancer cells. Cell survival and proliferation were measured using MTT and clonogenic assay. Flow cytometry with staining by propidium iodide (PI) was performed to study the cell cycle changes induced by Glu-GNPs, and western blotting was used to determine the expression of p53 and cyclin proteins that correlated to cell cycle regulation. With 2 Gy of ortho-voltage irradiation, Glu-GNP showed a 1.5-2.0 fold enhancement in growth inhibition when compared to x-rays alone. Comparing the cell cycle change, Glu-GNPs induced acceleration in the G0/G1 phase and accumulation of cells in the G2/M phase at 29.8% versus 18.4% for controls at 24 h. G2/M arrest was accompanied by decreased expression of p53 and cyclin A, and increased expression of cyclin B1 and cyclin E. In conclusion, Glu-GNPs trigger activation of the CDK kinases leading to cell cycle acceleration in the G0/G1 phase and accumulation in the G2/M phase. This activation is accompanied by a striking sensitization to ionizing radiation, which may have clinical implications.

  11. Wind tunnel investigations into stall regulation aerodynamics for horizontal axis wind turbines

    Energy Technology Data Exchange (ETDEWEB)

    Barnsley, M.J.; Wellicome, J.F. (Southampton Univ. (UK))

    1990-06-01

    The main objective of the present project is to gain detailed blade loading and flow information from a representative rotor over the full range of operating tip-speed ratios, to promote better understanding of the fundamental aerodynamics of stall regulation. It is hoped that in conjunction with theoretical models, this work will contribute towards enhanced or new predictive tools and design methods for stall regulated rotors. (author).

  12. Matrix-Dependent Regulation of AKT in Hepsin-Overexpressing PC3 Prostate Cancer Cells12

    Science.gov (United States)

    Wittig-Blaich, Stephanie M; Kacprzyk, Lukasz A; Eismann, Thorsten; Bewerunge-Hudler, Melanie; Kruse, Petra; Winkler, Eva; Strauss, Wolfgang S L; Hibst, Raimund; Steiner, Rudolf; Schrader, Mark; Mertens, Daniel; Sültmann, Holger; Wittig, Rainer

    2011-01-01

    The serine-protease hepsin is one of the most prominently overexpressed genes in human prostate carcinoma. Forced expression of the enzyme in mice prostates is associated with matrix degradation, invasive growth, and prostate cancer progression. Conversely, hepsin overexpression in metastatic prostate cancer cell lines was reported to induce cell cycle arrest and reduction of invasive growth in vitro. We used a system for doxycycline (dox)-inducible target gene expression in metastasis-derived PC3 cells to analyze the effects of hepsin in a quantitative manner. Loss of viability and adhesion correlated with hepsin expression levels during anchorage-dependent but not anchorage-independent growth. Full expression of hepsin led to cell death and detachment and was specifically associated with reduced phosphorylation of AKT at Ser473, which was restored by growth on matrix derived from RWPE1 normal prostatic epithelial cells. In the chorioallantoic membrane xenograft model, hepsin overexpression in PC3 cells reduced the viability of tumors but did not suppress invasive growth. The data presented here provide evidence that elevated levels of hepsin interfere with cell adhesion and viability in the background of prostate cancer as well as other tissue types, the details of which depend on the microenvironment provided. Our findings suggest that overexpression of the enzyme in prostate carcinogenesis must be spatially and temporally restricted for the efficient development of tumors and metastases. PMID:21750652

  13. Non-Cell-Autonomous Regulation of Prostate Epithelial Homeostasis by Androgen Receptor.

    Science.gov (United States)

    Zhang, Boyu; Kwon, Oh-Joon; Henry, Gervaise; Malewska, Alicia; Wei, Xing; Zhang, Li; Brinkley, William; Zhang, Yiqun; Castro, Patricia D; Titus, Mark; Chen, Rui; Sayeeduddin, Mohammad; Raj, Ganesh V; Mauck, Ryan; Roehrborn, Claus; Creighton, Chad J; Strand, Douglas W; Ittmann, Michael M; Xin, Li

    2016-09-15

    Prostate inflammation has been suggested as an etiology for benign prostatic hyperplasia (BPH). We show that decreased expression of the androgen receptor (AR) in luminal cells of human BPH specimens correlates with a higher degree of regional prostatic inflammation. However, the cause-and-effect relationship between the two events remains unclear. We investigated specifically whether attenuating AR activity in prostate luminal cells induces inflammation. Disrupting luminal cell AR signaling in mouse models promotes cytokine production cell-autonomously, impairs epithelial barrier function, and induces immune cell infiltration, which further augments local production of cytokines and chemokines including Il-1 and Ccl2. This inflammatory microenvironment promotes AR-independent prostatic epithelial proliferation, which can be abolished by ablating IL-1 signaling or depleting its major cellular source, the macrophages. This study demonstrates that disrupting luminal AR signaling promotes prostate inflammation, which may serve as a mechanism for resistance to androgen-targeted therapy for prostate-related diseases. PMID:27594448

  14. Matrix-Dependent Regulation of AKT in Hepsin-Overexpressing PC3 Prostate Cancer Cells

    Directory of Open Access Journals (Sweden)

    Stephanie M Wittig-Blaich

    2011-07-01

    Full Text Available The serine-protease hepsin is one of the most prominently overexpressed genes in human prostate carcinoma. Forced expression of the enzyme in mice prostates is associated with matrix degradation, invasive growth, and prostate cancer progression. Conversely, hepsin overexpression in metastatic prostate cancer cell lines was reported to induce cell cycle arrest and reduction of invasive growth in vitro. We used a system for doxycycline (dox-inducible target gene expression in metastasis-derived PC3 cells to analyze the effects of hepsin in a quantitative manner. Loss of viability and adhesion correlated with hepsin expression levels during anchorage-dependent but not anchorage-independent growth. Full expression of hepsin led to cell death and detachment and was specifically associated with reduced phosphorylation of AKT at Ser473, which was restored by growth on matrix derived from RWPE1 normal prostatic epithelial cells. In the chorioallantoic membrane xenograft model, hepsin overexpression in PC3 cells reduced the viability of tumors but did not suppress invasive growth. The data presented here provide evidence that elevated levels of hepsin interfere with cell adhesion and viability in the background of prostate cancer as well as other tissue types, the details of which depend on the microenvironment provided. Our findings suggest that overexpression of the enzyme in prostate carcinogenesis must be spatially and temporally restricted for the efficient development of tumors and metastases.

  15. Prostate specific membrane antigen (PSMA regulates angiogenesis independently of VEGF during ocular neovascularization.

    Directory of Open Access Journals (Sweden)

    Christina L Grant

    Full Text Available BACKGROUND: Aberrant growth of blood vessels in the eye forms the basis of many incapacitating diseases and currently the majority of patients respond to anti-angiogenic therapies based on blocking the principal angiogenic growth factor, vascular endothelial growth factor (VEGF. While highly successful, new therapeutic targets are critical for the increasing number of individuals susceptible to retina-related pathologies in our increasingly aging population. Prostate specific membrane antigen (PSMA is a cell surface peptidase that is absent on normal tissue vasculature but is highly expressed on the neovasculature of most solid tumors, where we have previously shown to regulate angiogenic endothelial cell invasion. Because pathologic angiogenic responses are often triggered by distinct signals, we sought to determine if PSMA also contributes to the pathologic angiogenesis provoked by hypoxia of the retina, which underlies many debilitating retinopathies. METHODOLOGY/PRINCIPAL FINDINGS: Using a mouse model of oxygen-induced retinopathy, we found that while developmental angiogenesis is normal in PSMA null mice, hypoxic challenge resulted in decreased retinal vascular pathology when compared to wild type mice as assessed by avascular area and numbers of vascular tufts/glomeruli. The vessels formed in the PSMA null mice were more organized and highly perfused, suggesting a more 'normal' phenotype. Importantly, the decrease in angiogenesis was not due to an impaired hypoxic response as levels of pro-angiogenic factors are comparable; indicating that PSMA regulation of angiogenesis is independent of VEGF. Furthermore, both systemic and intravitreal administration of a PSMA inhibitor in wild type mice undergoing OIR mimicked the PSMA null phenotype resulting in improved retinal vasculature. CONCLUSIONS/SIGNIFICANCE: Our data indicate that PSMA plays a VEGF-independent role in retinal angiogenesis and that the lack of or inhibition of PSMA may

  16. Effect of androgen withdrawal on activation of ERKs and expression of cell cycle regulation molecules in human prostate carcinoma cells

    Institute of Scientific and Technical Information of China (English)

    YE Ding-wei; LI Hui; TSENG Jane; CHAUVIN Priscilla; QIAN Song-xi; ZHENG Jia-fu; SUN Ying-hao; MA Yong-jiang

    2002-01-01

    Objective: To explore the possible mechanisms of growth regression of human androgen dependentprostate carcinoma cells caused by androgen withdrawal. Methods: After 24 h of treatment with 1×10-9mol/L dihydrotestosterone (DHT), the expression of phosphorylated ERK proteins and cell cycle regulationmolecules including CDK2, CDK4, CDK6 and P27kip1 in human androgen dependent prostate carcinoma cellline LNCaP was measured by Western blot analysis 0 h, 8 h and 24 h of after androgen withdrawal. Humanandrogen independent prostate carcinoma cell line PC-3 was also examined as control. Results: Down-regula-tion of phosphorylated ERK, CDK2, CDK4 and CDK6 and up-regulation of P27kip1 were found initially inLNCaP cell line 8 h after androgen withdrawal. The levels of phosphorylated ERK and CDKs decreased con-tinuously and reached the lowest after 24 h, while continuous elevation of P27kip1 was detected thereafter to 24h. No expression change of phosphorylated ERK, CDKs and P27kip1 were detected in PC-3 cell line. Conclu-sion: The androgen withdrawal can cause ERKs activation decrease and cell cycle regulation moleculeschanges, which may be one of the mechanisms for inhibited growth of androgen dependent prostate carcinomaafter androgen ablation by either operative or medicine methods.

  17. Development of a small molecule serum and glucocorticoid-regulated kinase 1 antagonist and its evaluation as a prostate cancer therapeutic

    Science.gov (United States)

    Sherk, Andrea B.; Frigo, Daniel E.; Schnackenberg, Christine G.; Bray, Jeffrey D.; Laping, Nicholas J.; Trizna, Walter; Hammond, Marlys; Patterson, Jaclyn R.; Thompson, Scott K.; Kazmin, Dmitri; Norris, John D.; McDonnell, Donald P.

    2008-01-01

    Androgens, through their actions on the androgen receptor (AR), are required for the development of the prostate and contribute to the pathological growth dysregulation observed in prostate cancers. Consequently, androgen ablation has become an essential component of the pharmacotherapy of prostate cancer. In this study, we explored the utility of targeting processes downstream of AR as an alternate approach for therapy. Specifically, we demonstrate that the serum and glucocorticoid-regulated kinase 1 (sgk1) gene is an androgen-regulated target gene in cellular models of prostate cancer. Furthermore, functional SGK1 protein, as determined by the phosphorylation of its target Nedd4-2, was also increased with androgen treatment. Importantly, we determined that RNAi-mediated knockdown of SGK1 expression attenuates androgen-mediated growth of the prostate cancer cell line, LNCaP. Given these findings, we explored the utility of SGK1 as a therapeutic target in prostate cancer by developing and evaluating a small molecule inhibitor of this enzyme. From these studies emerged GSK650394, a competitive inhibitor that quantitatively blocks the effect of androgens on LNCaP cell growth. Thus, in addition to androgen ablation, inhibition of pathways downstream of AR are likely to have therapeutic utility in prostate cancer. PMID:18794135

  18. Hepatic glycogen can regulate hypoglycemic counterregulation via a liver-brain axis.

    Science.gov (United States)

    Winnick, Jason J; Kraft, Guillaume; Gregory, Justin M; Edgerton, Dale S; Williams, Phillip; Hajizadeh, Ian A; Kamal, Maahum Z; Smith, Marta; Farmer, Ben; Scott, Melanie; Neal, Doss; Donahue, E Patrick; Allen, Eric; Cherrington, Alan D

    2016-06-01

    Liver glycogen is important for the counterregulation of hypoglycemia and is reduced in individuals with type 1 diabetes (T1D). Here, we examined the effect of varying hepatic glycogen content on the counterregulatory response to low blood sugar in dogs. During the first 4 hours of each study, hepatic glycogen was increased by augmenting hepatic glucose uptake using hyperglycemia and a low-dose intraportal fructose infusion. After hepatic glycogen levels were increased, animals underwent a 2-hour control period with no fructose infusion followed by a 2-hour hyperinsulinemic/hypoglycemic clamp. Compared with control treatment, fructose infusion caused a large increase in liver glycogen that markedly elevated the response of epinephrine and glucagon to a given hypoglycemia and increased net hepatic glucose output (NHGO). Moreover, prior denervation of the liver abolished the improved counterregulatory responses that resulted from increased liver glycogen content. When hepatic glycogen content was lowered, glucagon and NHGO responses to insulin-induced hypoglycemia were reduced. We conclude that there is a liver-brain counterregulatory axis that is responsive to liver glycogen content. It remains to be determined whether the risk of iatrogenic hypoglycemia in T1D humans could be lessened by targeting metabolic pathway(s) associated with hepatic glycogen repletion. PMID:27140398

  19. Human heterochromatin protein 1 isoforms regulate androgen receptor signaling in prostate cancer.

    Science.gov (United States)

    Itsumi, Momoe; Shiota, Masaki; Yokomizo, Akira; Kashiwagi, Eiji; Takeuchi, Ario; Tatsugami, Katsunori; Inokuchi, Junichi; Song, Yoohyun; Uchiumi, Takeshi; Naito, Seiji

    2013-06-01

    Androgen receptor (AR) signaling is critical for the tumorigenesis and development of prostate cancer, as well as the progression to castration-resistant prostate cancer. We previously showed that the heterochromatin protein 1 (HP1) β isoform plays a critical role in transactivation of AR signaling as an AR coactivator that promotes prostate cancer cell proliferation. However, the roles of other HP1 isoforms, HP1α and HP1γ, in AR expression and prostate cancer remain unclear. Here, we found that knockdown of HP1γ, but not HP1α, reduced AR expression and cell proliferation by inducing cell cycle arrest at G1 phase in LNCaP cells. Conversely, overexpression of full-length HP1α and its C-terminal deletion mutant increased AR expression and cell growth, whereas overexpression of HP1γ had no effect. Similarly, HP1α overexpression promoted 22Rv1 cell growth, whereas HP1γ knockdown reduced the proliferation of CxR cells, a castration-resistant LNCaP derivative. Taken together, HP1 isoforms distinctly augment AR signaling and cell growth in prostate cancer. Therefore, silencing of HP1β and HP1γ may be a promising therapeutic strategy for treatment of prostate cancer.

  20. VEGF dose regulates vascular stabilization through Semaphorin3A and the Neuropilin-1+ monocyte/TGF-β1 paracrine axis.

    Science.gov (United States)

    Groppa, Elena; Brkic, Sime; Bovo, Emmanuela; Reginato, Silvia; Sacchi, Veronica; Di Maggio, Nunzia; Muraro, Manuele G; Calabrese, Diego; Heberer, Michael; Gianni-Barrera, Roberto; Banfi, Andrea

    2015-10-01

    VEGF is widely investigated for therapeutic angiogenesis, but while short-term delivery is desirable for safety, it is insufficient for new vessel persistence, jeopardizing efficacy. Here, we investigated whether and how VEGF dose regulates nascent vessel stabilization, to identify novel therapeutic targets. Monoclonal populations of transduced myoblasts were used to homogeneously express specific VEGF doses in SCID mouse muscles. VEGF was abrogated after 10 and 17 days by Aflibercept treatment. Vascular stabilization was fastest with low VEGF, but delayed or prevented by higher doses, without affecting pericyte coverage. Rather, VEGF dose-dependently inhibited endothelial Semaphorin3A expression, thereby impairing recruitment of Neuropilin-1-expressing monocytes (NEM), TGF-β1 production and endothelial SMAD2/3 activation. TGF-β1 further initiated a feedback loop stimulating endothelial Semaphorin3A expression, thereby amplifying the stabilizing signals. Blocking experiments showed that NEM recruitment required endogenous Semaphorin3A and that TGF-β1 was necessary to start the Semaphorin3A/NEM axis. Conversely, Semaphorin3A treatment promoted NEM recruitment and vessel stabilization despite high VEGF doses or transient adenoviral delivery. Therefore, VEGF inhibits the endothelial Semaphorin3A/NEM/TGF-β1 paracrine axis and Semaphorin3A treatment accelerates stabilization of VEGF-induced angiogenesis. PMID:26323572

  1. Regulation of Akt/FOXO3a/GSK-3β/AR Signaling Network by Isoflavone in Prostate Cancer Cells*

    OpenAIRE

    Li, Yiwei; Wang, Zhiwei; Kong, Dejuan; Li, Ran; Sarkar, Sanila H.; Sarkar, Fazlul H

    2008-01-01

    We have previously shown that genistein could inhibit Akt activation and down-regulate AR (androgen receptor) and PSA (prostate-specific antigen) expression in prostate cancer (PCa) cells. However, pure genistein showed increased lymph node metastasis in an animal model, but such an adverse effect was not seen with isoflavone, suggesting that further mechanistic studies are needed for elucidating the role of isoflavone in PCa. It is known that FOXO3a and GSK-3β, target...

  2. Up-Regulated Expression of LAMP2 and Autophagy Activity during Neuroendocrine Differentiation of Prostate Cancer LNCaP Cells

    Science.gov (United States)

    Vara-Ciruelos, Diana; Ramos-Torres, Ágata; Altamirano-Dimas, Manuel; Díaz-Laviada, Inés; Rodríguez-Henche, Nieves

    2016-01-01

    Neuroendocrine (NE) prostate cancer (PCa) is a highly aggressive subtype of prostate cancer associated with resistance to androgen ablation therapy. In this study, we used LNCaP prostate cancer cells cultured in a serum-free medium for 6 days as a NE model of prostate cancer. Serum deprivation increased the expression of NE markers such as neuron-specific enolase (NSE) and βIII tubulin (βIII tub) and decreased the expression of the androgen receptor protein in LNCaP cells. Using cDNA microarrays, we compared gene expression profiles of NE cells and non-differentiated LNCaP cells. We identified up-regulation of 155 genes, among them LAMP2, a lysosomal membrane protein involved in lysosomal stability and autophagy. We then confirmed up-regulation of LAMP2 in NE cells by qRT-PCR, Western blot and confocal microscopy assays, showing that mRNA up-regulation correlated with increased levels of LAMP2 protein. Subsequently, we determined autophagy activity in NE cells by assessing the protein levels of SQSTM/p62 and LC3 by Western blot and LC3 and Atg5 mRNAs content by qRT-PCR. The decreased levels of SQSTM/p62 was accompanied by an enhanced expression of LC3 and ATG5, suggesting activation of autophagy in NE cells. Blockage of autophagy with 1μM AKT inhibitor IV, or by silencing Beclin 1 and Atg5, prevented NE cell differentiation, as revealed by decreased levels of the NE markers. In addition, AKT inhibitor IV as well as Beclin1 and Atg5 kwockdown attenuated LAMP2 expression in NE cells. On the other hand, LAMP2 knockdown by siRNA led to a marked blockage of autophagy, prevention of NE differentiation and decrease of cell survival. Taken together, these results suggest that LAMP2 overexpression assists NE differentiation of LNCaP cells induced by serum deprivation and facilitates autophagy activity in order to attain the NE phenotype and cell survival. LAMP2 could thus be a potential biomarker and potential target for NE prostate cancer. PMID:27627761

  3. BDNF-TrkB axis regulates migration of the lateral line primordium and modulates the maintenance of mechanoreceptor progenitors.

    Directory of Open Access Journals (Sweden)

    Eugene V Gasanov

    Full Text Available BDNF and its specialized receptor TrkB are expressed in the developing lateral line system of zebrafish, but their role in this organ is unknown. To tackle this problem in vivo, we used transgenic animals expressing fluorescent markers in different cell types of the lateral line and combined a BDNF gain-of-function approach by BDNF mRNA overexpression and by soaking embryos in a solution of BDNF, with a loss-of-function approach by injecting the antisence ntrk2b-morpholino and treating embryos with the specific Trk inhibitor K252a. Subsequent analysis demonstrated that the BDNF-TrkB axis regulates migration of the lateral line primordium. In particular, BDNF-TrkB influences the expression level of components of chemokine signaling including Cxcr4b, and the generation of progenitors of mechanoreceptors, at the level of expression of Atoh1a-Atp2b1a.

  4. Endocardial to myocardial notch-wnt-bmp axis regulates early heart valve development.

    Directory of Open Access Journals (Sweden)

    Yidong Wang

    Full Text Available Endocardial to mesenchymal transformation (EMT is a fundamental cellular process required for heart valve formation. Notch, Wnt and Bmp pathways are known to regulate this process. To further address how these pathways coordinate in the process, we specifically disrupted Notch1 or Jagged1 in the endocardium of mouse embryonic hearts and showed that Jagged1-Notch1 signaling in the endocardium is essential for EMT and early valvular cushion formation. qPCR and RNA in situ hybridization assays reveal that endocardial Jagged1-Notch1 signaling regulates Wnt4 expression in the atrioventricular canal (AVC endocardium and Bmp2 in the AVC myocardium. Whole embryo cultures treated with Wnt4 or Wnt inhibitory factor 1 (Wif1 show that Bmp2 expression in the AVC myocardium is dependent on Wnt activity; Wnt4 also reinstates Bmp2 expression in the AVC myocardium of endocardial Notch1 null embryos. Furthermore, while both Wnt4 and Bmp2 rescue the defective EMT resulting from Notch inhibition, Wnt4 requires Bmp for its action. These results demonstrate that Jagged1-Notch1 signaling in endocardial cells induces the expression of Wnt4, which subsequently acts as a paracrine factor to upregulate Bmp2 expression in the adjacent AVC myocardium to signal EMT.

  5. Dipeptidyl Peptidase-4 Regulation of SDF-1/CXCR4 Axis: Implications for Cardiovascular Disease.

    Science.gov (United States)

    Zhong, Jixin; Rajagopalan, Sanjay

    2015-01-01

    Dipeptidyl peptidase-4 (DPP4) is a ubiquitously expressed protease that regulates diverse number of physiological functions. As a dipeptidase, it exerts its catalytic effects on proteins/peptides with proline, alanine, or serine in the penultimate (P1) amino acid residue from the amino terminus. The evidence to date supports an important effect of DPP4 in catalytic cleavage of incretin peptides and this perhaps represents the main mechanism by which DPP4 inhibition improves glycemic control. DPP4 also plays an important role in the degradation of multiple chemokines of which stromal cell-derived factor-1 (SDF-1, also known as CXCL12) is perhaps an increasingly recognized target, given its importance in processes, such as hematopoiesis, angiogenesis, and stem cell homing. In the current review, we will summarize the importance of DPP4-mediated enzymatic processing of cytokines/chemokines with an emphasis on SDF-1 and resultant implications for cardiovascular physiology and disease. PMID:26441982

  6. TLR4-Activated MAPK-IL-6 Axis Regulates Vascular Smooth Muscle Cell Function

    Science.gov (United States)

    Lee, Guan-Lin; Wu, Jing-Yiing; Tsai, Chien-Sung; Lin, Chih-Yuan; Tsai, Yi-Ting; Lin, Chin-Sheng; Wang, Yi-Fu; Yet, Shaw-Fang; Hsu, Yu-Juei; Kuo, Cheng-Chin

    2016-01-01

    Migration of vascular smooth muscle cells (VSMCs) into the intima is considered to be a vital event in the pathophysiology of atherosclerosis. Despite substantial evidence supporting the pathogenic role of Toll-like receptor 4 (TLR4) in the progression of atherogenesis, its function in the regulation of VSMC migration remains unclear. The goal of the present study was to elucidate the mechanism by which TLR4 regulates VSMC migration. Inhibitor experiments revealed that TLR4-induced IL-6 secretion and VSMC migration were mediated via the concerted actions of MyD88 and TRIF on the activation of p38 MAPK and ERK1/2 signaling. Neutralizing anti-IL-6 antibodies abrogated TLR4-driven VSMC migration and F-actin polymerization. Blockade of p38 MAPK or ERK1/2 signaling cascade inhibited TLR4 agonist-mediated activation of cAMP response element binding protein (CREB). Moreover, siRNA-mediated suppression of CREB production repressed TLR4-induced IL-6 production and VSMC migration. Rac-1 inhibitor suppressed TLR4-driven VSMC migration but not IL-6 production. Importantly, the serum level of IL-6 and TLR4 endogenous ligand HMGB1 was significantly higher in patients with coronary artery diseases (CAD) than in healthy subjects. Serum HMGB1 level was positively correlated with serum IL-6 level in CAD patients. The expression of both HMGB1 and IL-6 was clearly detected in the atherosclerotic tissue of the CAD patients. Additionally, there was a positive association between p-CREB and HMGB1 in mouse atherosclerotic tissue. Based on our findings, we concluded that, upon ligand binding, TLR4 activates p38 MAPK and ERK1/2 signaling through MyD88 and TRIF in VSMCs. These signaling pathways subsequently coordinate an additive augmentation of CREB-driven IL-6 production, which in turn triggers Rac-1-mediated actin cytoskeleton to promote VSMC migration. PMID:27563891

  7. Hormonal status modifies renin-angiotensin system-regulating aminopeptidases and vasopressin-degrading activity in the hypothalamus-pituitary-adrenal axis of female mice.

    Science.gov (United States)

    García, María Jesús; Martínez-Martos, José Manuel; Mayas, María Dolores; Carrera, María Pilar; De la Chica, Susana; Cortés, Pedro; Ramírez-Expósito, María Jesús

    2008-07-01

    The hypothalamus-pituitary-adrenal axis (HPA) participates in the maintenance of cardiovascular functions and in the control of blood pressure. By other hand, it is known that blood pressure regulation and HPA activity are affected by sex hormones. The aim of the present work is to analyze the influence of estradiol and progesterone on renin-angiotensin system (RAS)-regulating aminopeptidase A, aminopeptidase B and aminopeptidase N activities and vasopressin-degrading activity in the HPA axis of ovariectomized mice and ovariectomized mice treated subscutaneously with different doses of estradiol and progesterone. Our data suggest that in female mice, estradiol and progesterone influence RAS-regulating and vasopressin-degrading activities at different levels of the HPA axis.

  8. Drosophila Syncrip binds the gurken mRNA localisation signal and regulates localised transcripts during axis specification

    Directory of Open Access Journals (Sweden)

    Suzanne M. McDermott

    2012-04-01

    In the Drosophila oocyte, mRNA transport and localised translation play a fundamental role in axis determination and germline formation of the future embryo. gurken mRNA encodes a secreted TGF-α signal that specifies dorsal structures, and is localised to the dorso-anterior corner of the oocyte via a cis-acting 64 nucleotide gurken localisation signal. Using GRNA chromatography, we characterised the biochemical composition of the ribonucleoprotein complexes that form around the gurken mRNA localisation signal in the oocyte. We identified a number of the factors already known to be involved in gurken localisation and translational regulation, such as Squid and Imp, in addition to a number of factors with known links to mRNA localisation, such as Me31B and Exu. We also identified previously uncharacterised Drosophila proteins, including the fly homologue of mammalian SYNCRIP/hnRNPQ, a component of RNA transport granules in the dendrites of mammalian hippocampal neurons. We show that Drosophila Syncrip binds specifically to gurken and oskar, but not bicoid transcripts. The loss-of-function and overexpression phenotypes of syncrip in Drosophila egg chambers show that the protein is required for correct grk and osk mRNA localisation and translational regulation. We conclude that Drosophila Syncrip is a new factor required for localisation and translational regulation of oskar and gurken mRNA in the oocyte. We propose that Syncrip/SYNCRIP is part of a conserved complex associated with localised transcripts and required for their correct translational regulation in flies and mammals.

  9. DIPEPTIDYL PEPTIDASE-4 REGULATION OF SDF-1/CXCR4 AXIS: IMPLICATIONS FOR CARDIOVASCULAR DISEASE

    Directory of Open Access Journals (Sweden)

    Jixin eZhong

    2015-09-01

    Full Text Available Dipeptidyl peptidase-4 (DPP4 is a ubiquitously expressed protease that regulates a diverse number of physiologic functions. As a dipeptidase it exerts its catalytic effects on proteins/peptides with proline, alanine or serine in the penultimate (P1 amino acid residue from the amino terminus. The evidence to date supports an important effect of DPP4 in catalytic cleavage of incretin peptides and this perhaps represents the main mechanism by which DPP4 inhibition improves glycemic control. DPP4 also plays an important role in the degradation of multiple chemokines of which such as stromal-cell-derived factor-1 (SDF-1, also known as CXCL12 is perhaps an increasingly recognized target, given its importance in processes such as hematopoiesis, angiogenesis and stem cell homing. In the current review, we will summarize the importance of DPP4-mediated enzymatic processing of cytokines/chemokines with an emphasis on SDF-1 and resultant implications for cardiovascular physiology and disease.

  10. The bone morphogenetic protein axis is a positive regulator of skeletal muscle mass

    Science.gov (United States)

    Chen, Justin L.; Qian, Hongwei; Liu, Yingying; Bernardo, Bianca C.; Beyer, Claudia; Watt, Kevin I.; Thomson, Rachel E.; Connor, Timothy; Turner, Bradley J.; McMullen, Julie R.; Larsson, Lars; McGee, Sean L.; Harrison, Craig A.

    2013-01-01

    Although the canonical transforming growth factor β signaling pathway represses skeletal muscle growth and promotes muscle wasting, a role in muscle for the parallel bone morphogenetic protein (BMP) signaling pathway has not been defined. We report, for the first time, that the BMP pathway is a positive regulator of muscle mass. Increasing the expression of BMP7 or the activity of BMP receptors in muscles induced hypertrophy that was dependent on Smad1/5-mediated activation of mTOR signaling. In agreement, we observed that BMP signaling is augmented in models of muscle growth. Importantly, stimulation of BMP signaling is essential for conservation of muscle mass after disruption of the neuromuscular junction. Inhibiting the phosphorylation of Smad1/5 exacerbated denervation-induced muscle atrophy via an HDAC4-myogenin–dependent process, whereas increased BMP–Smad1/5 activity protected muscles from denervation-induced wasting. Our studies highlight a novel role for the BMP signaling pathway in promoting muscle growth and inhibiting muscle wasting, which may have significant implications for the development of therapeutics for neuromuscular disorders. PMID:24145169

  11. Differential regulation of the c-Myc/Lin28 axis discriminates subclasses of rearranged MLL leukemia

    Science.gov (United States)

    Chen, Lili; Sun, Yuqing; Wang, Jingya; Jiang, Hui; Muntean, Andrew G.

    2016-01-01

    MLL rearrangements occur in myeloid and lymphoid leukemias and are generally associated with a poor prognosis, however this varies depending on the fusion partner. We modeled acute myeloid leukemia (AML) in mice using various MLL fusion proteins (MLL-FPs) and observed significantly different survival outcomes. To better understand the differences between these leukemias, we examined the genome wide expression profiles of leukemic cells transformed with different MLL-FPs. RNA-sequencing and pathway analysis identified the c-Myc transcriptional program as one of the top distinguishing features. c-Myc protein levels were highly correlative with AML disease latency in mice. Functionally, overexpression of c-Myc resulted in a more aggressive proliferation rate in MLL-FP cell lines. While all MLL-FP transformed cells displayed sensitivity to BET inhibitors, high c-Myc expressing cells showed greater resistance to Brd4 inhibition. The Myc target Lin28B was also differentially expressed in MLL-FP cell lines in agreement with c-Myc expression. Examination of Lin28B miRNAs targets revealed that let-7g was significantly increased in leukemic cells associated with the longest disease latency and forced let-7g expression induced differentiation of leukemic blasts. Thus, differential regulation of the c-Myc/Lin28/let-7g program by different MLL-FPs is functionally related to disease latency and BET inhibitor resistance in MLL leukemias. PMID:27007052

  12. Amyloid precursor protein regulates migration and metalloproteinase gene expression in prostate cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Miyazaki, Toshiaki; Ikeda, Kazuhiro; Horie-Inoue, Kuniko [Division of Gene Regulation and Signal Transduction, Research Center for Genomic Medicine, Saitama Medical University, Saitama 350-1241 (Japan); Inoue, Satoshi, E-mail: INOUE-GER@h.u-tokyo.ac.jp [Division of Gene Regulation and Signal Transduction, Research Center for Genomic Medicine, Saitama Medical University, Saitama 350-1241 (Japan); Department of Geriatric Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655 (Japan); Department of Anti-Aging Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655 (Japan)

    2014-09-26

    Highlights: • APP knockdown reduced proliferation and migration of prostate cancer cells. • APP knockdown reduced expression of metalloproteinase and EMT-related genes. • APP overexpression promoted LNCaP cell migration. • APP overexpression increased expression of metalloproteinase and EMT-related genes. - Abstract: Amyloid precursor protein (APP) is a type I transmembrane protein, and one of its processed forms, β-amyloid, is considered to play a central role in the development of Alzheimer’s disease. We previously showed that APP is a primary androgen-responsive gene in prostate cancer and that its increased expression is correlated with poor prognosis for patients with prostate cancer. APP has also been implicated in several human malignancies. Nevertheless, the mechanism underlying the pro-proliferative effects of APP on cancers is still not well-understood. In the present study, we explored a pathophysiological role for APP in prostate cancer cells using siRNA targeting APP (siAPP). The proliferation and migration of LNCaP and DU145 prostate cancer cells were significantly suppressed by siAPP. Differentially expressed genes in siAPP-treated cells compared to control siRNA-treated cells were identified by microarray analysis. Notably, several metalloproteinase genes, such as ADAM10 and ADAM17, and epithelial–mesenchymal transition (EMT)-related genes, such as VIM, and SNAI2, were downregulated in siAPP-treated cells as compared to control cells. The expression of these genes was upregulated in LNCaP cells stably expressing APP when compared with control cells. APP-overexpressing LNCaP cells exhibited enhanced migration in comparison to control cells. These results suggest that APP may contribute to the proliferation and migration of prostate cancer cells by modulating the expression of metalloproteinase and EMT-related genes.

  13. The CDX1–microRNA-215 axis regulates colorectal cancer stem cell differentiation

    Science.gov (United States)

    Jones, Matthew F.; Hara, Toshifumi; Francis, Princy; Li, Xiao Ling; Bilke, Sven; Zhu, Yuelin; Pineda, Marbin; Subramanian, Murugan; Bodmer, Walter F.; Lal, Ashish

    2015-01-01

    The transcription factor caudal-type homeobox 1 (CDX1) is a key regulator of differentiation in the normal colon and in colorectal cancer (CRC). CDX1 activates the expression of enterocyte genes, but it is not clear how the concomitant silencing of stem cell genes is achieved. MicroRNAs (miRNAs) are important mediators of gene repression and have been implicated in tumor suppression and carcinogenesis, but the roles of miRNAs in differentiation, particularly in CRC, remain poorly understood. Here, we identified microRNA-215 (miR-215) as a direct transcriptional target of CDX1 by using high-throughput small RNA sequencing to profile miRNA expression in two pairs of CRC cell lines: CDX1-low HCT116 and HCT116 with stable CDX1 overexpression, and CDX1-high LS174T and LS174T with stable CDX1 knockdown. Validation of candidate miRNAs identified by RNA-seq in a larger cell-line panel revealed miR-215 to be most significantly correlated with CDX1 expression. Quantitative ChIP–PCR and promoter luciferase assays confirmed that CDX1 directly activates miR-215 transcription. miR-215 expression is depleted in FACS-enriched cancer stem cells compared with unsorted samples. Overexpression of miR-215 in poorly differentiated cell lines causes a decrease in clonogenicity, whereas miR-215 knockdown increases clonogenicity and impairs differentiation in CDX1-high cell lines. We identified the genome-wide targets of miR-215 and found that miR-215 mediates the repression of cell cycle and stemness genes downstream of CDX1. In particular, the miR-215 target gene BMI1 has been shown to promote stemness and self-renewal and to vary inversely with CDX1. Our work situates miR-215 as a link between CDX1 expression and BMI1 repression that governs differentiation in CRC. PMID:25775580

  14. Enlarged prostate

    Science.gov (United States)

    BPH; Benign prostatic hyperplasia (hypertrophy); Prostate - enlarged ... Lepor H. Evaluation and nonsurgical management of benign prostatic hyperplasia. In: Wein AJ, ed. Campbell-Walsh Urology . 10th ...

  15. The PPARγ ligand ciglitazone regulates androgen receptor activation differently in androgen-dependent versus androgen-independent human prostate cancer cells

    International Nuclear Information System (INIS)

    The androgen receptor (AR) regulates growth and progression of androgen-dependent as well as androgen-independent prostate cancer cells. Peroxisome proliferator-activated receptor gamma (PPARγ) agonists have been reported to reduce AR activation in androgen-dependent LNCaP prostate cancer cells. To determine whether PPARγ ligands are equally effective at inhibiting AR activity in androgen-independent prostate cancer, we examined the effect of the PPARγ ligands ciglitazone and rosiglitazone on C4-2 cells, an androgen- independent derivative of the LNCaP cell line. Luciferase-based reporter assays and Western blot analysis demonstrated that PPARγ ligand reduced dihydrotestosterone (DHT)-induced increases in AR activity in LNCaP cells. However, in C4-2 cells, these compounds increased DHT-induced AR driven luciferase activity. In addition, ciglitazone did not significantly alter DHT-mediated increases in prostate specific antigen (PSA) protein or mRNA levels within C4-2 cells. siRNA-based experiments demonstrated that the ciglitazone-induced regulation of AR activity observed in C4-2 cells was dependent on the presence of PPARγ. Furthermore, overexpression of the AR corepressor cyclin D1 inhibited the ability of ciglitazone to induce AR luciferase activity in C4-2 cells. Thus, our data suggest that both PPARγ and cyclin D1 levels influence the ability of ciglitazone to differentially regulate AR signaling in androgen-independent C4-2 prostate cancer cells.

  16. Prostate Ultrasound

    Science.gov (United States)

    ... News Physician Resources Professions Site Index A-Z Ultrasound - Prostate Ultrasound of the prostate uses sound waves ... the limitations of Prostate Ultrasound Imaging? What is Ultrasound Imaging of the Prostate? Ultrasound is safe and ...

  17. lncRNA H19/miR-675 axis regulates cardiomyocyte apoptosis by targeting VDAC1 in diabetic cardiomyopathy

    Science.gov (United States)

    Li, Xiangquan; Wang, Hao; Yao, Biao; Xu, Weiting; Chen, Jianchang; Zhou, Xiang

    2016-01-01

    We previously established a rat model of diabetic cardiomyopathy (DCM) and found that the expression of lncRNA H19 was significantly downregulated. The present study was designed to investigate the pathogenic role of H19 in the development of DCM. Overexpression of H19 in diabetic rats attenuated oxidative stress, inflammation and apoptosis, and consequently improved left ventricular function. High glucose was associated with reduced H19 expression and increased cardiomyocyte apoptosis. To explore the molecular mechanisms involved, we performed in vitro experiments using cultured neonatal rat cardiomyocytes. Our results showed that miR-675 expression was decreased in cardiomyocytes transfected with H19 siRNA. The 3′UTR of VDAC1 was cloned downstream of a luciferase reporter construct and cotransfected into HEK293 cells with miR-675 mimic. The results of luciferase assay indicated that VDAC1 might be a direct target of miR-675. The expression of VDAC1 was upregulated in cardiomyocytes transfected with miR-675 antagomir, which consequently promotes cellular apoptosis. Moreover, enforced expression of H19 was found to reduce VDAC1 expression and inhibit apoptosis in cardiomyocytes exposed to high glucose. In conclusion, our study demonstrates that H19/miR-675 axis is involved in the regulation of high glucose-induced apoptosis by targeting VDAC1, which may provide a novel therapeutic strategy for the treatment of DCM. PMID:27796346

  18. MicroRNA-17-92 regulates myoblast proliferation and differentiation by targeting the ENH1/Id1 signaling axis

    Science.gov (United States)

    Qiu, H; Liu, N; Luo, L; Zhong, J; Tang, Z; Kang, K; Qu, J; Peng, W; Liu, L; Li, L; Gou, D

    2016-01-01

    Myogenesis is an important biological process that occurs during both skeletal muscle regeneration and postnatal growth. Growing evidence points to the critical role of microRNAs (miRNAs) in myogenesis. Our analysis of miRNA expression patterns reveal that miRNAs of miR-17-92 cluster are dramatically downregulated in C2C12 cells after myogenesis stimulation, are strongly induced in mouse skeletal muscle after injury and decrease steadily thereafter and are downregulated with age in skeletal muscle during mouse and porcine postnatal growth. However, their roles in muscle developmental processes remain elusive. We show that the miR-17-92 cluster promotes mouse myoblast proliferation but inhibits myotube formation. miR-17, -20a and -92a target the actin-associated protein enigma homolog 1 (ENH1). The silencing of ENH1 increased the nuclear accumulation of the inhibitor of differentiation 1 (Id1) and represses myogenic differentiation. Furthermore, the injection of adenovirus expressing miR-20a into the tibialia anterior muscle downregulates ENH1 and delays regeneration. In addition, the downregulation of miR-17-92 during myogenesis is transcriptionally regulated by E2F1. Overall, our results reveal a E2F1/miR-17-92/ENH1/Id1 regulatory axis during myogenesis. PMID:27315298

  19. Protective Effects of Berberine on Isoproterenol-Induced Acute Myocardial Ischemia in Rats through Regulating HMGB1-TLR4 Axis

    Directory of Open Access Journals (Sweden)

    Tianzhu Zhang

    2014-01-01

    Full Text Available Berberine, an isoquinoline alkaloid originally isolated from the Chinese herb Coptis chinensis (Huanglian, has been shown to display a wide array of pharmacological activities. The present study was to investigate the effects of berberine against myocardial ischemia produced in rats by isoproterenol. 50 male Sprague-Dawley rats were randomized equally into five groups: a control group, an untreated model group, berberine (30, 60 mg/kg treatment, or propranolol (30 mg/kg. Rats were treated for 12 days and then given isoproterenol, 85 mg/kg for 2 consecutive days by subcutaneous injection. ST-segment elevation was measured after the last administration. Serum levels of creatine kinase isoenzyme (CK-MB, lactate dehydrogenase (LDH, tumor necrosis factor-α (TNF-α, and interleukin-6 (IL-6 were measured after the rats were sacrificed. The hearts were excised for determining heart weight index, microscopic examination, high mobility group box 1 (HMGB1, toll-like receptor (TLR4, prodeath protein (Bax, antideath protein (Bcl-2, and tumor necrosis factor (TNF-α protein were determined by western blot. Berberine decreased the ST elevation induced by acute myocardial ischemia, and decreased serum levels of CK-MB, LDH, TNF-α, and IL-6. Berberine increased total superoxide dismutase (T-SOD activity and decreased malondialdehyde (MDA content in myocardial tissue. Berberine can regulate HMGB1-TLR4 axis to protect myocardial ischemia.

  20. Regulation of Matrix Metalloproteinase-2 Activity by COX-2-PGE2-pAKT Axis Promotes Angiogenesis in Endometriosis

    Science.gov (United States)

    Ray, Amlan K.; DasMahapatra, Pramathes; Swarnakar, Snehasikta

    2016-01-01

    Endometriosis is characterized by the ectopic development of the endometrium which relies on angiogenesis. Although studies have identified the involvement of different matrix metalloproteinases (MMPs) in endometriosis, no study has yet investigated the role of MMP-2 in endometriosis-associated angiogenesis. The present study aims to understand the regulation of MMP-2 activity in endothelial cells and on angiogenesis during progression of ovarian endometriosis. Histological and biochemical data showed increased expressions of vascular endothelial growth factor (VEGF), VEGF receptor-2, cycloxygenase (COX)-2, von Willebrand factor along with angiogenesis during endometriosis progression. Women with endometriosis showed decreased MMP-2 activity in eutopic endometrium as compared to women without endometriosis. However, ectopic ovarian endometrioma showed significantly elevated MMP-2 activity with disease severity. In addition, increased MT1MMP and decreased tissue inhibitors of metalloproteinases (TIMP)-2 expressions were found in the late stages of endometriosis indicating more MMP-2 activation with disease progression. In vitro study using human endothelial cells showed that prostaglandin E2 (PGE2) significantly increased MMP-2 activity as well as tube formation. Inhibition of COX-2 and/or phosphorylated AKT suppressed MMP-2 activity and endothelial tube formation suggesting involvement of PGE2 in regulation of MMP-2 activity during angiogenesis. Moreover, specific inhibition of MMP-2 by chemical inhibitor significantly reduced cellular migration, invasion and tube formation. In ovo assay showed decreased angiogenic branching upon MMP-2 inhibition. Furthermore, a significant reduction of lesion numbers was observed upon inhibition of MMP-2 and COX-2 in mouse model of endometriosis. In conclusion, our study establishes the involvement of MMP-2 activity via COX-2-PGE2-pAKT axis in promoting angiogenesis during endometriosis progression. PMID:27695098

  1. Regulation of Connective Tissue Growth Factor and Cardiac Fibrosis by an SRF/MicroRNA-133a Axis.

    Directory of Open Access Journals (Sweden)

    Aude Angelini

    Full Text Available Myocardial fibrosis contributes to the remodeling of heart and the loss of cardiac function leading to heart failure. SRF is a transcription factor implicated in the regulation of a large variety of genes involved in cardiac structure and function. To investigate the impact of an SRF overexpression in heart, we developed a new cardiac-specific and tamoxifen-inducible SRF overexpression mouse model by the Cre/loxP strategy. Here, we report that a high level overexpression of SRF leads to severe modifications of cardiac cytoarchitecture affecting the balance between cardiomyocytes and cardiac fibroblasts and also a profound alteration of cardiac gene expression program. The drastic development of fibrosis was characterized by intense sirius red staining and associated with an increased expression of genes encoding extracellular matrix proteins such as fibronectin, procollagen type 1α1 and type 3α1 and especially connective tissue growth factor (CTGF. Furthermore miR-133a, one of the most predominant cardiac miRNAs, is strongly downregulated when SRF is overexpressed. By comparison a low level overexpression of SRF has minor impact on these different processes. Investigation with miR-133a, antimiR-133a and AdSRF-VP16 experiments in H9c2 cardiac cells demonstrated that: 1-miR-133a acts as a repressor of SRF and CTGF expression; 2-a simultaneous overexpression of SRF by AdSRF-VP16 and inhibition of miR-133a by a specific antimiR increase CTGF expression; 3-miR-133a overexpression can block the upregulation of CTGF induced by AdSRF-VP16. Taken together, these findings reveal a key role of the SRF/CTGF/miR-133a axis in the regulation of cardiac fibrosis.

  2. Potential roles for GNIH and GNRH-II in reproductive axis regulation of an opportunistically breeding songbird.

    Science.gov (United States)

    Perfito, Nicole; Zann, Richard; Ubuka, Takayoshi; Bentley, George; Hau, Michaela

    2011-08-01

    The ability to breed at any time of year enables opportunistically breeding species to respond to good conditions whenever they occur. We investigate the neuroendocrine basis for this relatively unusual reproductive pattern in the avian world. One proposed mechanism for year-round breeding ability is tonic activation of gonadotropin-releasing hormone-I (GnRH-I) production that is flexibly modified by gonadotropin-inhibitory hormone (GnIH) production during unfavorable conditions. GnIH could inhibit GnRH secretion from the hypothalamus and/or inhibit GnRH action on the anterior pituitary gland. We studied neuroendocrine patterns in wild Australian zebra finches (Taeniopygia guttata) sampled during a breeding period in Southern Australia, a non-breeding period in central Australia, and in juvenile males in the latter location. We asked whether patterns in immunoreactivity of three neuropeptides important for reproductive axis regulation, GnRH-I, GnRH-II and GnIH, during periods of breeding and non-breeding reflect this flexibility. We found that the numbers and sizes of immunoreactive (-ir) GnRH-I cells did not vary between breeding stages and ages. Contrary to our predictions, irGnIH cell number and size, as well as the synthesis of GnIH mRNA were similar in breeding and non-breeding conditions. However, breeding males had more and larger irGnRH-II cells in the midbrain compared to non-breeding males. Hence, while changes in irGnIH cells are not associated with fluctuations in gonadotropin secretion or gonad volume, the regulation of irGnRH-II cells might represent a previously-unidentified mechanism by which reproductive flexibility can be achieved; namely via behavioral neurotransmitter actions of GnRH-II rather than through the typical sensory-CNS integration-GnRH-I route.

  3. Chemoresistance in prostate cancer cells is regulated by miRNAs and Hedgehog pathway.

    Directory of Open Access Journals (Sweden)

    Saurabh Singh

    Full Text Available Many prostate cancers relapse due to the generation of chemoresistance rendering first-line treatment drugs like paclitaxel (PTX ineffective. The present study aims to determine the role of miRNAs and Hedgehog (Hh pathway in chemoresistant prostate cancer and to evaluate the combination therapy using Hh inhibitor cyclopamine (CYA. Studies were conducted on PTX resistant DU145-TXR and PC3-TXR cell lines and clinical prostate tissues. Drug sensitivity and apoptosis assays showed significantly improved cytotoxicity with combination of PTX and CYA. To distinguish the presence of cancer stem cell like side populations (SP, Hoechst 33342 flow cytometry method was used. PTX resistant DU145 and PC3 cells, as well as human prostate cancer tissue possess a distinct SP fraction. Nearly 75% of the SP cells are in the G0/G1 phase compared to 62% for non-SP cells and have higher expression of stem cell markers as well. SP cell fraction was increased following PTX monotherapy and treatment with CYA or CYA plus PTX effectively reduced their numbers suggesting the effectiveness of combination therapy. SP fraction cells were allowed to differentiate and reanalyzed by Hoechst staining and gene expression analysis. Post differentiation, SP cells constitute 15.8% of total viable cells which decreases to 0.6% on treatment with CYA. The expression levels of P-gp efflux protein were also significantly decreased on treatment with PTX and CYA combination. MicroRNA profiling of DU145-TXR and PC3-TXR cells and prostate cancer tissue from the patients showed decreased expression of tumor suppressor miRNAs such as miR34a and miR200c. Treatment with PTX and CYA combination restored the expression of miR200c and 34a, confirming their role in modulating chemoresistance. We have shown that supplementing mitotic stabilizer drugs such as PTX with Hh-inhibitor CYA can reverse PTX chemoresistance and eliminate SP fraction in androgen independent, metastatic prostate cancer cell

  4. A Critical Role of the PTEN/PDGF Signaling Network for the Regulation of Radiosensitivity in Adenocarcinoma of the Prostate

    Energy Technology Data Exchange (ETDEWEB)

    Christensen, Michael, E-mail: mechristense@uwalumni.com [Department of Radiation Oncology, Wayne State University School of Medicine, Barbara Ann Karmanos Cancer Center, Detroit, Michigan (United States); Najy, Abdo J. [Department of Pathology, Wayne State University School of Medicine, Barbara Ann Karmanos Cancer Center, Detroit, Michigan (United States); Snyder, Michael; Movilla, Lisa S. [Department of Radiation Oncology, Wayne State University School of Medicine, Barbara Ann Karmanos Cancer Center, Detroit, Michigan (United States); Kim, Hyeong-Reh Choi [Department of Pathology, Wayne State University School of Medicine, Barbara Ann Karmanos Cancer Center, Detroit, Michigan (United States)

    2014-01-01

    Purpose: Loss or mutation of the phosphate and tensin homologue (PTEN) is a common genetic abnormality in prostate cancer (PCa) and induces platelet-derived growth factor D (PDGF D) signaling. We examined the role of the PTEN/PDGF axis on radioresponse using a murine PTEN null prostate epithelial cell model. Methods and Materials: PTEN wild-type (PTEN{sup +/+}) and PTEN knockout (PTEN{sup −/−}) murine prostate epithelial cell lines were used to examine the relationship between the PTEN status and radiosensitivity and also to modulate the PDGF D expression levels. PTEN{sup −/−} cells were transduced with a small hairpin RNA (shRNA) lentiviral vector containing either scrambled nucleotides (SCRM) or sequences targeted to PDGF D (shPDGF D). Tumorigenesis and morphogenesis of these cell lines were evaluated in vivo via subcutaneous injection of male nude mice and in vitro using Matrigel 3-dimensional (3D) culture. Effects of irradiation on clonogenic survival, cell migration, and invasion were measured with respect to the PTEN status and the PDGF D expression level. In addition, apoptosis and cell cycle redistribution were examined as potential mechanisms for differences seen. Results: PTEN{sup −/−} cells were highly tumorigenic in animals and effectively formed foci in 3D culture. Importantly, loss of PDGF D in these cell lines drastically diminished these phenotypes. Furthermore, PTEN{sup −/−} cells demonstrated increased clonogenic survival in vitro compared to PTEN{sup +/+}, and attenuation of PDGF D significantly reversed this radioresistant phenotype. PTEN{sup −/−} cells displayed greater migratory and invasive potential at baseline as well as after irradiation. Both the basal and radiation-induced migratory and invasive phenotypes in PTEN{sup −/−} cells required PDGF D expression. Interestingly, these differences were independent of apoptosis and cell cycle redistribution, as they showed no significant difference. Conclusions: We propose

  5. Up-regulated microRNA-143 in cancer stem cells differentiation promotes prostate cancer cells metastasis by modulating FNDC3B expression

    International Nuclear Information System (INIS)

    Metastatic prostate cancer is a leading cause of cancer-related death in men. Cancer stem cells (CSCs) are involved in tumor progression and metastasis, including in prostate cancer. There is an obvious and urgent need for effective cancer stem cells specific therapies in metastatic prostate cancer. MicroRNAs (miRNAs) are an important class of pervasive genes that are involved in a variety of biological functions, especially in cancer. The goal of this study was to identify miRNAs involved in prostate cancer metastasis and cancer stem cells. A microarray and qRT-PCR were performed to investigate the miRNA expression profiles in PC-3 sphere cells and adherent cells. A transwell assay was used to evaluate the migration of PC-3 sphere cells and adherent cells. MiR-143 was silenced with antisense oligonucleotides in PC-3, PC-3-M and LNCaP cells. The role of miR-143 in prostate cancer metastasis was measured by wound-healing and transwell assays in vitro and bioluminescence imaging in vivo. Bioinformatics and luciferase report assays were used to identify the target of miR-143. The expression of miR-143 and the migration capability were reduced in PC-3 sphere cells and progressively increased during sphere re-adherent culture. Moreover, the down-regulation of miR-143 suppressed prostate cancer cells migration and invasion in vitro and systemically inhibited metastasis in vivo. Fibronectin type III domain containing 3B (FNDC3B), which regulates cell motility, was identified as a target of miR-143. The inhibition of miR-143 increased the expression of FNDC3B protein but not FNDC3B mRNA in vitro and vivo. These data demonstrate for the first time that miR-143 was up-regulated during the differentiation of prostate cancer stem cells and promoted prostate cancer metastasis by repressing FNDC3B expression. This sheds a new insight into the post-transcriptional regulation of cancer stem cells differentiation by miRNAs, a potential approach for the treatment of prostate cancer

  6. Gonadotropin Inhibitory Hormone Down-Regulates the Brain-Pituitary Reproductive Axis of Male European Sea Bass (Dicentrarchus labrax).

    Science.gov (United States)

    Paullada-Salmerón, José A; Cowan, Mairi; Aliaga-Guerrero, María; Morano, Francesca; Zanuy, Silvia; Muñoz-Cueto, José A

    2016-06-01

    Gonadotropin-inhibitory hormone (GnIH) inhibits gonadotropin synthesis and release from the pituitary of birds and mammals. However, the physiological role of orthologous GnIH peptides on the reproductive axis of fish is still uncertain, and their actions on the main neuroendocrine systems controlling reproduction (i.e., GnRHs, kisspeptins) have received little attention. In a recent study performed in the European sea bass, we cloned a cDNA encoding a precursor polypeptide that contained C-terminal MPMRFamide (sbGnIH-1) and MPQRFamide (sbGnIH-2) peptide sequences, developed a specific antiserum against sbGnIH-2, and characterized its central and pituitary GnIH projections in this species. In this study, we analyzed the effects of intracerebroventricular injection of sbGnIH-1 and sbGnIH-2 on brain and pituitary expression of reproductive hormone genes (gnrh1, gnrh2, gnrh3, kiss1, kiss2, gnih, lhbeta, fshbeta), and their receptors (gnrhr II-1a, gnrhr II-2b, kiss1r, kiss2r, and gnihr) as well as on plasma Fsh and Lh levels. In addition, we determined the effects of GnIH on pituitary somatotropin (Gh) expression. The results obtained revealed the inhibitory role of sbGnIH-2 on brain gnrh2, kiss1, kiss2, kiss1r, gnih, and gnihr transcripts and on pituitary fshbeta, lhbeta, gh, and gnrhr-II-1a expression, whereas sbGnIH-1 only down-regulated brain gnrh1 expression. However, at different doses, central administration of both sbGnIH-1 and sbGnIH-2 decreased Lh plasma levels. Our work represents the first study reporting the effects of centrally administered GnIH in fish and provides evidence of the differential actions of sbGnIH-1 and sbGnIH-2 on the reproductive axis of sea bass, the main inhibitory role being exerted by the sbGnIH-2 peptide. PMID:26984999

  7. Berberine Ameliorates Nonbacterial Prostatitis via Multi-Target Metabolic Network Regulation

    OpenAIRE

    Sun, Hui; Wang, Huiyu; Zhang, Aihua; Yan, Guangli; Zhang, Yue; An, Na; Wang, Xijun

    2015-01-01

    Metabolomics has been increasingly applied to discovering biomarkers and identifying perturbed pathways. Berberine has been shown to exhibit anti-inflammatory, antioxidant, and anticancer properties, but its mechanisms for treating nonbacterial prostatitis (NBP) remain unclear completely. We developed the untargeted metabolomics approach based on UPLC-Q-TOF-HDMS to profile the metabolite changes in urine samples in order to discover novel potential biomarkers to clarify mechanisms of berberin...

  8. Identification of genes regulating migration and invasion using a new model of metastatic prostate cancer

    International Nuclear Information System (INIS)

    Understanding the complex, multistep process of metastasis remains a major challenge in cancer research. Metastasis models can reveal insights in tumor development and progression and provide tools to test new intervention strategies. To develop a new cancer metastasis model, we used DU145 human prostate cancer cells and performed repeated rounds of orthotopic prostate injection and selection of subsequent lymph node metastases. Tumor growth, metastasis, cell migration and invasion were analyzed. Microarray analysis was used to identify cell migration- and cancer-related genes correlating with metastasis. Selected genes were silenced using siRNA, and their roles in cell migration and invasion were determined in transwell migration and Matrigel invasion assays. Our in vivo cycling strategy created cell lines with dramatically increased tumorigenesis and increased ability to colonize lymph nodes (DU145LN1-LN4). Prostate tumor xenografts displayed increased vascularization, enlarged podoplanin-positive lymphatic vessels and invasive margins. Microarray analysis revealed gene expression profiles that correlated with metastatic potential. Using gene network analysis we selected 3 significantly upregulated cell movement and cancer related genes for further analysis: EPCAM (epithelial cell adhesion molecule), ITGB4 (integrin β4) and PLAU (urokinase-type plasminogen activator (uPA)). These genes all showed increased protein expression in the more metastatic DU145-LN4 cells compared to the parental DU145. SiRNA knockdown of EpCAM, integrin-β4 or uPA all significantly reduced cell migration in DU145-LN4 cells. In contrast, only uPA siRNA inhibited cell invasion into Matrigel. This role of uPA in cell invasion was confirmed using the uPA inhibitors, amiloride and UK122. Our approach has identified genes required for the migration and invasion of metastatic tumor cells, and we propose that our new in vivo model system will be a powerful tool to interrogate the metastatic

  9. In vivo targeting of ADAM9 gene expression using lentivirus-delivered shRNA suppresses prostate cancer growth by regulating REG4 dependent cell cycle progression.

    Directory of Open Access Journals (Sweden)

    Che-Ming Liu

    Full Text Available Cancer cells respond to stress by activating a variety of survival signaling pathways. A disintegrin and metalloproteinase (ADAM 9 is upregulated during cancer progression and hormone therapy, functioning in part through an increase in reactive oxygen species. Here, we present in vitro and in vivo evidence that therapeutic targeting of ADAM9 gene expression by lentivirus-delivered small hairpin RNA (shRNA significantly inhibited proliferation of human prostate cancer cell lines and blocked tumor growth in a murine model of prostate cancer bone metastasis. Cell cycle studies confirmed an increase in the G1-phase and decrease in the S-phase population of cancer cells under starvation stress conditions, which correlated with elevated intracellular superoxide levels. Microarray data showed significantly decreased levels of regenerating islet-derived family member 4 (REG4 expression in prostate cancer cells with knockdown of ADAM9 gene expression. This REG4 downregulation also resulted in induction of expression of p21(Cip1/WAF1, which negatively regulates cyclin D1 and blocks the G1/S transition. Our data reveal a novel molecular mechanism of ADAM9 in the regulation of prostate cancer cell proliferation, and suggests a combined modality of ADAM9 shRNA gene therapy and cytotoxic agents for hormone refractory and bone metastatic prostate cancer.

  10. Disorder, Promiscuous Interactions, and Stochasticity Regulate State Switching in the Unstable Prostate.

    Science.gov (United States)

    Kulkarni, Prakash; Getzenberg, Robert H

    2016-10-01

    A causal link between benign prostatic hyperplasia (BPH) and prostate cancer has long been suspected but not widely accepted. A new model is proposed that supports such a connection. In contrast to the prevailing wisdom, our model, that draws on dynamical systems theory, suggests that in response to stress, epithelial cells in the unstable gland can give rise to both types of diseases via a phenotypic switching mechanism. The central idea is that phenotypic switching is a stochastic process which exploits the plasticity of the epithelial cell. It is driven by 'noise' contributed by the conformational dynamics of proteins that are intrinsically disordered. In a system that is noisy when stressed, disorder promotes promiscuity, unmasks latent information, and rewires the network to cause phenotypic switching. Cells with newly acquired phenotypes can transcend the traditional zonal boundaries to give rise to BPH or prostate cancer depending on the microenvironment. Establishing causality between the two diseases may provide us with an opportunity to better understand their etiology and guide prevention and treatment strategies. J. Cell. Biochem. 117: 2235-2240, 2016. © 2016 Wiley Periodicals, Inc. PMID:27152744

  11. The CXCL12/CXCR4 axis promotes ligand-independent activation of the androgen receptor.

    Science.gov (United States)

    Kasina, Sathish; Macoska, Jill A

    2012-04-01

    The molecular mechanisms responsible for the transition of some prostate cancers from androgen ligand-dependent to androgen ligand-independent are incompletely established. Molecules that are ligands for G protein coupled receptors (GPCRs) have been implicated in ligand-independent androgen receptor (AR) activation. The purpose of this study was to examine whether CXCL12, the ligand for the GPCR, CXCR4, might mediate prostate cancer cell proliferation through AR-dependent mechanisms involving functional transactivation of the AR in the absence of androgen. The results of these studies showed that activation of the CXCL12/CXCR4 axis promoted: The nuclear accumulation of both wild-type and mutant AR in several prostate epithelial cell lines; AR-dependent proliferative responses; nuclear accumulation of the AR co-regulator SRC-1 protein; SRC-1:AR protein:protein association; co-localization of AR and SRC-1 on the promoters of AR-regulated genes; AR- and SRC-1 dependent transcription of AR-regulated genes; AR-dependent secretion of the AR-regulated PSA protein; P13K-dependent phosphorylation of AR; MAPK-dependent phosphorylation of SRC-1, and both MAPK- and P13K-dependent secretion of the PSA protein, in the absence of androgen. Taken together, these studies identify CXCL12 as a novel, non-steroidal growth factor that promotes the growth of prostate epithelial cells through AR-dependent mechanisms in the absence of steroid hormones. These findings support the development of novel therapeutics targeting the CXCL12/CXCR4 axis as an ancillary to those targeting the androgen/AR axis to effectively treat castration resistant/recurrent prostate tumors.

  12. Co-regulation analysis of closely linked genes identifies a highly recurrent gain on chromosome 17q25.3 in prostate cancer

    International Nuclear Information System (INIS)

    Transcriptional profiling of prostate cancer (PC) has unveiled new markers of neoplasia and allowed insights into mechanisms underlying this disease. Genomewide analyses have also identified new chromosomal abnormalities associated with PC. The combination of both classes of data for the same sample cohort might provide better criteria for identifying relevant factors involved in neoplasia. Here we describe transcriptional signatures identifying distinct normal and tumoral prostate tissue compartments, and the inference and demonstration of a new, highly recurrent copy number gain on chromosome 17q25.3. We have applied transcriptional profiling to tumoral and non-tumoral prostate samples with relatively homogeneous epithelial representations as well as pure stromal tissue from peripheral prostate and cultured cell lines, followed by quantitative RT-PCR validations and immunohistochemical analysis. In addition, we have performed in silico colocalization analysis of co-regulated genes and validation by fluorescent in situ hybridization (FISH). The transcriptomic analysis has allowed us to identify signatures corresponding to non-tumoral luminal and tumoral epithelium, basal epithelial cells, and prostate stromal tissue. In addition, in silico analysis of co-regulated expression of physically linked genes has allowed us to predict the occurrence of a copy number gain at chromosomal region 17q25.3. This computational inference was validated by fluorescent in situ hybridization, which showed gains in this region in over 65% of primary and metastatic tumoral samples. Our approach permits to directly link gene copy number variations with transcript co-regulation in association with neoplastic states. Therefore, transcriptomic studies of carefully selected samples can unveil new diagnostic markers and transcriptional signatures highly specific of PC, and lead to the discovery of novel genomic abnormalities that may provide additional insights into the causes and mechanisms

  13. Co-regulation analysis of closely linked genes identifies a highly recurrent gain on chromosome 17q25.3 in prostate cancer

    Directory of Open Access Journals (Sweden)

    Martínez-A Carlos

    2008-10-01

    Full Text Available Abstract Background Transcriptional profiling of prostate cancer (PC has unveiled new markers of neoplasia and allowed insights into mechanisms underlying this disease. Genomewide analyses have also identified new chromosomal abnormalities associated with PC. The combination of both classes of data for the same sample cohort might provide better criteria for identifying relevant factors involved in neoplasia. Here we describe transcriptional signatures identifying distinct normal and tumoral prostate tissue compartments, and the inference and demonstration of a new, highly recurrent copy number gain on chromosome 17q25.3. Methods We have applied transcriptional profiling to tumoral and non-tumoral prostate samples with relatively homogeneous epithelial representations as well as pure stromal tissue from peripheral prostate and cultured cell lines, followed by quantitative RT-PCR validations and immunohistochemical analysis. In addition, we have performed in silico colocalization analysis of co-regulated genes and validation by fluorescent in situ hybridization (FISH. Results The transcriptomic analysis has allowed us to identify signatures corresponding to non-tumoral luminal and tumoral epithelium, basal epithelial cells, and prostate stromal tissue. In addition, in silico analysis of co-regulated expression of physically linked genes has allowed us to predict the occurrence of a copy number gain at chromosomal region 17q25.3. This computational inference was validated by fluorescent in situ hybridization, which showed gains in this region in over 65% of primary and metastatic tumoral samples. Conclusion Our approach permits to directly link gene copy number variations with transcript co-regulation in association with neoplastic states. Therefore, transcriptomic studies of carefully selected samples can unveil new diagnostic markers and transcriptional signatures highly specific of PC, and lead to the discovery of novel genomic abnormalities

  14. Down-regulation of ATM Protein Sensitizes Human Prostate Cancer Cells to Radiation-induced Apoptosis*

    OpenAIRE

    Truman, Jean-Philip; Gueven, Nuri; Lavin, Martin; Leibel, Steven; Kolesnick, Richard; Fuks, Zvi; Haimovitz-Friedman, Adriana

    2005-01-01

    Treatment with the protein kinase C activator 12-O tetradecanoylphorbol 12-acetate (TPA) enables radiation-resistant LNCaP human prostate cancer cells to undergo radiation-induced apoptosis, mediated via activation of the enzyme ceramide synthase (CS) and de novo synthesis of the sphingolipid ceramide (Garzotto, M., Haimovitz-Friedman, A., Liao, W. C., White-Jones, M., Huryk, R., Heston, D. W. W., Cardon-Cardo, C., Kolesnick, R., and Fuks, Z. (1999) Cancer Res. 59, 5194-5201). Here, we show t...

  15. A role for the androgen metabolite, 5alpha androstane 3beta, 17beta diol (3β-diol) in the regulation of the hypothalamo-pituitary-adrenal axis.

    Science.gov (United States)

    Handa, Robert J; Sharma, Dharmendra; Uht, Rosalie

    2011-01-01

    Activation of the hypothalamo-pituitary-adrenal (HPA) axis is a basic reaction of animals to environmental perturbations that threaten homeostasis. These responses are ultimately regulated by neurons residing within the paraventricular nucleus (PVN) of the hypothalamus. Within the PVN, corticotrophin-releasing hormone (CRH), vasopressin (AVP), and oxytocin (OT) expressing neurons are critical as they can regulate both neuroendocrine and autonomic responses. Estradiol (E2) and testosterone (T) are well known reproductive hormones; however, they have also been shown to modulate stress reactivity. In rodent models, evidence shows that under some conditions E2 enhances stress activated adrenocorticotropic hormone (ACTH) and corticosterone secretion. In contrast, T decreases the gain of the HPA axis. The modulatory role of testosterone was originally thought to be via 5 alpha reduction to the potent androgen dihydrotestosterone (DHT) and its subsequent binding to the androgen receptor, whereas E2 effects were thought to be mediated by estrogen receptors alpha (ERalpha) and beta (ERbeta). However, DHT has been shown to be metabolized to the ERbeta agonist, 5α- androstane 3β, 17β Diol (3β-Diol). The actions of 3β-Diol on the HPA axis are mediated by ERbeta which inhibits the PVN response to stressors. In gonadectomized rats, ERbeta agonists reduce CORT and ACTH responses to restraint stress, an effect that is also present in wild-type but not ERbeta-knockout mice. The neurobiological mechanisms underlying the ability of ERbeta to alter HPA reactivity are not currently known. CRH, AVP, and OT have all been shown to be regulated by estradiol and recent studies indicate an important role of ERbeta in these regulatory processes. Moreover, activation of the CRH and AVP promoters has been shown to occur by 3β-Diol binding to ERbeta and this is thought to occur through alternate pathways of gene regulation. Based on available data, a novel and important role of 3β-Diol in

  16. A Role for the Androgen Metabolite, 5alpha androstane, 3beta, 17beta Diol (3b-DIol in the regulation of the hypothalamo-pituitary-adrenal axis.

    Directory of Open Access Journals (Sweden)

    Robert James Handa

    2011-11-01

    Full Text Available Activation of the hypothalamo-pituitary-adrenal (HPA axis is a basic reaction of animals to environmental perturbations that threaten homeostasis. These responses are ultimately regulated by neurons residing within the paraventricular nucleus of the hypothalamus (PVN. Within the PVN, corticotropin-releasing hormone (CRH, vasopressin (AVP and oxytocin (OT expressing neurons are critical as they can regulate both neuroendocrine and autonomic responses. Estradiol (E2 and testosterone (T are well known reproductive hormones, however, they have also been shown to modulate stress reactivity. In rodent models, evidence shows that under some conditions E2 enhances stress activated ACTH and corticosterone secretion. In contrast, T decreases the gain of the HPA axis. The modulatory role of testosterone was originally thought to be via 5 alpha reduction to the potent androgen, dihydrotestosterone, whereas E2 effects were thought to be mediated by both estrogen receptors alpha (ERα and beta (ERβ. However, DHT has been shown to be metabolized to the ERβ agonist, 5alpha- androstane 3beta,17beta diol (3b-Diol. The actions of 3β-Diol on the HPA axis are mediated by ERbeta which inhibits the PVN response to stressors. In gonadectomized rats, ERbeta agonists reduce CORT and ACTH responses to restraint stress, an effect that is also present in wild-type but not ERbeta knockout mice. The neurobiological mechanisms underlying the actions of ERbeta to alter HPA reactivity are not currently known. CRH, AVP and OT have all been shown to be regulated by estradiol and recent studies indicate an important role of ERbeta in these regulatory processes. Moreover, activation of the CRH and AVP promoters have been shown by 3β-Diol binding to ERbeta and this is thought to be through alternate pathways of gene regulation. Based on available data, a novel and important role for 3beta Diol in the regulation of the HPA axis is suggested.

  17. A Role for the Androgen Metabolite, 5alpha Androstane 3beta, 17beta Diol (3β-Diol) in the Regulation of the Hypothalamo-Pituitary–Adrenal Axis

    Science.gov (United States)

    Handa, Robert J.; Sharma, Dharmendra; Uht, Rosalie

    2011-01-01

    Activation of the hypothalamo-pituitary–adrenal (HPA) axis is a basic reaction of animals to environmental perturbations that threaten homeostasis. These responses are ultimately regulated by neurons residing within the paraventricular nucleus (PVN) of the hypothalamus. Within the PVN, corticotrophin-releasing hormone (CRH), vasopressin (AVP), and oxytocin (OT) expressing neurons are critical as they can regulate both neuroendocrine and autonomic responses. Estradiol (E2) and testosterone (T) are well known reproductive hormones; however, they have also been shown to modulate stress reactivity. In rodent models, evidence shows that under some conditions E2 enhances stress activated adrenocorticotropic hormone (ACTH) and corticosterone secretion. In contrast, T decreases the gain of the HPA axis. The modulatory role of testosterone was originally thought to be via 5 alpha reduction to the potent androgen dihydrotestosterone (DHT) and its subsequent binding to the androgen receptor, whereas E2 effects were thought to be mediated by estrogen receptors alpha (ERalpha) and beta (ERbeta). However, DHT has been shown to be metabolized to the ERbeta agonist, 5α- androstane 3β, 17β Diol (3β-Diol). The actions of 3β-Diol on the HPA axis are mediated by ERbeta which inhibits the PVN response to stressors. In gonadectomized rats, ERbeta agonists reduce CORT and ACTH responses to restraint stress, an effect that is also present in wild-type but not ERbeta-knockout mice. The neurobiological mechanisms underlying the ability of ERbeta to alter HPA reactivity are not currently known. CRH, AVP, and OT have all been shown to be regulated by estradiol and recent studies indicate an important role of ERbeta in these regulatory processes. Moreover, activation of the CRH and AVP promoters has been shown to occur by 3β-Diol binding to ERbeta and this is thought to occur through alternate pathways of gene regulation. Based on available data, a novel and important role of 3

  18. Down-Regulation of Notch-1 Is Associated With Akt and FoxM1 in Inducing Cell Growth Inhibition and Apoptosis in Prostate Cancer Cells

    OpenAIRE

    Wang, Zhiwei; Li, Yiwei; Ahmad, Aamir; Banerjee, Sanjeev; Azmi, Asfar S; Kong, Dejuan; Wojewoda, Christine; Miele, Lucio; Sarkar, Fazlul H

    2011-01-01

    Although many studies have been done to uncover the mechanisms by which down-regulation of Notch-1 exerts its anti-tumor activity against a variety of human malignancies, the precise molecular mechanisms remain unclear. In the present study, we investigated the cellular consequence of Notch-1 down-regulation and also assessed the molecular consequence of Notch-1-mediated alterations of its downstream targets on cell viability and apoptosis in prostate cancer (PCa) cells. We found that the dow...

  19. MiR-128b is down-regulated in gastric cancer and negatively regulates tumour cell viability by targeting PDK1/Akt/NF-κB axis

    Indian Academy of Sciences (India)

    Ling Zhang; Jun Lei; Zi-Ling Fang; Jian-Ping Xiong

    2016-03-01

    Gastric cancer (GC) is the fourth most prevalent type of cancer worldwide, which is usually caused by the interaction between environmental and genetic factors, or epigenetic aspects. Referring to the non-coding RNAs, miR-128b has been reported to be associated with many tumour cases, and exerts distinct functions in different types of cancers. However, the function of miR-128b in GC onset and progression largely remains unknown. In the present study, we found that miR-128b expression was down-regulated in tissues from 18 GC patients and 3 carcinoma cell lines. In turn, over-expression of miR-128b suppressed GC cell proliferation, invasion and promoted apoptosis. Moreover, miR-128b was predicted to bind the 3'UTR of PDK1 gene using bioinformatic target-screening tools. Accordingly, ectopic expression of miR-128b inhibited the PDK1 expression at both transcriptional and post-transcriptional levels, and furthermore, the expression of gene tailed by the 3′UTR of PDK1 gene was significantly decreased in a dualluciferase reporter assay, suggesting that PDK1 was a direct target of miR-128b in GC cells. In the conditon of miR-128b over-expression, we also observed spontaneous inactivation of the Akt/NF-κB signalling, implying PDK1 was a potential regulator of this pathway. In conclusion, our study shed some novel light on miR-128b-PDK1/Akt/NF-κB axis on GC progression.

  20. Androgen receptor non-nuclear regulation of prostate cancer cell invasion mediated by Src and matriptase.

    Science.gov (United States)

    Zarif, Jelani C; Lamb, Laura E; Schulz, Veronique V; Nollet, Eric A; Miranti, Cindy K

    2015-03-30

    Castration-resistant prostate cancers still depend on nuclear androgen receptor (AR) function despite their lack of dependence on exogenous androgen. Second generation anti-androgen therapies are more efficient at blocking nuclear AR; however resistant tumors still develop. Recent studies indicate Src is highly active in these resistant tumors. By manipulating AR activity in several different prostate cancer cell lines through RNAi, drug treatment, and the use of a nuclear-deficient AR mutant, we demonstrate that androgen acting on cytoplasmic AR rapidly stimulates Src tyrosine kinase via a non-genomic mechanism. Cytoplasmic AR, acting through Src enhances laminin integrin-dependent invasion. Active Matriptase, which cleaves laminin, is elevated within minutes after androgen stimulation, and is subsequently shed into the medium. Matriptase activation and shedding induced by cytoplasmic AR is dependent on Src. Concomitantly, CDCP1/gp140, a Matriptase and Src substrate that controls integrin-based migration, is activated. However, only inhibition of Matriptase, but not CDCP1, suppresses the AR/Src-dependent increase in invasion. Matriptase, present in conditioned medium from AR-stimulated cells, is sufficient to enhance invasion in the absence of androgen. Thus, invasion is stimulated by a rapid but sustained increase in Src activity, mediated non-genomically by cytoplasmic AR, leading to rapid activation and shedding of the laminin protease Matriptase.

  1. Regulation of cholesterol 25-hydroxylase expression by vitamin D3 metabolites in human prostate stromal cells

    International Nuclear Information System (INIS)

    Vitamin D3 plays an important role in the control of cell proliferation and differentiation. Cholesterol 25-hydroxylase (CH25H) is an enzyme converting cholesterol into 25-hydroxycholesterol. Vitamin D3 as well as 25-hydroxycholesterol has been shown to inhibit cell growth and induce cell apoptosis. Here we show that 10 nM 1α,25(OH)2D3 and 500 nM 25OHD3 upregulate CH25H mRNA expression in human primary prostate stromal cells (P29SN). Protein synthesis inhibitor cycloheximide does not block 1α,25(OH)2D3 mediated upregulation of CH25H mRNA. Transcription inhibitor actinomycin D blocks basal level as well as 1α,25(OH)2D3 induced CH25H mRNA expression. 1α,25(OH)2D3 has no effect on CH25H mRNA stability. 25-Hydroxycholesterol significantly decreased the P29SN cell number. A CH25H enzyme inhibitor, desmosterol, increases basal cell number but has no significant effect on vitamin D3 treated cells. Our data suggest that ch25h could be a vitamin D3 target gene and may partly mediate anti-proliferative action of vitamin D3 in human primary prostate stromal cells

  2. Elevated expression of prostate cancer-associated genes is linked to down-regulation of microRNAs

    International Nuclear Information System (INIS)

    Recent evidence suggests that the prostate cancer (PCa)-specific up-regulation of certain genes such as AMACR, EZH2, PSGR, PSMA and TRPM8 could be associated with an aberrant expression of non-coding microRNAs (miRNA). In silico analyses were used to search for miRNAs being putative regulators of PCa-associated genes. The expression of nine selected miRNAs (hsa-miR-101, -138, -186, -224, -26a, -26b, -374a, -410, -660) as well as of the aforementioned PCa-associated genes was analyzed by quantitative PCR using 50 malignant (Tu) and matched non-malignant (Tf) tissue samples from prostatectomy specimens as well as 30 samples from patients with benign prostatic hyperplasia (BPH). Then, correlations between paired miRNA and target gene expression levels were analyzed. Furthermore, the effect of exogenously administered miR-26a on selected target genes was determined by quantitative PCR and Western Blot in various PCa cell lines. A luciferase reporter assay was used for target validation. The expression of all selected miRNAs was decreased in PCa tissue samples compared to either control group (Tu vs Tf: -1.35 to -5.61-fold; Tu vs BPH: -1.17 to -5.49-fold). The down-regulation of most miRNAs inversely correlated with an up-regulation of their putative target genes with Spearman correlation coefficients ranging from -0.107 to -0.551. MiR-186 showed a significantly diminished expression in patients with non-organ confined PCa and initial metastases. Furthermore, over-expression of miR-26a reduced the mRNA and protein expression of its potential target gene AMACR in vitro. Using the luciferase reporter assay AMACR was validated as new target for miR-26a. The findings of this study indicate that the expression of specific miRNAs is decreased in PCa and inversely correlates with the up-regulation of their putative target genes. Consequently, miRNAs could contribute to oncogenesis and progression of PCa via an altered miRNA-target gene-interaction

  3. Hypothalamic-pituitary-adrenal axis activation and immune regulation in heat-stressed sheep after supplementation with polyunsaturated fatty acids.

    Science.gov (United States)

    Caroprese, M; Ciliberti, M G; Annicchiarico, G; Albenzio, M; Muscio, A; Sevi, A

    2014-07-01

    The aim of this study was to assess the effects of supplementation with polyunsaturated fatty acids from different sources on immune regulation and hypothalamic-pituitary-adrenal (HPA) axis activation in heat-stressed sheep. The experiment was carried out during the summer 2012. Thirty-two Comisana ewes were divided into 4 groups (8 sheep/group): (1) supplemented with whole flaxseed (FS); (2) supplemented with Ascophyllum nodosum (AG); (3) supplemented with a combination of flaxseed and A. nodosum (FS+AG); and (4) control (C; no supplementation). On d 22 of the experiment, cortisol concentrations in sheep blood were measured after an injection of ACTH. Cellular immune response was evaluated by intradermic injection of phytohemagglutinin (PHA) at 0, 15, and 30 d of the trial. Humoral response to ovalbumin (OVA) was measured at 0, 15, and 30 d. At 0, 15, and 30 d of the experiment, blood samples were collected from each ewe to determine production of T-helper (Th)1 cytokines (IL-12 and IFN-γ), and Th2 cytokines (IL-10, IL-4, IL-13), and concentrations of heat shock proteins (HSP) 70 and 90. Ewes supplemented with flaxseed alone had greater cortisol concentrations and a longer-lasting cell-mediated immune response compared with ewes in the control and other groups. Anti-OVA IgG concentrations increased in all groups throughout the trial, even though ewes in the FS+AG group had the lowest anti-OVA IgG concentrations at 15 d. The level of IL-10 increased in all groups throughout the experiment; the FS+AG group had the lowest IL-13 concentration at 15 and 30 d. The concentration of HSP 70 increased in AG ewes at the end of the experiment and decreased in FS ewes, whereas that of HSP 90 increased in FS ewes compared with FS+AG ewes. Flaxseed supplementation was found to influence in vivo HPA activation in heat-stressed sheep, resulting in increased cortisol concentrations, probably to meet increased energy demand for thermoregulation. Flaxseed supplementation also

  4. Transcriptional and post-transcriptional regulation of Sprouty1, a receptor tyrosine kinase inhibitor in prostate cancer.

    Science.gov (United States)

    Darimipourain, M; Wang, S; Ittmann, M; Kwabi-Addo, B

    2011-12-01

    Sprouty1 (Spry1) is a negative regulator of fibroblast growth factor signaling with a potential tumor suppressor function in prostate cancer (PCa). Spry1 is downregulated in human PCa, and Spry1 expression can markedly inhibit PCa proliferation in vitro. We have reported DNA methylation as a mechanism for controlling Spry1 expression. However, promoter methylation does not seem to explain gene silencing in all PCa cases studied to suggest other mechanisms of gene inactivation, such as alterations in trans-acting factors and/or post-transcriptional activity may be responsible for the decreased expression in those cases. Binding sites for Wilm's tumor (WT1) transcription factors EGR1, EGR3 and WTE are highly conserved between the mouse and human Spry1 promoter regions, suggesting an evolutionary conserved mechanism(s) involving WT1 and EGR in Spry1 regulation. Spry1 mRNA contains multiple microRNA (miRNA) binding sites in its 3'UTR region suggesting post-transcriptional control. We demonstrate that Spry1 is a target for miR-21-mediated gene silencing. miRNA-based therapeutic approaches to treat cancer are emerging. Spry1 is highly regulated by miRNAs and could potentially be an excellent candidate for such approaches. PMID:21826097

  5. 动物GH/IGF-Ⅰ轴调控机制的研究进展%Advances on the Regulation Mechanism of Growth Hormone/IGF- Ⅰ Axis

    Institute of Scientific and Technical Information of China (English)

    顾志良; 王慧娟; 郁建锋

    2011-01-01

    生长轴是动物体内下丘脑—垂体—靶器官一系列激素及其受体所组成的神经内分泌系统.通过提高生长轴中生长激素(GH)和胰岛素样生长因子-Ⅰ (IGF-Ⅰ)水平,促进增重、提高饲料转化率和改善肉品质,是畜禽生长调控的一种新途径.GH通过IGF-Ⅰ介导调节动物生长和细胞分化等,文章综述了GH/IGF-Ⅰ轴的组成、功能,以及GH调控IGF-Ⅰ表达的分子机理.%The growth axis is a neuroendocrine system, which is composed of series of hormones and their receptors from the hypothalamus-pituitary-target organ in xrivo of animals. Increasing the GH and IGF- I levels in the growth axis, to promote weight gain, feed conversion rate and improve meat quality, which is a new approach of animal growth regulation. GH mediated by IGF- I regulates animal growth and cell differentiation. We will discuss the constitution and function of GH/IGF-I axis, and mechanism of growth hormone regulation of IGF- I expression in this review.

  6. p38MAPK activation is involved in androgen-independent proliferation of human prostate cancer cells by regulating IL-6 secretion

    International Nuclear Information System (INIS)

    Increased levels of serum interleukin-6 (IL-6) are frequently observed in patients with advanced, hormone-refractory prostate cancer. However, the precise mechanism of IL-6 regulation is still largely unknown. Since prostate cancer gradually progresses to an androgen-independent state despite the stress caused by various therapeutic agents, we hypothesized the stress-activated protein kinases (SAPKs) involvement in androgen-independent growth or IL-6 secretion of prostate cancer cells. Using PC-3 and DU145 human prostate cancer cells, we analyzed the role of SAPKs in IL-6 mediated cell growth and found that the p38MAPK and JNK are involved in androgen-independent cancer cell growth. Furthermore, IL-6 secretion by PC-3 and DU145 cells was significantly suppressed by SAPKs inhibitor, especially by p38MAPK inhibitor SB203580, but not by JNK inhibitor SP600125 nor by MEK inhibitor, PD98059. These results raised the possibility that the IL-6 mediated androgen-independent proliferation of PC-3 and DU145 cells is regulated at least partly via SAPKs signaling pathway especially through p38MAPK activation

  7. Juglone, isolated from Juglans mandshurica Maxim, induces apoptosis via down-regulation of AR expression in human prostate cancer LNCaP cells.

    Science.gov (United States)

    Xu, Huali; Yu, Xiaofeng; Qu, Shaochun; Sui, Dayun

    2013-06-15

    Juglone is a natural compound which has been isolated from Juglans mandshurica Maxim. Recent studies have shown that juglone had various pharmacological effects such as anti-viral, anti-bacterial and anti-cancer. However, its anti-cancer activity on human prostate cancer LNCaP cell has not been examined. Thus, the current study was designed to elucidate the molecular mechanism of apoptosis induced by juglone in androgen-sensitive prostate cancer LNCaP cells. MTT assay was performed to examine the anti-proliferative effect of juglone. Occurrence of apoptosis was detected by Hoechst 33342 staining and flow cytometry in LNCaP cells treated with juglone for 24h. The result shown that juglone inhibited the growth of LNCaP cells in a dose-dependent manner. Morphological changes of apoptotic body formation after juglone treatment were observed by Hoechst 33342 staining. This apoptotic induction was associated with loss of mitochondrial membrane potential, and caspase-3, -9 activation. Moreover, we found that juglone significantly inhibited the expression levels of androgen receptor (AR) and prostate-specific antigen (PSA) in a dose-dependent manner, as well as abrogated up-regulation of AR and PSA genes with and/or without dihydrotestosterone (DHT). Take together, our results demonstrated that juglone might induce the apoptosis in LNCaP cell via down-regulation of AR expression. Therefore, our results indicated that juglone may be a potential candidate of drug for androgen-sensitive prostate cancer.

  8. The PPAR{gamma} ligand ciglitazone regulates androgen receptor activation differently in androgen-dependent versus androgen-independent human prostate cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Moss, Patrice E.; Lyles, Besstina E.; Stewart, LaMonica V., E-mail: lstewart@mmc.edu

    2010-12-10

    The androgen receptor (AR) regulates growth and progression of androgen-dependent as well as androgen-independent prostate cancer cells. Peroxisome proliferator-activated receptor gamma (PPAR{gamma}) agonists have been reported to reduce AR activation in androgen-dependent LNCaP prostate cancer cells. To determine whether PPAR{gamma} ligands are equally effective at inhibiting AR activity in androgen-independent prostate cancer, we examined the effect of the PPAR{gamma} ligands ciglitazone and rosiglitazone on C4-2 cells, an androgen- independent derivative of the LNCaP cell line. Luciferase-based reporter assays and Western blot analysis demonstrated that PPAR{gamma} ligand reduced dihydrotestosterone (DHT)-induced increases in AR activity in LNCaP cells. However, in C4-2 cells, these compounds increased DHT-induced AR driven luciferase activity. In addition, ciglitazone did not significantly alter DHT-mediated increases in prostate specific antigen (PSA) protein or mRNA levels within C4-2 cells. siRNA-based experiments demonstrated that the ciglitazone-induced regulation of AR activity observed in C4-2 cells was dependent on the presence of PPAR{gamma}. Furthermore, overexpression of the AR corepressor cyclin D1 inhibited the ability of ciglitazone to induce AR luciferase activity in C4-2 cells. Thus, our data suggest that both PPAR{gamma} and cyclin D1 levels influence the ability of ciglitazone to differentially regulate AR signaling in androgen-independent C4-2 prostate cancer cells.

  9. The Hippo Pathway Effector YAP Regulates Motility, Invasion, and Castration-Resistant Growth of Prostate Cancer Cells

    OpenAIRE

    Lin ZHANG; Yang, Shuping; Chen, Xingcheng; Stauffer, Seth; Yu, Fang; Lele, Subodh M.; Fu, Kai; Datta, Kaustubh; Palermo, Nicholas; Chen, Yuanhong; Dong, Jixin

    2015-01-01

    Yes-associated protein (YAP) is an effector of the Hippo tumor suppressor pathway. The functional significance of YAP in prostate cancer has remained elusive. In this study, we first show that enhanced expression of YAP is able to transform immortalized prostate epithelial cells and promote migration and invasion in both immortalized and cancerous prostate cells. We found that YAP mRNA was upregulated in androgen-insensitive prostate cancer cells (LNCaP-C81 and LNCaP-C4-2 cells) compared to t...

  10. HDAC6 regulates androgen receptor hypersensitivity and nuclear localization via modulating Hsp90 acetylation in castration-resistant prostate cancer.

    Science.gov (United States)

    Ai, Junkui; Wang, Yujuan; Dar, Javid A; Liu, June; Liu, Lingqi; Nelson, Joel B; Wang, Zhou

    2009-12-01

    The development of castration-resistant prostate cancer (PCa) requires that under castration conditions, the androgen receptor (AR) remains active and thus nuclear. Heat shock protein 90 (Hsp90) plays a key role in androgen-induced and -independent nuclear localization and activation of AR. Histone deacetylase 6 (HDAC6) is implicated, but has not been proven, in regulating AR activity via modulating Hsp90 acetylation. Here, we report that knockdown of HDAC6 in C4-2 cells using short hairpin RNA impaired ligand-independent nuclear localization of endogenous AR and inhibited PSA expression and cell growth in the absence or presence of dihydrotestosterone (DHT). The dose-response curve of DHT-stimulated C4-2 colony formation was shifted by shHDAC6 such that approximately 10-fold higher concentration of DHT is required, indicating a requirement for HDAC6 in AR hypersensitivity. HDAC6 knockdown also inhibited C4-2 xenograft tumor establishment in castrated, but not in testes-intact, nude mice. Studies using HDAC6-deficient mouse embryonic fibroblasts cells showed that inhibition of AR nuclear localization by HDAC6 knockdown can be largely alleviated by expressing a deacetylation mimic Hsp90 mutant. Taken together, our studies suggest that HDAC6 regulates AR hypersensitivity and nuclear localization, mainly via modulating HSP90 acetylation. Targeting HDAC6 alone or in combination with other therapeutic approaches is a promising new strategy for prevention and/or treatment of castration-resistant PCa.

  11. Prostate tumor-derived exosomes down-regulate NKG2D expression on natural killer cells and CD8+ T cells: mechanism of immune evasion.

    Directory of Open Access Journals (Sweden)

    Marie Lundholm

    Full Text Available Tumor-derived exosomes, which are nanometer-sized extracellular vesicles of endosomal origin, have emerged as promoters of tumor immune evasion but their role in prostate cancer (PC progression is poorly understood. In this study, we investigated the ability of prostate tumor-derived exosomes to downregulate NKG2D expression on natural killer (NK and CD8+ T cells. NKG2D is an activating cytotoxicity receptor whose aberrant loss in cancer plays an important role in immune suppression. Using flow cytometry, we found that exosomes produced by human PC cells express ligands for NKG2D on their surface. The NKG2D ligand-expressing prostate tumor-derived exosomes selectively induced downregulation of NKG2D on NK and CD8+ T cells in a dose-dependent manner, leading to impaired cytotoxic function in vitro. Consistent with these findings, patients with castration-resistant PC (CRPC showed a significant decrease in surface NKG2D expression on circulating NK and CD8+ T cells compared to healthy individuals. Tumor-derived exosomes are likely involved in this NKG2D downregulation, since incubation of healthy lymphocytes with exosomes isolated from serum or plasma of CRPC patients triggered downregulation of NKG2D expression in effector lymphocytes. These data suggest prostate tumor-derived exosomes as down-regulators of the NKG2D-mediated cytotoxic response in PC patients, thus promoting immune suppression and tumor escape.

  12. Differential regulation of glutathione S—transferase Yb1 mRNA levels in rat prostate,liver and brain by androgen

    Institute of Scientific and Technical Information of China (English)

    ZHANGYUAN; CHAWNSHANGCHANG; 等

    1995-01-01

    Northern blot analysis of glutathione S-transferase (GST)Yb1 mRNA in different tissues of male and female rate revealed that its tissue-specific transcription patterns were highly sex hormone related.Although the GST Yb1 mRNA could be detected in most of the tissues examined at various levels,the highest abundance was observed in the ventral prostate,uterus and liver,which were the main the ventral prostate,uterus and liver,which were the main target tissue for androgen,estrogen and glucocorticoid respectively.The effect of androgen on the transcription of GST YB1 was also tissue-specific.Since androgen with drawal by castration caused the up-regulation of GST Yb1 mRNA in the ventral prostate but down-regulation in the liver and no effect in the brain,evalution of this system for studying the regulation mechanisms of gene expression by which androgen exerts its differential effects has been discussed.

  13. The Carboxyl Tail of Connexin32 Regulates Gap Junction Assembly in Human Prostate and Pancreatic Cancer Cells*

    Science.gov (United States)

    Katoch, Parul; Mitra, Shalini; Ray, Anuttoma; Kelsey, Linda; Roberts, Brett J.; Wahl, James K.; Johnson, Keith R.; Mehta, Parmender P.

    2015-01-01

    Connexins, the constituent proteins of gap junctions, are transmembrane proteins. A connexin (Cx) traverses the membrane four times and has one intracellular and two extracellular loops with the amino and carboxyl termini facing the cytoplasm. The transmembrane and the extracellular loop domains are highly conserved among different Cxs, whereas the carboxyl termini, often called the cytoplasmic tails, are highly divergent. We have explored the role of the cytoplasmic tail of Cx32, a Cx expressed in polarized and differentiated cells, in regulating gap junction assembly. Our results demonstrate that compared with the full-length Cx32, the cytoplasmic tail-deleted Cx32 is assembled into small gap junctions in human pancreatic and prostatic cancer cells. Our results further document that the expression of the full-length Cx32 in cells, which express the tail-deleted Cx32, increases the size of gap junctions, whereas the expression of the tail-deleted Cx32 in cells, which express the full-length Cx32, has the opposite effect. Moreover, we show that the tail is required for the clustering of cell-cell channels and that in cells expressing the tail-deleted Cx32, the expression of cell surface-targeted cytoplasmic tail alone is sufficient to enhance the size of gap junctions. Our live-cell imaging data further demonstrate that gap junctions formed of the tail-deleted Cx32 are highly mobile compared with those formed of full-length Cx32. Our results suggest that the cytoplasmic tail of Cx32 is not required to initiate the assembly of gap junctions but for their subsequent growth and stability. Our findings suggest that the cytoplasmic tail of Cx32 may be involved in regulating the permeability of gap junctions by regulating their size. PMID:25548281

  14. Endoglin-mediated suppression of prostate cancer invasion is regulated by activin and bone morphogenetic protein type II receptors.

    Directory of Open Access Journals (Sweden)

    Michael J Breen

    Full Text Available Mortality from prostate cancer (PCa is due to the formation of metastatic disease. Understanding how that process is regulated is therefore critical. We previously demonstrated that endoglin, a type III transforming growth factor β (TGFβ superfamily receptor, suppresses human PCa cell invasion and metastasis. Endoglin-mediated suppression of invasion was also shown by us to be dependent upon the type I TGFβ receptor, activin receptor-like kinase 2 (ALK2, and the downstream effector, Smad1. In this study we demonstrate for the first time that two type II TGFβ receptors are required for endoglin-mediated suppression of invasion: activin A receptor type IIA (ActRIIA and bone morphogenetic protein receptor type II (BMPRII. Downstream signaling through these receptors is predominantly mediated by Smad1. ActRIIA stimulates Smad1 activation in a kinase-dependent manner, and this is required for suppression of invasion. In contrast BMPRII regulates Smad1 in a biphasic manner, promoting Smad1 signaling through its kinase domain but suppressing it through its cytoplasmic tail. BMPRII's Smad1-regulatory effects are dependent upon its expression level. Further, its ability to suppress invasion is independent of either kinase function or tail domain. We demonstrate that ActRIIA and BMPRII physically interact, and that each also interacts with endoglin. The current findings demonstrate that both BMPRII and ActRIIA are necessary for endoglin-mediated suppression of human PCa cell invasion, that they have differential effects on Smad1 signaling, that they make separate contributions to regulation of invasion, and that they functionally and physically interact.

  15. Triptolide inhibits the proliferation of prostate cancer cells and down-regulates SUMO-specific protease 1 expression.

    Directory of Open Access Journals (Sweden)

    Weiwei Huang

    Full Text Available Recently, traditional Chinese medicine and medicinal herbs have attracted more attentions worldwide for its anti-tumor efficacy. Celastrol and Triptolide, two active components extracted from the Chinese herb Tripterygium wilfordii Hook F (known as Lei Gong Teng or Thunder of God Vine, have shown anti-tumor effects. Celastrol was identified as a natural 26 s proteasome inhibitor which promotes cell apoptosis and inhibits tumor growth. The effect and mechanism of Triptolide on prostate cancer (PCa is not well studied. Here we demonstrated that Triptolide, more potent than Celastrol, inhibited cell growth and induced cell death in LNCaP and PC-3 cell lines. Triptolide also significantly inhibited the xenografted PC-3 tumor growth in nude mice. Moreover, Triptolide induced PCa cell apoptosis through caspases activation and PARP cleavage. Unbalance between SUMOylation and deSUMOylation was reported to play an important role in PCa progression. SUMO-specific protease 1 (SENP1 was thought to be a potential marker and therapeutical target of PCa. Importantly, we observed that Triptolide down-regulated SENP1 expression in both mRNA and protein levels in dose-dependent and time-dependent manners, resulting in an enhanced cellular SUMOylation in PCa cells. Meanwhile, Triptolide decreased AR and c-Jun expression at similar manners, and suppressed AR and c-Jun transcription activity. Furthermore, knockdown or ectopic SENP1, c-Jun and AR expression in PCa cells inhibited the Triptolide anti-PCa effects. Taken together, our data suggest that Triptolide is a natural compound with potential therapeutic value for PCa. Its anti-tumor activity may be attributed to mechanisms involving down-regulation of SENP1 that restores SUMOylation and deSUMOyaltion balance and negative regulation of AR and c-Jun expression that inhibits the AR and c-Jun mediated transcription in PCa.

  16. Bioactive compounds from Paecilomyces tenuipes regulating the function of the hypothalamo-hypophyseal system axis in chronic unpredictable stress rats

    Institute of Scientific and Technical Information of China (English)

    YIN Yan-yan; MING Liang; ZHENG Li-fang; KAN Hong-wei; LI Chun-ru; LI Wei-ping

    2007-01-01

    Background A bioactive compound from Paecilomyces tenuipes (BGPT) has an inhibitory effect on monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B) in vitro and in vivo, which indicates BCPT may be a potential antidepressant. In this study we aimed to study the antidepressant effects of BCPT in the chronic unpredictable stress(CUS) model in rats and explore underlying mechanisms in the hypothalamic-pituitary-adrenal (HPA) axis.Methods The antidepressant effects of BCPT were studied in the chronic unpredictable stress model in rats. Animals were housed isolated, except the control group. Rats were exposed daily to different random stressors from day 1 to 21.Awarding response was detected by calculating the 24-hour consumption of sucrose water. Cortisol (CORT) and adrenocorticotropic hormone (ATCH) contents in serum and arginine vasopressin (AVP) contents in the pituitary body were detected by radio immunoassays. Total RNA of hippocampus or hypothalamus was extracted and subjected to reverse transcription-polymerase chain reaction (RT-PCR) for the measurement of corticotrophin releasing hormone(CRH) mRNA or mineralocorticoid receptor (MR) mRNA and glucocorticoid receptor (GR) mRNA levels. Statistical analyses were performed using one way analysis of variance (ANOVA) followed by Student-Newman-Keuls (SNK) test.Results Chronic unpredictable stress resulted in reduction of sensitivity to reward and abnormality in the HPA axis in the animal model. BCPT improved the reward reaction as measured by increasing sucrose consumption, remarkably reduced serum CORT and ACTH levels and the AVP content in the pituitary body in the CUS-treated rats, decreased the expression of CRH mRNA, enhanced the expression of hippocampus MR mRNA, GR mRNA and decreased the ratio of MR/GR.Conclusions BCPT has potentially antidepressant-like activity and normalized the HPA axis hyperactivity in a CUS model of depression in rats. This may be an important mechanism of its antidepressant effect.

  17. The Nrf1 and Nrf2 Balance in Oxidative Stress Regulation and Androgen Signaling in Prostate Cancer Cells

    Energy Technology Data Exchange (ETDEWEB)

    Schultz, Michelle A. [Department of Pharmacology, Tulane University Medical Center, 1430 Tulane Avenue, New Orleans, LA 70112 (United States); Abdel-Mageed, Asim B. [Department of Urology, Tulane University Medical Center, 1430 Tulane Avenue, New Orleans, LA 70112 (United States); Mondal, Debasis, E-mail: dmondal@tulane.edu [Department of Pharmacology, Tulane University Medical Center, 1430 Tulane Avenue, New Orleans, LA 70112 (United States)

    2010-06-21

    Reactive oxygen species (ROS) signaling has recently sparked a surge of interest as being the molecular underpinning for cancer cell survival, but the precise mechanisms involved have not been completely elucidated. This review covers the possible roles of two ROS-induced transcription factors, Nrf1 and Nrf2, and the antioxidant proteins peroxiredoxin-1 (Prx-1) and Thioredoxin-1 (Txn-1) in modulating AR expression and signaling in aggressive prostate cancer (PCa) cells. In androgen independent (AI) C4-2B cells, in comparison to the parental androgen dependent (AD) LNCaP cells, we present evidence of high Nrf1 and Prx-1 expression and low Nrf2 expression in these aggressive PCa cells. Furthermore, in DHT treated C4-2B cells, increased expression of the p65 (active) isoform of Nrf1 correlated with enhanced AR transactivation. Our findings implicate a crucial balance of Nrf1 and Nrf2 signaling in regulating AR activity in AI-PCa cells. Here we will discuss how understanding the mechanisms by which oxidative stress may affect AR signaling may aid in developing novel therapies for AI-PCa.

  18. Regulation of the pentose phosphate pathway by an androgen receptor-mTOR-mediated mechanism and its role in prostate cancer cell growth.

    Science.gov (United States)

    Tsouko, E; Khan, A S; White, M A; Han, J J; Shi, Y; Merchant, F A; Sharpe, M A; Xin, L; Frigo, D E

    2014-05-26

    Cancer cells display an increased demand for glucose. Therefore, identifying the specific aspects of glucose metabolism that are involved in the pathogenesis of cancer may uncover novel therapeutic nodes. Recently, there has been a renewed interest in the role of the pentose phosphate pathway in cancer. This metabolic pathway is advantageous for rapidly growing cells because it provides nucleotide precursors and helps regenerate the reducing agent NADPH, which can contribute to reactive oxygen species (ROS) scavenging. Correspondingly, clinical data suggest glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the pentose phosphate pathway, is upregulated in prostate cancer. We hypothesized that androgen receptor (AR) signaling, which plays an essential role in the disease, mediated prostate cancer cell growth in part by increasing flux through the pentose phosphate pathway. Here, we determined that G6PD, NADPH and ribose synthesis were all increased by AR signaling. Further, this process was necessary to modulate ROS levels. Pharmacological or molecular inhibition of G6PD abolished these effects and blocked androgen-mediated cell growth. Mechanistically, regulation of G6PD via AR in both hormone-sensitive and castration-resistant models of prostate cancer was abolished following rapamycin treatment, indicating that AR increased flux through the pentose phosphate pathway by the mammalian target of rapamycin (mTOR)-mediated upregulation of G6PD. Accordingly, in two separate mouse models of Pten deletion/elevated mTOR signaling, Pb-Cre;Pten(f/f) and K8-CreER(T2);Pten(f/f), G6PD levels correlated with prostate cancer progression in vivo. Importantly, G6PD levels remained high during progression to castration-resistant prostate cancer. Taken together, our data suggest that AR signaling can promote prostate cancer through the upregulation of G6PD and therefore, the flux of sugars through the pentose phosphate pathway. Hence, these findings support a

  19. Prostate cancer

    Energy Technology Data Exchange (ETDEWEB)

    Murphy, G.P.; Kuss, R., Khoury, S.; Chatelain, C.; Denis, L.

    1987-01-01

    This book contains over 70 selections. Some of the titles are: Place of the Computed Tomography in the Staging of Prostatic Cancer; Magnetic Resonance Imaging (MRI) in Staging of the Prostatic Cancer; Magnetic Resonance Imaging of the Prostate; Long-Term Results in Radiotherapy of Prostatic Cancer; Interstitial Irradiation Using I-125 Seeds; and Treatment of Cancer of the Prostate by Use of Physiotherapy: Long-Term Results.

  20. Cyclin-dependent kinase 5 acts as a critical determinant of AKT-dependent proliferation and regulates differential gene expression by the androgen receptor in prostate cancer cells.

    Science.gov (United States)

    Lindqvist, Julia; Imanishi, Susumu Y; Torvaldson, Elin; Malinen, Marjo; Remes, Mika; Örn, Fanny; Palvimo, Jorma J; Eriksson, John E

    2015-06-01

    Contrary to cell cycle-associated cyclin-dependent kinases, CDK5 is best known for its regulation of signaling processes in differentiated cells and its destructive activation in Alzheimer's disease. Recently, CDK5 has been implicated in a number of different cancers, but how it is able to stimulate cancer-related signaling pathways remains enigmatic. Our goal was to study the cancer-promoting mechanisms of CDK5 in prostate cancer. We observed that CDK5 is necessary for proliferation of several prostate cancer cell lines. Correspondingly, there was considerable growth promotion when CDK5 was overexpressed. When examining the reasons for the altered proliferation effects, we observed that CDK5 phosphorylates S308 on the androgen receptor (AR), resulting in its stabilization and differential expression of AR target genes including several growth-priming transcription factors. However, the amplified cell growth was found to be separated from AR signaling, further corroborated by CDK5-dependent proliferation of AR null cells. Instead, we found that the key growth-promoting effect was due to specific CDK5-mediated AKT activation. Down-regulation of CDK5 repressed AKT phosphorylation by altering its intracellular localization, immediately followed by prominent cell cycle inhibition. Taken together, these results suggest that CDK5 acts as a crucial signaling hub in prostate cancer cells by controlling androgen responses through AR, maintaining and accelerating cell proliferation through AKT activation, and releasing cell cycle breaks. PMID:25851605

  1. A potential kidney-bone axis involved in the rapid minute-to-minute regulation of plasma Ca2+

    DEFF Research Database (Denmark)

    Nordholm, Anders; Mace, Maria L; Gravesen, Eva;

    2015-01-01

    BACKGROUND: Understanding the regulation of mineral homeostasis and function of the skeleton as buffer for Calcium and Phosphate has regained new interest with introduction of the syndrome "Chronic Kidney Disease-Mineral and Bone Disorder"(CKD-MBD). The very rapid minute-to-minute regulation...

  2. Marsdenia tenacissima extract suppresses A549 cell migration through regulation of CCR5-CCL5 axis, Rho C, and phosphorylated FAK.

    Science.gov (United States)

    Lin, Sen-Sen; Li, Fang-Fang; Sun, Li; Fan, Wei; Gu, Ming; Zhang, Lu-Yong; Qin, Song; Yuan, Sheng-Tao

    2016-03-01

    Marsdenia tenacissima, a traditional Chinese medicine, is long been used to treat various diseases including asthma, cancer, trachitis, tonsillitis, pharyngitis, cystitis, and pneumonia. Although Marsdenia tenacissima has been demonstrated to have strong anti-tumor effects against primary tumors, its effect on cancer metastasis remains to be defined, and the molecular mechanism underlying the anti-metastatic effect is unknown. In the present study, we investigated the effects of XAP (an extract of Marsdenia tenacissima) on A549 lung cancer cell migration and explored the role of CCR5-CCL5 axis in the anti-metastatic effects of XAP. Our resutls showed that XAP inhibited A549 lung cancer cell migration and invasion in a dose-dependent manner. The protein levels of CCR5, but not CCR9 and CXCR4, were decreased by XAP. The secretion of CCL5, the ligand of CCR5, was reduced by XAP. XAP down-regulated Rho C expression and FAK phosphorylation. In conclusion, XAP inhibited A549 cell migration and invasion through down-regulation of CCR5-CCL5 axis, Rho C, and FAK. PMID:27025367

  3. Marsdenia tenacissima extract suppresses A549 cell migration through regulation of CCR5-CCL5 axis, Rho C, and phosphorylated FAK.

    Science.gov (United States)

    Lin, Sen-Sen; Li, Fang-Fang; Sun, Li; Fan, Wei; Gu, Ming; Zhang, Lu-Yong; Qin, Song; Yuan, Sheng-Tao

    2016-03-01

    Marsdenia tenacissima, a traditional Chinese medicine, is long been used to treat various diseases including asthma, cancer, trachitis, tonsillitis, pharyngitis, cystitis, and pneumonia. Although Marsdenia tenacissima has been demonstrated to have strong anti-tumor effects against primary tumors, its effect on cancer metastasis remains to be defined, and the molecular mechanism underlying the anti-metastatic effect is unknown. In the present study, we investigated the effects of XAP (an extract of Marsdenia tenacissima) on A549 lung cancer cell migration and explored the role of CCR5-CCL5 axis in the anti-metastatic effects of XAP. Our resutls showed that XAP inhibited A549 lung cancer cell migration and invasion in a dose-dependent manner. The protein levels of CCR5, but not CCR9 and CXCR4, were decreased by XAP. The secretion of CCL5, the ligand of CCR5, was reduced by XAP. XAP down-regulated Rho C expression and FAK phosphorylation. In conclusion, XAP inhibited A549 cell migration and invasion through down-regulation of CCR5-CCL5 axis, Rho C, and FAK.

  4. Protein signaling and regulation of gene transcription in leukemia: role of the Casein Kinase II-Ikaros axis.

    Science.gov (United States)

    Gowda, Chandrika S; Song, Chunhua; Ding, Yali; Kapadia, Malika; Dovat, Sinisa

    2016-03-01

    Protein signaling and regulation of gene expression are the two major mechanisms that regulate cellular proliferation in leukemia. Discerning the function of these processes is essential for understanding the pathogenesis of leukemia and for developing the targeted therapies. Here, we provide an overview of one of the mechanisms that regulates gene transcription in leukemia. This mechanism involves the direct interaction between Casein Kinase II (CK2) and the Ikaros transcription factor. Ikaros (IKZF1) functions as a master regulator of hematopoiesis and a tumor suppressor in acute lymphoblastic leukemia (ALL). Impaired Ikaros function results in the development of high-risk leukemia. Ikaros binds to the upstream regulatory elements of its target genes and regulates their transcription via chromatin remodeling. In vivo, Ikaros is a target for CK2, a pro-oncogenic kinase. CK2 directly phosphorylates Ikaros at multiple amino acids. Functional experiments showed that CK2-mediated phosphorylation of Ikaros, regulates Ikaros' DNA binding affinity, subcellular localization and protein stability. Recent studies revealed that phosphorylation of Ikaros by CK2 regulates Ikaros binding and repression of the terminal deoxytransferase (TdT) gene in normal thymocytes and in T-cell ALL. Available data suggest that the oncogenic activity of CK2 in leukemia involves functional inactivation of Ikaros and provide a rationale for CK2 inhibitors as a potential treatment for ALL. PMID:26912004

  5. Weight loss by calorie restriction versus bariatric surgery differentially regulates the hypothalamo-pituitary-adrenocortical axis in male rats.

    Science.gov (United States)

    Grayson, Bernadette E; Hakala-Finch, Andrew P; Kekulawala, Melani; Laub, Holly; Egan, Ann E; Ressler, Ilana B; Woods, Stephen C; Herman, James P; Seeley, Randy J; Benoit, Stephen C; Ulrich-Lai, Yvonne M

    2014-12-01

    Behavioral modifications for the treatment of obesity, including caloric restriction, have notoriously low long-term success rates relative to bariatric weight-loss surgery. The reasons for the difference in sustained weight loss are not clear. One possibility is that caloric restriction alone activates the stress-responsive hypothalamo-pituitary-adrenocortical (HPA) axis, undermining the long-term maintenance of weight loss, and that this is abrogated after bariatric surgery. Accordingly, we compared the HPA response to weight loss in five groups of male rats: (1) high-fat diet-induced obese (DIO) rats treated with Roux-en-Y gastric bypass surgery (RYGB, n = 7), (2) DIO rats treated with vertical sleeve gastrectomy (VSG, n = 11), (3) DIO rats given sham surgery and subsequently restricted to the food intake of the VSG/RYGB groups (Pair-fed, n = 11), (4) ad libitum-fed DIO rats given sham surgery (Obese, n = 11) and (5) ad libitum chow-fed rats given sham surgery (Lean, n = 12). Compared with Lean controls, food-restricted rats exhibited elevated morning (nadir) non-stress plasma corticosterone concentration and increased hypothalamic corticotropin-releasing hormone and vasopressin mRNA expression, indicative of basal HPA activation. This was largely prevented when weight loss was achieved by bariatric surgery. DIO increased HPA activation by acute (novel environment) stress and this was diminished by bariatric surgery-, but not pair-feeding-, induced weight loss. These results indicate that the HPA axis is differentially affected by weight loss from caloric restriction versus bariatric surgery, and this may contribute to the differing long-term effectiveness of these two weight-loss approaches. PMID:25238021

  6. Wnt Inhibitory Factor 1 (Wif1) Is Regulated by Androgens and Enhances Androgen-Dependent Prostate Development

    OpenAIRE

    Keil, Kimberly P.; Mehta, Vatsal; Branam, Amanda M.; Abler, Lisa L.; Buresh-Stiemke, Rita A.; Joshi, Pinak S.; Schmitz, Christopher T.; Marker, Paul C.; Vezina, Chad M.

    2012-01-01

    Fetal prostate development from urogenital sinus (UGS) epithelium requires androgen receptor (AR) activation in UGS mesenchyme (UGM). Despite growing awareness of sexually dimorphic gene expression in the UGS, we are still limited in our knowledge of androgen-responsive genes in UGM that initiate prostate ductal development. We found that WNT inhibitory factor 1 (Wif1) mRNA is more abundant in male vs. female mouse UGM in which its expression temporally and spatially overlaps androgen-respons...

  7. Wnt inhibitory factor 1 (Wif1) is regulated by androgens and enhances androgen-dependent prostate development.

    Science.gov (United States)

    Keil, Kimberly P; Mehta, Vatsal; Branam, Amanda M; Abler, Lisa L; Buresh-Stiemke, Rita A; Joshi, Pinak S; Schmitz, Christopher T; Marker, Paul C; Vezina, Chad M

    2012-12-01

    Fetal prostate development from urogenital sinus (UGS) epithelium requires androgen receptor (AR) activation in UGS mesenchyme (UGM). Despite growing awareness of sexually dimorphic gene expression in the UGS, we are still limited in our knowledge of androgen-responsive genes in UGM that initiate prostate ductal development. We found that WNT inhibitory factor 1 (Wif1) mRNA is more abundant in male vs. female mouse UGM in which its expression temporally and spatially overlaps androgen-responsive steroid 5α-reductase 2 (Srd5a2). Wif1 mRNA is also present in prostatic buds during their elongation and branching morphogenesis. Androgens are necessary and sufficient for Wif1 expression in mouse UGS explant mesenchyme, and testicular androgens remain necessary for normal Wif1 expression in adult mouse prostate stroma. WIF1 contributes functionally to prostatic bud formation. In the presence of androgens, exogenous WIF1 protein increases prostatic bud number and UGS basal epithelial cell proliferation without noticeably altering the pattern of WNT/β-catenin-responsive Axin2 or lymphoid enhancer binding factor 1 (Lef1) mRNA. Wif1 mutant male UGSs exhibit increased (Sfrp)2 and (Sfrp)3 expression and form the same number of prostatic buds as the wild-type control males. Collectively our results reveal Wif1 as one of the few known androgen-responsive genes in the fetal mouse UGM and support the hypothesis that androgen-dependent Wif1 expression is linked to the mechanism of androgen-induced prostatic bud formation.

  8. Regulating the stability and localization of CDK inhibitor p27(Kip1) via CSN6-COP1 axis.

    Science.gov (United States)

    Choi, Hyun Ho; Guma, Sergei; Fang, Lekun; Phan, Liem; Ivan, Cristina; Baggerly, Keith; Sood, Anil; Lee, Mong-Hong

    2015-01-01

    The COP9 signalosome subunit 6 (CSN6), which is involved in ubiquitin-mediated protein degradation, is overexpressed in many types of cancer. CSN6 is critical in causing p53 degradation and malignancy, but its target in cell cycle progression is not fully characterized. Constitutive photomorphogenic 1 (COP1) is an E3 ubiquitin ligase associating with COP9 signalosome to regulate important target proteins for cell growth. p27 is a critical G1 CDK inhibitor involved in cell cycle regulation, but its upstream regulators are not fully characterized. Here, we show that the CSN6-COP1 link is regulating p27(Kip1) stability, and that COP1 is a negative regulator of p27(Kip1). Ectopic expression of CSN6 can decrease the expression of p27(Kip1), while CSN6 knockdown leads to p27(Kip1) stabilization. Mechanistic studies show that CSN6 interacts with p27(Kip1) and facilitates ubiquitin-mediated degradation of p27(Kip1). CSN6-mediated p27 degradation depends on the nuclear export of p27(Kip1), which is regulated through COP1 nuclear exporting signal. COP1 overexpression leads to the cytoplasmic distribution of p27, thereby accelerating p27 degradation. Importantly, the negative impact of COP1 on p27 stability contributes to elevating expression of genes that are suppressed through p27 mediation. Kaplan-Meier analysis of tumor samples demonstrates that high COP1 expression was associated with poor overall survival. These data suggest that tumors with CSN6/COP1 deregulation may have growth advantage by regulating p27 degradation and subsequent impact on p27 targeted genes. PMID:25945542

  9. Regulation of DNA synthesis and the cell cycle in human prostate cancer cells and lymphocytes by ovine uterine serpin

    Directory of Open Access Journals (Sweden)

    Hansen Peter J

    2008-01-01

    Full Text Available Abstract Background Uterine serpins are members of the serine proteinase inhibitor superfamily. Like some other serpins, these proteins do not appear to be functional proteinase inhibitors. The most studied member of the group, ovine uterine serpin (OvUS, inhibits proliferation of several cell types including activated lymphocytes, bovine preimplantation embryos, and cell lines for lymphoma, canine primary osteosarcoma and human prostate cancer (PC-3 cells. The goal for the present study was to evaluate the mechanism by which OvUS inhibits cell proliferation. In particular, it was tested whether inhibition of DNA synthesis in PC-3 cells involves cytotoxic actions of OvUS or the induction of apoptosis. The effect of OvUS in the production of the autocrine and angiogenic cytokine interleukin (IL-8 by PC-3 cells was also determined. Finally, it was tested whether OvUS blocks specific steps in the cell cycle using both PC-3 cells and lymphocytes. Results Recombinant OvUS blocked proliferation of PC-3 cells at concentrations as low as 8 μg/ml as determined by measurements of [3H]thymidine incorporation or ATP content per well. Treatment of PC-3 cells with OvUS did not cause cytotoxicity or apoptosis or alter interleukin-8 secretion into medium. Results from flow cytometry experiments showed that OvUS blocked the entry of PC-3 cells into S phase and the exit from G2/M phase. In addition, OvUS blocked entry of lymphocytes into S phase following activation of proliferation with phytohemagglutinin. Conclusion Results indicate that OvUS acts to block cell proliferation through disruption of the cell cycle dynamics rather than induction of cytotoxicity or apoptosis. The finding that OvUS can regulate cell proliferation makes this one of only a few serpins that function to inhibit cell growth.

  10. PFKL/miR-128 axis regulates glycolysis by inhibiting AKT phosphorylation and predicts poor survival in lung cancer.

    Science.gov (United States)

    Yang, Jie; Li, Jingqiu; Le, Yanping; Zhou, Chengwei; Zhang, Shun; Gong, Zhaohui

    2016-01-01

    MicroRNAs (miRNAs) affect cancer cell glucose metabolism by targeting mRNAs of diverse enzymes that have been implicated in oxidative phosphorylation (OXPHOS) and glycolytic pathways. However, the mechanisms that underlie miRNA-mediated regulation of phosphofructokinase (PFK), a key rate-limiting enzyme in glycolysis, remain largely unknown. Here, we show that miR-128 directly targets PFK liver type (PFKL) in lung cancer cells and regulates endogenous expression of PFKL at both the mRNA and protein levels. In line with this, overexpression of miR-128 decreased glucose uptake and lactate production, as well as increased cellular ATP content. Interestingly, knockdown of miR-128 was shown to promote lung cancer cell growth and colony formation. Moreover, we observed that miR-128 expression inversely correlated with PFKL mRNA levels in clinic lung cancer samples and that increased PFKL expression predicted poor overall survival in lung cancer patients. Mechanistically, we showed that miR-128 regulates PFKL via a feedback loop that involves inhibition of the AKT signaling pathway. Together, our results suggest that miR-128 acts as a metabolic regulator in lung cancer cells that may be therapeutically exploited. PMID:27186417

  11. Altered LKB1/CREB-regulated transcription co-activator (CRTC) signaling axis promotes esophageal cancer cell migration and invasion.

    Science.gov (United States)

    Gu, Y; Lin, S; Li, J-L; Nakagawa, H; Chen, Z; Jin, B; Tian, L; Ucar, D A; Shen, H; Lu, J; Hochwald, S N; Kaye, F J; Wu, L

    2012-01-26

    LKB1 is a tumor susceptibility gene for the Peutz-Jeghers cancer syndrome and is a target for mutational inactivation in sporadic human malignancies. LKB1 encodes a serine/threonine kinase that has critical roles in cell growth, polarity and metabolism. A novel and important function of LKB1 is its ability to regulate the phosphorylation of CREB-regulated transcription co-activators (CRTCs) whose aberrant activation is linked with oncogenic activities. However, the roles and mechanisms of LKB1 and CRTC in the pathogenesis of esophageal cancer have not been previously investigated. In this study, we observed altered LKB1-CRTC signaling in a subset of human esophageal cancer cell lines and patient samples. LKB1 negatively regulates esophageal cancer cell migration and invasion in vitro. Mechanistically, we determined that CRTC signaling becomes activated because of LKB1 loss, which results in the transcriptional activation of specific downstream targets including LYPD3, a critical mediator for LKB1 loss-of-function. Our data indicate that de-regulated LKB1-CRTC signaling might represent a crucial mechanism for esophageal cancer progression.

  12. Integrative Genomics Outlines a Biphasic Glucose Response and a ChREBP-RORγ Axis Regulating Proliferation in β Cells

    DEFF Research Database (Denmark)

    Schmidt, Søren Fisker; Madsen, Jesper Grud Skat; Frafjord, Kari Østerli;

    2016-01-01

    -sensing transcription factor ChREBP directly activates first wave enhancers, whereas repression and activation of second wave enhancers are indirect. By integrating motif enrichment within late-regulated enhancers with expression profiles of the associated transcription factors, we have identified multiple putative...

  13. Prostate biopsy

    Science.gov (United States)

    ... from the prostate through the scope. Perineal - through perineum (the skin between the anus and the scrotum). ... pain. A small cut is made in the perineum. A needle is inserted to collect prostate tissue.

  14. Prostate Cancer

    Science.gov (United States)

    ... man's bladder that produces fluid for semen. Prostate cancer is common among older men. It is rare ... younger than 40. Risk factors for developing prostate cancer include being over 65 years of age, family ...

  15. Bisphenol A Modifies the Regulation Exerted by Testosterone on 5α-Reductase Isozymes in Ventral Prostate of Adult Rats

    Directory of Open Access Journals (Sweden)

    Pilar Sánchez

    2013-01-01

    Full Text Available The development, growth, and function of the prostate gland depend on androgen stimulation. The primary androgen in prostate is 5-dihydrotestosterone (DHT which is synthesized from circulating testosterone (T through the action of 5-reductase (5-R. Although 5-R occurs as five isozymes, only 5-R1 and 5-R2 are physiologically involved in steroidogenesis. The endocrine disruptor bisphenol A (BPA alters sexual organs, including the prostate. Our previous findings indicated that BPA decreased the expression of 5-R1 and 5-R2 in rat prostate but also circulating T. Thus, it is unclear whether BPA exerts this effect on 5-R isozymes by reducing circulating T or by any other mechanism. In this study, we examine the effects of short-term exposure to BPA at doses below 25 g/Kg/d and above 300 g/Kg/d of the TDI on mRNA levels of 5-R1 and 5-R2 in prostate of adult castrated rats supplemented with T to achieve constant circulating T levels. mRNA levels were measured by absolute quantitative RT-PCR, T levels by RIA, and DHT levels by ELISA. Our results indicated that in castrated rats treated with T BPA at the two doses studied significantly decreased the mRNA levels of both 5-R isozymes in a dose-dependent manner without modifications in circulating T.

  16. Gene expression down-regulation in CD90+ prostate tumor-associated stromal cells involves potential organ-specific genes

    International Nuclear Information System (INIS)

    The prostate stroma is a key mediator of epithelial differentiation and development, and potentially plays a role in the initiation and progression of prostate cancer. The tumor-associated stroma is marked by increased expression of CD90/THY1. Isolation and characterization of these stromal cells could provide valuable insight into the biology of the tumor microenvironment. Prostate CD90+ stromal fibromuscular cells from tumor specimens were isolated by cell-sorting and analyzed by DNA microarray. Dataset analysis was used to compare gene expression between histologically normal and tumor-associated stromal cells. For comparison, stromal cells were also isolated and analyzed from the urinary bladder. The tumor-associated stromal cells were found to have decreased expression of genes involved in smooth muscle differentiation, and those detected in prostate but not bladder. Other differential expression between the stromal cell types included that of the CXC-chemokine genes. CD90+ prostate tumor-associated stromal cells differed from their normal counterpart in expression of multiple genes, some of which are potentially involved in organ development

  17. Regulation of coronary vascular tone via redox modulation in the alpha1-adrenergic-angiotensin-endothelin axis of the myocardium.

    Science.gov (United States)

    Yamaguchi, Osamu; Kaneshiro, Takashi; Saitoh, Shu-ichi; Ishibashi, Toshiyuki; Maruyama, Yukio; Takeishi, Yasuchika

    2009-01-01

    We hypothesized that alpha(1)-adrenoceptor stimulation of cardiac myocytes results in the production of an endothelin (ET)-releasing factor that stimulates the coronary vasculature to release ET and, by manipulating the redox state of cardiac and vascular cells, may influence the extent of alpha(1)-adrenergic-ET-1 vasoconstriction. Dihydroethidium (DHE) and dichlorodihydrofluorescein (DCF) intensities were increased by phenylephrine stimulation in isolated rat cardiac myocytes, which were enhanced by the mitochondrial electron transport chain complex I inhibitor rotenone (DHE: 20.4 +/- 1.2-fold and DCF: 25.2 +/- 0.9-fold, n = 8, P < 0.01, respectively) but not by the NADPH oxidase inhibitor apocynin. Olmesartan, an angiotensin II type 1 receptor antagonist, and enalaprilate did not change DHE and DCF intensities by phenylephrine. Next, we measured the vasoconstriction of isolated, pressurized rat coronary arterioles (diameter: 74 +/- 8 microm) in response to supernatant collected from isolated cardiac myocytes. The addition of supernatant from phenylephrine-stimulated myocytes to a 2-ml vessel bath (n = 8 each) caused volume-dependent vasoconstriction (500 microl: -14.8 +/- 2.2%). Olmesartan and TA0201, an ET type A receptor antagonist, converted vasoconstriction into vasodilation (8.5 +/- 1.2% and 10.5 +/- 0.5%, P < 0.01, respectively) in response to supernatant from phenylephrine-stimulated myocytes, which was eliminated with catalase. Vasoconstriction was weakened using supernatant from phenylephrine with rotenone-treated myocytes. Treatment of arterioles with apocynin to myocyte supernatant converted vasoconstriction into vasodilation (7.8 +/- 0.8%, P < 0.01). These results suggest that alpha(1)-adrenergic stimulation in cardiac myocytes produces angiotensin I and H(2)O(2) and that angiotensin releases ET-1 through NADPH oxidase in coronary arterioles. Thus, coronary vasoconstriction via the alpha-adrenergic-angiotensin-ET axis appears to require redox

  18. Autonomous and nonautonomous regulation of axis formation by antagonistic signaling via 7-span cAMP receptors and GSK3 in Dictyostelium.

    Science.gov (United States)

    Ginsburg, G T; Kimmel, A R

    1997-08-15

    Early during Dictyostelium development a fundamental cell-fate decision establishes the anteroposterior (prestalk/prespore) axis. Signaling via the 7-transmembrane cAMP receptor CAR4 is essential for creating and maintaining a normal pattern; car4-null alleles have decreased levels of prestalk-specific mRNAs but enhanced expression of prespore genes. car4- cells produce all of the signals required for prestalk differentiation but lack an extracellular factor necessary for prespore differentiation of wild-type cells. This secreted factor decreases the sensitivity of prespore cells to inhibition by the prestalk morphogen DIF-1. At the cell autonomous level, CAR4 is linked to intracellular circuits that activate prestalk but inhibit prespore differentiation. The autonomous action of CAR4 is antagonistic to the positive intracellular signals mediated by another cAMP receptor, CAR1 and/or CAR3. Additional data indicate that these CAR-mediated pathways converge at the serine/threonine protein kinase GSK3, suggesting that the anterior (prestalk)/posterior (prespore) axis of Dictyostelium is regulated by an ancient mechanism that is shared by the Wnt/Fz circuits for dorsoventral patterning during early Xenopus development and establishing Drosophila segment polarity.

  19. MicroRNA-196b regulates the homeobox B7-vascular endothelial growth factor axis in cervical cancer.

    Directory of Open Access Journals (Sweden)

    Christine How

    Full Text Available The down-regulation of microRNA-196b (miR-196b has been reported, but its contribution to cervical cancer progression remains to be investigated. In this study, we first demonstrated that miR-196b down-regulation was significantly associated with worse disease-free survival (DFS for cervical cancer patients treated with combined chemo-radiation. Secondly, using a tri-modal approach for target identification, we determined that homeobox-B7 (HOXB7 was a bona fide target for miR-196b, and in turn, vascular endothelial growth factor (VEGF was a downstream transcript regulated by HOXB7. Reconstitution of miR-196b expression by transient transfection resulted in reduced cell growth, clonogenicity, migration and invasion in vitro, as well as reduced tumor angiogenesis and tumor cell proliferation in vivo. Concordantly, siRNA knockdown of HOXB7 or VEGF phenocopied the biological effects of miR-196b over-expression. Our findings have demonstrated that the miR-196b/HOXB7/VEGF pathway plays an important role in cervical cancer progression; hence targeting this pathway could be a promising therapeutic strategy for the future management of this disease.

  20. The HIF-2α-MALAT1-miR-216b axis regulates multi-drug resistance of hepatocellular carcinoma cells via modulating autophagy.

    Science.gov (United States)

    Yuan, Peng; Cao, Weibin; Zang, Quanling; Li, Guixin; Guo, Xiangfei; Fan, Jianghe

    2016-09-23

    In this study, we firstly investigated the association among lncRNA MALAT1, HIF-1α and HIF-2α in hepatocellular carcinoma (HCC) cells. Then, we investigated the regulative effect of MALAT1 on multi-drug resistance (MDR) in HCC cells and the underlying mechanism. The results showed that MALAT1 was over two times higher in BEL-7402/5-FU cells than in BEL-7402 cells. It was HIF-2α, but not HIF-1α induced MALAT1 upregulation in HCC cells. Dual luciferase assay demonstrated that there were at least two binding sites of miR-26b in MALAT1. Therefore, we infer that there is a HIF-2α-MALAT1-miR-216b axis in HCC cells. Cell viability assay showed that both MALAT1 siRNA and miR-216b mimics reduced IC50 of 5-FU, ADR and MMC in BEL-7402/5-FU cells. MALAT1 siRNA and miR-216b mimics showed similar effect as 3-MA on reducing LC3-II levels, inhibiting p62 degradation and suppressing GFP-LC3 puncta formation in BEL-7402/5-FU cells. Flow cytometric analysis showed that 3-MA treatment, MALAT1 siRNA and miR-216b mimics all promoted 5-FU induced apoptosis in BEL-7402/5-FU cells. Therefore, this study firstly revealed that there is a HIF-2α-MALAT1-miR-216b axis regulating MDR of HCC cells via modulating autophagy. PMID:27524242

  1. Role of estrogen receptors (ERs and G protein-coupled estrogen receptor (GPER in regulation of hypothalamic-pituitary-testis axis and spermatogenesis

    Directory of Open Access Journals (Sweden)

    Adele eChimento

    2014-01-01

    Full Text Available Male reproductive function is under the control of both gonadotropins and androgens through a negative feedback loop that involves the hypothalamus, pituitary and testis known as hypothalamus-pituitary-gonadal axis (HPG. Indeed, also estrogens play an important role in regulating HPG axis but the relative contribution to the inhibition of gonadotropins secretion exerted by the amount of estrogens produced within the hypothalamus and/or the pituitary or by the amount of circulating estrogens are still ongoing. Moreover, it is known that maintenance of spermatogenesis is controlled by gonadotrophins and testosterone, the effects of which are modulated by a complex network of locally produced factors, including estrogens. Physiological effects of estrogens are mediated by the classical nuclear estrogen receptor alpha (ESR1 and estrogen receptor beta (ESR2, which mediate both genomic and rapid signaling events. In addition, estrogens induce rapid non-genomic responses through a membrane-associated G protein-coupled receptor (GPER. Ours and other studies reported that, in the testis, GPER is expressed in both normal germ cells and somatic cells and it is involved in mediating the estrogen action in spermatogenesis controlling proliferative and/or apoptotic events. Interestingly, GPER expression has been revealed also in hypothalamus and in pituitary. However, its role in mediating estrogen rapid actions in this context is under investigation. Recent studies indicate that GPER is involved in modulating GnRH release as well as gonadotropins secretion. In this review, we will summarize the current knowledge concerning the role of estrogen/estrogen receptors (ERs molecular pathways in regulating GnRH, FSH and LH release at hypothalamic and pituitary level in male as well as in controlling specific testicular functions such as spermatogenesis, focusing our attention mainly on estrogen signaling mediated by GPER.

  2. Salvianolic Acid A Protects the Peripheral Nerve Function in Diabetic Rats through Regulation of the AMPK-PGC1α-Sirt3 Axis

    Directory of Open Access Journals (Sweden)

    Guanhua Du

    2012-09-01

    Full Text Available Salvianolic acid A (SalA is one of the main efficacious, water-soluble constituents of Salvia miltiorrhiza Bunge. This study investigated the protective effects of SalA on peripheral nerve in diabetic rats. Administration of SalA (0.3, 1 and 3 mg/kg, ig was started from the 5th week after strepotozotocin (STZ60 mg/kg intraperitoneal injection and continued for 8 weeks. Paw withdrawal mechanical threshold (PWMT and motor nerve conduction velocity (MNCV were used to assess peripheral nerve function. The western blot methods were employed to test the expression levels of serine-threonine liver kinase B1 (LKB1, AMP-activated protein kinase (AMPK, peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1α, silent information regulator protein3 (sirtuin 3/Sirt3 and neuronal nitric oxide synthase (nNOS in sciatic nerve. Results showed that SalA administration could increase PWMT and MNCV in diabetic rats; reduce the deterioration of sciatic nerve pathology; increase AMPK phosphorylation level, up-regulate PGC-1α, Sirt3 and nNOS expression, but had no influence on LKB1. These results suggest that SalA has protective effects against diabetic neuropathy. The beneficial effects of SalA on peripheral nerve function in diabetic rats might be attributed to improvements in glucose metabolism through regulation of the AMPK-PGC1α-Sirt3 axis.

  3. A miR-335/COX-2/PTEN axis regulates the secretory phenotype of senescent cancer-associated fibroblasts

    Science.gov (United States)

    Kabir, Tasnuva D.; Leigh, Ross J.; Tasena, Hataitip; Mellone, Massimiliano; Coletta, Ricardo D.; Parkinson, Eric K.; Prime, Stephen S.; Thomas, Gareth J.; Paterson, Ian C.; Zhou, Donghui; McCall, John; Speight, Paul M.; Lambert, Daniel W.

    2016-01-01

    Senescent cancer-associated fibroblasts (CAF) develop a senescence-associated secretory phenotype (SASP) that is believed to contribute to cancer progression. The mechanisms underlying SASP development are, however, poorly understood. Here we examined the functional role of microRNA in the development of the SASP in normal fibroblasts and CAF. We identified a microRNA, miR-335, up-regulated in the senescent normal fibroblasts and CAF and able to modulate the secretion of SASP factors and induce cancer cell motility in co-cultures, at least in part by suppressing the expression of phosphatase and tensin homologue (PTEN). Additionally, elevated levels of cyclo-oxygenase 2 (PTGS2; COX-2) and prostaglandin E2 (PGE2) secretion were observed in senescent fibroblasts, and inhibition of COX-2 by celecoxib reduced the expression of miR-335, restored PTEN expression and decreased the pro-tumourigenic effects of the SASP. Collectively these data demonstrate the existence of a novel miRNA/PTEN-regulated pathway modulating the inflammasome in senescent fibroblasts. PMID:27385366

  4. Mesenchymal stem cells regulate mechanical properties of human degenerated nucleus pulposus cells through SDF-1/CXCR4/AKT axis.

    Science.gov (United States)

    Liu, Ming-Han; Bian, Bai-Shi-Jiao; Cui, Xiang; Liu, Lan-Tao; Liu, Huan; Huang, Bo; Cui, You-Hong; Bian, Xiu-Wu; Zhou, Yue

    2016-08-01

    Transplantation of mesenchymal stem cells (MSCs) into the degenerated intervertebral disc (IVD) has shown promise for decelerating or arresting IVD degeneration. Cellular mechanical properties play crucial roles in regulating cell-matrix interactions, potentially reflecting specific changes that occur based on cellular phenotype and behavior. However, the effect of co-culturing of MSCs with nucleus pulposus cells (NPCs) on the mechanical properties of NPCs remains unknown. In our study, we demonstrated that co-culture of degenerated NPCs with MSCs resulted in significantly decreased mechanical moduli (elastic modulus, relaxed modulus, and instantaneous modulus) and increased biological activity (proliferation and expression of matrix genes) in degenerated NPCs, but not normal NPCs. SDF-1, CXCR4 ligand, was highly expressed in MSCs when co-cultured with degenerated NPCs. Inhibition of SDF-1 using CXCR4 antagonist AMD3100 or knocking-down CXCR4 in degenerated NPCs abolished the MSCs-induced decrease in the mechanical moduli and increased biological activity of degenerated NPCs, suggesting a crucial role for SDF-1/CXCR4 signaling. AKT and FAK inhibition attenuated the MSCs- or SDF-1-induced decrease in the mechanical moduli of degenerated NPCs. In conclusion, it was demonstrated in vitro that MSCs regulate the mechanical properties of degenerated NPCs through SDF-1/CXCR4/AKT signaling. These findings highlight a possible mechanical mechanism for MSCs-induced modulation with degenerated NPCs, which may be applicable to MSCs-based therapy for disc degeneration.

  5. Atlas of prostate cancer heritability in European and African-American men pinpoints tissue-specific regulation

    DEFF Research Database (Denmark)

    Gusev, Alexander; Shi, Huwenbo; Kichaev, Gleb;

    2016-01-01

    Although genome-wide association studies have identified over 100 risk loci that explain ∼33% of familial risk for prostate cancer (PrCa), their functional effects on risk remain largely unknown. Here we use genotype data from 59,089 men of European and African American ancestries combined with c...

  6. In vivo quantitative phosphoproteomic profiling identifies novel regulators of castration-resistant prostate cancer growth

    DEFF Research Database (Denmark)

    Jiang, Nan; Hjorth-Jensen, Kim; Hekmat, Omid;

    2015-01-01

    Prostate cancer remains a leading cause of cancer-related mortality worldwide owing to our inability to treat effectively castration-resistant tumors. To understand the signaling mechanisms sustaining castration-resistant growth, we implemented a mass spectrometry-based quantitative proteomic app...

  7. Progress against Prostate Cancer

    Science.gov (United States)

    ... this page please turn Javascript on. Feature: Prostate Cancer Progress Against Prostate Cancer Past Issues / Winter 2010 Table of Contents ... Read More "Prostate Cancer" Articles Progress Against Prostate Cancer / Prostate Cancer Research Trial Helps John Spencer Treat His ...

  8. Learning about Prostate Cancer

    Science.gov (United States)

    ... of Information on Prostate Cancer What is prostate cancer? Prostate cancer is the most common cancer in American ... of page Additional Resources of Information on Prostate Cancer Prostate Cancer [nlm.nih.gov] From Medline Plus Medical ...

  9. Stages of Prostate Cancer

    Science.gov (United States)

    ... Renal Cell) Cancer Leukemia Lung Cancer Lymphoma Pancreatic Cancer Prostate Cancer Skin Cancer Thyroid Cancer Uterine Cancer All ... Cancer Treatment Prostate Cancer Prevention Genetics of Prostate Cancer Prostate Cancer Screening Research Prostate Cancer Treatment (PDQ®)–Patient ...

  10. The Prostaglandin E2-EP3 Receptor Axis Regulates Anaplasma phagocytophilum-Mediated NLRC4 Inflammasome Activation.

    Science.gov (United States)

    Wang, Xiaowei; Shaw, Dana K; Hammond, Holly L; Sutterwala, Fayyaz S; Rayamajhi, Manira; Shirey, Kari Ann; Perkins, Darren J; Bonventre, Joseph V; Velayutham, Thangam S; Evans, Sean M; Rodino, Kyle G; VieBrock, Lauren; Scanlon, Karen M; Carbonetti, Nicholas H; Carlyon, Jason A; Miao, Edward A; McBride, Jere W; Kotsyfakis, Michail; Pedra, Joao H F

    2016-08-01

    Rickettsial agents are sensed by pattern recognition receptors but lack pathogen-associated molecular patterns commonly observed in facultative intracellular bacteria. Due to these molecular features, the order Rickettsiales can be used to uncover broader principles of bacterial immunity. Here, we used the bacterium Anaplasma phagocytophilum, the agent of human granulocytic anaplasmosis, to reveal a novel microbial surveillance system. Mechanistically, we discovered that upon A. phagocytophilum infection, cytosolic phospholipase A2 cleaves arachidonic acid from phospholipids, which is converted to the eicosanoid prostaglandin E2 (PGE2) via cyclooxygenase 2 (COX2) and the membrane associated prostaglandin E synthase-1 (mPGES-1). PGE2-EP3 receptor signaling leads to activation of the NLRC4 inflammasome and secretion of interleukin (IL)-1β and IL-18. Importantly, the receptor-interacting serine/threonine-protein kinase 2 (RIPK2) was identified as a major regulator of the immune response against A. phagocytophilum. Accordingly, mice lacking COX2 were more susceptible to A. phagocytophilum, had a defect in IL-18 secretion and exhibited splenomegaly and damage to the splenic architecture. Remarkably, Salmonella-induced NLRC4 inflammasome activation was not affected by either chemical inhibition or genetic ablation of genes associated with PGE2 biosynthesis and signaling. This divergence in immune circuitry was due to reduced levels of the PGE2-EP3 receptor during Salmonella infection when compared to A. phagocytophilum. Collectively, we reveal the existence of a functionally distinct NLRC4 inflammasome illustrated by the rickettsial agent A. phagocytophilum. PMID:27482714

  11. ACE2/Ang 1-7 axis: A critical regulator of epicardial adipose tissue inflammation and cardiac dysfunction in obesity.

    Science.gov (United States)

    Patel, Vaibhav B; Basu, Ratnadeep; Oudit, Gavin Y

    2016-01-01

    Obesity is characterized by an excessive fat accumulation in adipose tissues leading to weight gain and is increasing in prevalence and is strongly associated with metabolic and cardiovascular disorders. The renin-angiotensin system (RAS) has emerged as a key pathogenic mechanism for these disorders; activated RAS and angiotensin (Ang) II production results in worsening of cardiovascular diseases and angiotensin converting enzyme 2 (ACE2) negatively regulates RAS by metabolizing Ang II into Ang 1-7. ACE2 is expressed in the adipocytes and its expression is upregulated in response to high fat diet induced obesity in mice. Loss of ACE2 results in heart failure with preserved ejection fraction which is mediated in part by epicardial adipose tissue inflammation. Angiotensin 1-7 reduces the obesity associated cardiac dysfunction predominantly via its role in adiponectin expression and attenuation of epicardial adipose tissue inflammation. Human heart disease is also linked with inflammed epicardial adipose tissue. Here, we discuss the important interpretation of the novel of ACE2/Ang 1-7 pathway in obesity associated cardiac dysfunction. PMID:27617176

  12. The Prostaglandin E2-EP3 Receptor Axis Regulates Anaplasma phagocytophilum-Mediated NLRC4 Inflammasome Activation

    Science.gov (United States)

    Wang, Xiaowei; Shaw, Dana K.; Hammond, Holly L.; Sutterwala, Fayyaz S.; Rayamajhi, Manira; Shirey, Kari Ann; Perkins, Darren J.; Bonventre, Joseph V.; Velayutham, Thangam S.; Evans, Sean M.; Rodino, Kyle G.; VieBrock, Lauren; Scanlon, Karen M.; Carbonetti, Nicholas H.; Carlyon, Jason A.; Miao, Edward A.; McBride, Jere W.; Kotsyfakis, Michail

    2016-01-01

    Rickettsial agents are sensed by pattern recognition receptors but lack pathogen-associated molecular patterns commonly observed in facultative intracellular bacteria. Due to these molecular features, the order Rickettsiales can be used to uncover broader principles of bacterial immunity. Here, we used the bacterium Anaplasma phagocytophilum, the agent of human granulocytic anaplasmosis, to reveal a novel microbial surveillance system. Mechanistically, we discovered that upon A. phagocytophilum infection, cytosolic phospholipase A2 cleaves arachidonic acid from phospholipids, which is converted to the eicosanoid prostaglandin E2 (PGE2) via cyclooxygenase 2 (COX2) and the membrane associated prostaglandin E synthase-1 (mPGES-1). PGE2-EP3 receptor signaling leads to activation of the NLRC4 inflammasome and secretion of interleukin (IL)-1β and IL-18. Importantly, the receptor-interacting serine/threonine-protein kinase 2 (RIPK2) was identified as a major regulator of the immune response against A. phagocytophilum. Accordingly, mice lacking COX2 were more susceptible to A. phagocytophilum, had a defect in IL-18 secretion and exhibited splenomegaly and damage to the splenic architecture. Remarkably, Salmonella-induced NLRC4 inflammasome activation was not affected by either chemical inhibition or genetic ablation of genes associated with PGE2 biosynthesis and signaling. This divergence in immune circuitry was due to reduced levels of the PGE2-EP3 receptor during Salmonella infection when compared to A. phagocytophilum. Collectively, we reveal the existence of a functionally distinct NLRC4 inflammasome illustrated by the rickettsial agent A. phagocytophilum. PMID:27482714

  13. Activation of AKT negatively regulates the pro-apoptotic function of death-associated protein kinase 3 (DAPK3) in prostate cancer.

    Science.gov (United States)

    Das, Trinath P; Suman, Suman; Papu John, A M Sashi; Pal, Deeksha; Edwards, Angelena; Alatassi, Houda; Ankem, Murali K; Damodaran, Chendil

    2016-07-28

    The activation of AKT governs many signaling pathways and promotes cell growth and inhibits apoptosis in human malignancies including prostate cancer (CaP). Here, we investigated the molecular association between AKT activation and the function of death-associated protein kinase 3 (DAPK3) in CaP. An inverse correlation of pAKT and DAPK3 expression was seen in a panel of CaP cell lines. Inhibition of AKT by wortmannin/LY294002 or overexpression of DAPK3 reverts the proliferative function of AKT in CaP cells. On the other hand, ectopic expression of AKT inhibited DAPK3 function and induced proliferation of CaP cells. In addition, AKT over-expressed tumors exhibit aggressive growth when compared to control vector in xenograft models. The immunohistochemistry results revealed a down-regulation of DAPK3 expression in AKT over-expressed tumors as compared to control tumors. Finally, we examined the expression pattern of AKT and DAPK3 in human CaP specimens - the expected gradual increase and nuclear localization of pAKT was seen in higher Gleason score samples versus benign hyperplasia (BPH). On the contrary, reduced expression of DAPK3 was seen in higher Gleason stages versus BPH. This suggests that inhibition of DAPK3 may be a contributing factor to the carcinogenesis of the prostate. Understanding the mechanism by which AKT negatively regulates DAPK3 function may suggest whether DAPK3 can be a therapeutic target for CaP. PMID:27126362

  14. N-methyl-D-aspartate (NMDA) and the regulation of mitogen-activated protein kinase (MAPK) signaling pathways: a revolving neurochemical axis for therapeutic intervention?

    Science.gov (United States)

    Haddad, John J

    2005-11-01

    Excitatory synaptic transmission in the central nervous system (CNS) is mediated by the release of glutamate from presynaptic terminals onto postsynaptic channels gated by N-methyl-D-aspartate (NMDA) and non-NMDA (AMPA and KA) receptors. Extracellular signals control diverse neuronal functions and are responsible for mediating activity-dependent changes in synaptic strength and neuronal survival. Influx of extracellular calcium ([Ca(2+)](e)) through the NMDA receptor (NMDAR) is required for neuronal activity to change the strength of many synapses. At the molecular level, the NMDAR interacts with signaling modules, which, like the mitogen-activated protein kinase (MAPK) superfamily, transduce excitatory signals across neurons. Recent burgeoning evidence points to the fact that MAPKs play a crucial role in regulating the neurochemistry of NMDARs, their physiologic and biochemical/biophysical properties, and their potential role in pathophysiology. It is the purpose of this review to discuss: (i) the MAPKs and their role in a plethora of cellular functions; (ii) the role of MAPKs in regulating the biochemistry and physiology of NMDA receptors; (iii) the kinetics of MAPK-NMDA interactions and their biologic and neurochemical properties; (iv) how cellular signaling pathways, related cofactors and intracellular conditions affect NMDA-MAPK interactions and (v) the role of NMDA-MAPK pathways in pathophysiology and the evolution of disease conditions. Given the versatility of the NMDA-MAPK interactions, the NMDA-MAPK axis will likely form a neurochemical target for therapeutic interventions.

  15. The Role of Estrogen Receptor β in Prostate Cancer

    OpenAIRE

    Christoforou, Paraskevi; Christopoulos, Panagiotis F; Koutsilieris, Michael

    2014-01-01

    Although androgen receptor (AR) signaling is the main molecular tool regulating growth and function of the prostate gland, estrogen receptor β (ERβ) is involved in the differentiation of prostatic epithelial cells and numerous antiproliferative actions on prostate cancer cells. However, ERβ splice variants have been associated with prostate cancer initiation and progression mechanisms. ERβ is promising as an anticancer therapy and in the prevention of prostate cancer. Herein, we review the re...

  16. The role of Estrogen Receptor Beta in Prostate Cancer.

    OpenAIRE

    Christoforou, Paraskevi; Christopoulos, Panagiotis F; Koutsilieris, Michael

    2014-01-01

    Although androgen receptor (AR) signaling is the main molecular tool regulating growth and function of prostate gland, estrogen receptor beta (ERβ) is involved contributive in the differentiation of prostatic epithelial cells and numerous antiproliferative actions on prostate cancer cells. However, ERβ splice variants have been associated with prostate cancer initiation and progression mechanisms. Nowadays, ERß is a promising target as an anticancer therapy and prevention for prostate cancer....

  17. Androgen-targeted therapy induced epithelial mesenchymal plasticity and neuroendocrine transdifferentiation in prostate cancer: an opportunity for intervention

    Directory of Open Access Journals (Sweden)

    Mannan eNouri

    2014-12-01

    Full Text Available Androgens regulate biological pathways to promote proliferation, differentiation and survival of benign and malignant prostate tissue. Androgen receptor targeted therapies exploit this dependence and are used in advanced prostate cancer to control disease progression. Contemporary treatment regimens involve sequential use of inhibitors of androgen synthesis or androgen receptor function. Although targeting the androgen axis has clear therapeutic benefit, its effectiveness is temporary, as prostate tumor cells adapt to survive and grow. The removal of androgens (androgen deprivation has been shown to activate both epithelial-to-mesenchymal transition (EMT and neuroendocrine transdifferentiation programs. EMT has established roles in promoting biological phenotypes associated with tumor progression (migration/invasion, tumor cell survival, cancer stem cell-like properties, resistance to radiation and chemotherapy in multiple human cancer types. Neuroendocrine transdifferentiation in prostate cancer is associated with resistance to therapy, visceral metastasis and aggressive disease. Thus, activation of these programs via inhibition of the androgen axis provides a mechanism by which tumor cells can adapt to promote disease recurrence and progression. Brachyury, Axl, MEK and aurora kinase A are molecular drivers of these programs, and inhibitors are currently in clinical trials to determine therapeutic applications. Understanding tumor cell plasticity will be important in further defining the rational use of androgen targeted therapies clinically and provides an opportunity for intervention to prolong survival of men with metastatic prostate cancer.

  18. Loss of let-7 up-regulates EZH2 in prostate cancer consistent with the acquisition of cancer stem cell signatures that are attenuated by BR-DIM.

    Directory of Open Access Journals (Sweden)

    Dejuan Kong

    Full Text Available The emergence of castrate-resistant prostate cancer (CRPC contributes to the high mortality of patients diagnosed with prostate cancer (PCa, which in part could be attributed to the existence and the emergence of cancer stem cells (CSCs. Recent studies have shown that deregulated expression of microRNAs (miRNAs contributes to the initiation and progression of PCa. Among several known miRNAs, let-7 family appears to play a key role in the recurrence and progression of PCa by regulating CSCs; however, the mechanism by which let-7 family contributes to PCa aggressiveness is unclear. Enhancer of Zeste homolog 2 (EZH2, a putative target of let-7 family, was demonstrated to control stem cell function. In this study, we found loss of let-7 family with corresponding over-expression of EZH2 in human PCa tissue specimens, especially in higher Gleason grade tumors. Overexpression of let-7 by transfection of let-7 precursors decreased EZH2 expression and repressed clonogenic ability and sphere-forming capacity of PCa cells, which was consistent with inhibition of EZH2 3'UTR luciferase activity. We also found that the treatment of PCa cells with BR-DIM (formulated DIM: 3,3'-diindolylmethane by Bio Response, Boulder, CO, abbreviated as BR-DIM up-regulated let-7 and down-regulated EZH2 expression, consistent with inhibition of self-renewal and clonogenic capacity. Moreover, BR-DIM intervention in our on-going phase II clinical trial in patients prior to radical prostatectomy showed upregulation of let-7 consistent with down-regulation of EZH2 expression in PCa tissue specimens after BR-DIM intervention. These results suggest that the loss of let-7 mediated increased expression of EZH2 contributes to PCa aggressiveness, which could be attenuated by BR-DIM treatment, and thus BR-DIM is likely to have clinical impact.

  19. Fibroblast growth factor-2 up-regulates the expression of nestin through the Ras–Raf–ERK–Sp1 signaling axis in C6 glioma cells

    Energy Technology Data Exchange (ETDEWEB)

    Chang, Kai-Wei [Institute of Molecular and Cellular Biology, National Taiwan University, Taipei 106, Taiwan (China); Huang, Yuan-Li [Department of Biotechnology, College of Health Science, Asia University, Taichung 413, Taiwan (China); Wong, Zong-Ruei; Su, Peng-Han [Institute of Molecular and Cellular Biology, National Taiwan University, Taipei 106, Taiwan (China); Huang, Bu-Miin [Department of Cell Biology and Anatomy, National Cheng-Kung University, Tainan 701, Taiwan (China); Ju, Tsai-Kai [Instrumentation Center, National Taiwan University, Taipei 106, Taiwan (China); Technology Commons, College of Life Science, National Taiwan University, Taipei 106, Taiwan (China); Yang, Hsi-Yuan, E-mail: hyhy@ntu.edu.tw [Institute of Molecular and Cellular Biology, National Taiwan University, Taipei 106, Taiwan (China)

    2013-05-17

    Highlights: •Nestin expression in C6 glioma cells is induced by FGF-2. •Nestin expression is induced by FGF-2 via de novo RNA and protein synthesis. •The FGFR inhibitor SU5402 blocks the FGF-2-induced nestin expression. •The mRNA of FGFR1 and 3 are detected in C6 glioma cells. •Ras–Raf–ERK–Sp1 signaling pathway is responsibe for FGF-2-induced nestin expression. -- Abstract: Nestin is a 240-kDa intermediate filament protein expressed mainly in neural and myogenic stem cells. Although a substantial number of studies have focused on the expression of nestin during development of the central nervous system, little is known about the factors that induce and regulate its expression. Fibroblast growth factor-2 (FGF-2) is an effective mitogen and stimulates the proliferation and differentiation of a subset of nestin-expressing cells, including neural progenitor cells, glial precursor cells, and smooth muscle cells. To assess whether FGF-2 is a potent factor that induces the expression of nestin, C6 glioma cells were used. The results showed that nestin expression was up-regulated by FGF-2 via de novo RNA and protein synthesis. Our RT-PCR results showed that C6 glioma cells express FGFR1/3, and FGFRs is required for FGF-2-induced nestin expression. Further signaling analysis also revealed that FGF-2-induced nestin expression is mediated through FGFR–MAPK–ERK signaling axis and the transcriptional factor Sp1. These findings provide new insight into the regulation of nestin in glial system and enable the further studies on the function of nestin in glial cells.

  20. Castration induces up-regulation of intratumoral androgen biosynthesis and androgen receptor expression in an orthotopic VCaP human prostate cancer xenograft model.

    Science.gov (United States)

    Knuuttila, Matias; Yatkin, Emrah; Kallio, Jenny; Savolainen, Saija; Laajala, Teemu D; Aittokallio, Tero; Oksala, Riikka; Häkkinen, Merja; Keski-Rahkonen, Pekka; Auriola, Seppo; Poutanen, Matti; Mäkelä, Sari

    2014-08-01

    Androgens are key factors involved in the development and progression of prostate cancer (PCa), and PCa growth can be suppressed by androgen deprivation therapy. In a considerable proportion of men receiving androgen deprivation therapy, however, PCa progresses to castration-resistant PCa (CRPC), making the development of efficient therapies challenging. We used an orthotopic VCaP human PCa xenograft model to study cellular and molecular changes in tumors after androgen deprivation therapy (castration). Tumor growth was monitored through weekly serum prostate-specific antigen measurements, and mice with recurrent tumors after castration were randomized to treatment groups. Serum prostate-specific antigen concentrations showed significant correlation with tumor volume. Castration-resistant tumors retained concentrations of intratumoral androgen (androstenedione, testosterone, and 5α-dihydrotestosterone) at levels similar to tumors growing in intact hosts. Accordingly, castration induced up-regulation of enzymes involved in androgen synthesis (CYP17A1, AKR1C3, and HSD17B6), as well as expression of full-length androgen receptor (AR) and AR splice variants (AR-V1 and AR-V7). Furthermore, AR target gene expression was maintained in castration-resistant xenografts. The AR antagonists enzalutamide (MDV3100) and ARN-509 suppressed PSA production of castration-resistant tumors, confirming the androgen dependency of these tumors. Taken together, the findings demonstrate that our VCaP xenograft model exhibits the key characteristics of clinical CRPC and thus provides a valuable tool for identifying druggable targets and for testing therapeutic strategies targeting AR signaling in CRPC.

  1. Prostate Cancer

    OpenAIRE

    Eggener, Scott

    2011-01-01

    Prostate cancer continues to be a significant public health issue worldwide, particularly in countries where men have life expectancies long enough to clinically manifest the disease. In many countries, it remains one of the leading causes of cancer-related morbidity and mortality.Although significant progress has been made over the past few decades, many elements regarding the diagnosis and management of patients with prostate cancer remain enigmatic. In this Prostate Cancer special issue, o...

  2. Atlas of prostate cancer heritability in European and African-American men pinpoints tissue-specific regulation.

    Science.gov (United States)

    Gusev, Alexander; Shi, Huwenbo; Kichaev, Gleb; Pomerantz, Mark; Li, Fugen; Long, Henry W; Ingles, Sue A; Kittles, Rick A; Strom, Sara S; Rybicki, Benjamin A; Nemesure, Barbara; Isaacs, William B; Zheng, Wei; Pettaway, Curtis A; Yeboah, Edward D; Tettey, Yao; Biritwum, Richard B; Adjei, Andrew A; Tay, Evelyn; Truelove, Ann; Niwa, Shelley; Chokkalingam, Anand P; John, Esther M; Murphy, Adam B; Signorello, Lisa B; Carpten, John; Leske, M Cristina; Wu, Suh-Yuh; Hennis, Anslem J M; Neslund-Dudas, Christine; Hsing, Ann W; Chu, Lisa; Goodman, Phyllis J; Klein, Eric A; Witte, John S; Casey, Graham; Kaggwa, Sam; Cook, Michael B; Stram, Daniel O; Blot, William J; Eeles, Rosalind A; Easton, Douglas; Kote-Jarai, Zsofia; Al Olama, Ali Amin; Benlloch, Sara; Muir, Kenneth; Giles, Graham G; Southey, Melissa C; Fitzgerald, Liesel M; Gronberg, Henrik; Wiklund, Fredrik; Aly, Markus; Henderson, Brian E; Schleutker, Johanna; Wahlfors, Tiina; Tammela, Teuvo L J; Nordestgaard, Børge G; Key, Tim J; Travis, Ruth C; Neal, David E; Donovan, Jenny L; Hamdy, Freddie C; Pharoah, Paul; Pashayan, Nora; Khaw, Kay-Tee; Stanford, Janet L; Thibodeau, Stephen N; McDonnell, Shannon K; Schaid, Daniel J; Maier, Christiane; Vogel, Walther; Luedeke, Manuel; Herkommer, Kathleen; Kibel, Adam S; Cybulski, Cezary; Wokolorczyk, Dominika; Kluzniak, Wojciech; Cannon-Albright, Lisa; Teerlink, Craig; Brenner, Hermann; Dieffenbach, Aida K; Arndt, Volker; Park, Jong Y; Sellers, Thomas A; Lin, Hui-Yi; Slavov, Chavdar; Kaneva, Radka; Mitev, Vanio; Batra, Jyotsna; Spurdle, Amanda; Clements, Judith A; Teixeira, Manuel R; Pandha, Hardev; Michael, Agnieszka; Paulo, Paula; Maia, Sofia; Kierzek, Andrzej; Conti, David V; Albanes, Demetrius; Berg, Christine; Berndt, Sonja I; Campa, Daniele; Crawford, E David; Diver, W Ryan; Gapstur, Susan M; Gaziano, J Michael; Giovannucci, Edward; Hoover, Robert; Hunter, David J; Johansson, Mattias; Kraft, Peter; Le Marchand, Loic; Lindström, Sara; Navarro, Carmen; Overvad, Kim; Riboli, Elio; Siddiq, Afshan; Stevens, Victoria L; Trichopoulos, Dimitrios; Vineis, Paolo; Yeager, Meredith; Trynka, Gosia; Raychaudhuri, Soumya; Schumacher, Frederick R; Price, Alkes L; Freedman, Matthew L; Haiman, Christopher A; Pasaniuc, Bogdan

    2016-04-07

    Although genome-wide association studies have identified over 100 risk loci that explain ∼33% of familial risk for prostate cancer (PrCa), their functional effects on risk remain largely unknown. Here we use genotype data from 59,089 men of European and African American ancestries combined with cell-type-specific epigenetic data to build a genomic atlas of single-nucleotide polymorphism (SNP) heritability in PrCa. We find significant differences in heritability between variants in prostate-relevant epigenetic marks defined in normal versus tumour tissue as well as between tissue and cell lines. The majority of SNP heritability lies in regions marked by H3k27 acetylation in prostate adenoc7arcinoma cell line (LNCaP) or by DNaseI hypersensitive sites in cancer cell lines. We find a high degree of similarity between European and African American ancestries suggesting a similar genetic architecture from common variation underlying PrCa risk. Our findings showcase the power of integrating functional annotation with genetic data to understand the genetic basis of PrCa.

  3. Atlas of prostate cancer heritability in European and African-American men pinpoints tissue-specific regulation

    Science.gov (United States)

    Gusev, Alexander; Shi, Huwenbo; Kichaev, Gleb; Pomerantz, Mark; Li, Fugen; Long, Henry W.; Ingles, Sue A.; Kittles, Rick A.; Strom, Sara S.; Rybicki, Benjamin A.; Nemesure, Barbara; Isaacs, William B.; Zheng, Wei; Pettaway, Curtis A.; Yeboah, Edward D.; Tettey, Yao; Biritwum, Richard B.; Adjei, Andrew A.; Tay, Evelyn; Truelove, Ann; Niwa, Shelley; Chokkalingam, Anand P.; John, Esther M.; Murphy, Adam B.; Signorello, Lisa B.; Carpten, John; Leske, M. Cristina; Wu, Suh-Yuh; Hennis, Anslem J. M.; Neslund-Dudas, Christine; Hsing, Ann W.; Chu, Lisa; Goodman, Phyllis J.; Klein, Eric A.; Witte, John S.; Casey, Graham; Kaggwa, Sam; Cook, Michael B.; Stram, Daniel O.; Blot, William J.; Eeles, Rosalind A.; Easton, Douglas; Kote-Jarai, ZSofia; Al Olama, Ali Amin; Benlloch, Sara; Muir, Kenneth; Giles, Graham G.; Southey, Melissa C.; Fitzgerald, Liesel M.; Gronberg, Henrik; Wiklund, Fredrik; Aly, Markus; Henderson, Brian E.; Schleutker, Johanna; Wahlfors, Tiina; Tammela, Teuvo L. J.; Nordestgaard, Børge G.; Key, Tim J.; Travis, Ruth C.; Neal, David E.; Donovan, Jenny L.; Hamdy, Freddie C.; Pharoah, Paul; Pashayan, Nora; Khaw, Kay-Tee; Stanford, Janet L.; Thibodeau, Stephen N.; McDonnell, Shannon K.; Schaid, Daniel J.; Maier, Christiane; Vogel, Walther; Luedeke, Manuel; Herkommer, Kathleen; Kibel, Adam S.; Cybulski, Cezary; Wokolorczyk, Dominika; Kluzniak, Wojciech; Cannon-Albright, Lisa; Teerlink, Craig; Brenner, Hermann; Dieffenbach, Aida K.; Arndt, Volker; Park, Jong Y.; Sellers, Thomas A.; Lin, Hui-Yi; Slavov, Chavdar; Kaneva, Radka; Mitev, Vanio; Batra, Jyotsna; Spurdle, Amanda; Clements, Judith A.; Teixeira, Manuel R.; Pandha, Hardev; Michael, Agnieszka; Paulo, Paula; Maia, Sofia; Kierzek, Andrzej; Cook, Margaret; Guy, Michelle; Govindasami, Koveela; Leongamornlert, Daniel; Sawyer, Emma J.; Wilkinson, Rosemary; Saunders, Edward J.; Tymrakiewicz, Malgorzata; Dadaev, Tokhir; Morgan, Angela; Fisher, Cyril; Hazel, Steve; Livni, Naomi; Lophatananon, Artitaya; Pedersen, John; Hopper, John L.; Adolfson, Jan; Stattin, Paer; Johansson, Jan-Erik; Cavalli-Bjoerkman, Carin; Karlsson, Ami; Broms, Michael; Auvinen, Anssi; Kujala, Paula; Maeaettaenen, Liisa; Murtola, Teemu; Taari, Kimmo; Weischer, Maren; Nielsen, Sune F.; Klarskov, Peter; Roder, Andreas; Iversen, Peter; Wallinder, Hans; Gustafsson, Sven; Cox, Angela; Brown, Paul; George, Anne; Marsden, Gemma; Lane, Athene; Davis, Michael; Zheng, Wei; Signorello, Lisa B.; Blot, William J.; Tillmans, Lori; Riska, Shaun; Wang, Liang; Rinckleb, Antje; Lubiski, Jan; Stegmaier, Christa; Pow-Sang, Julio; Park, Hyun; Radlein, Selina; Rincon, Maria; Haley, James; Zachariah, Babu; Kachakova, Darina; Popov, Elenko; Mitkova, Atanaska; Vlahova, Aleksandrina; Dikov, Tihomir; Christova, Svetlana; Heathcote, Peter; Wood, Glenn; Malone, Greg; Saunders, Pamela; Eckert, Allison; Yeadon, Trina; Kerr, Kris; Collins, Angus; Turner, Megan; Srinivasan, Srilakshmi; Kedda, Mary-Anne; Alexander, Kimberly; Omara, Tracy; Wu, Huihai; Henrique, Rui; Pinto, Pedro; Santos, Joana; Barros-Silva, Joao; Conti, David V.; Albanes, Demetrius; Berg, Christine; Berndt, Sonja I.; Campa, Daniele; Crawford, E. David; Diver, W. Ryan; Gapstur, Susan M.; Gaziano, J. Michael; Giovannucci, Edward; Hoover, Robert; Hunter, David J.; Johansson, Mattias; Kraft, Peter; Le Marchand, Loic; Lindström, Sara; Navarro, Carmen; Overvad, Kim; Riboli, Elio; Siddiq, Afshan; Stevens, Victoria L.; Trichopoulos, Dimitrios; Vineis, Paolo; Yeager, Meredith; Trynka, Gosia; Raychaudhuri, Soumya; Schumacher, Frederick R.; Price, Alkes L.; Freedman, Matthew L.; Haiman, Christopher A.; Pasaniuc, Bogdan

    2016-01-01

    Although genome-wide association studies have identified over 100 risk loci that explain ∼33% of familial risk for prostate cancer (PrCa), their functional effects on risk remain largely unknown. Here we use genotype data from 59,089 men of European and African American ancestries combined with cell-type-specific epigenetic data to build a genomic atlas of single-nucleotide polymorphism (SNP) heritability in PrCa. We find significant differences in heritability between variants in prostate-relevant epigenetic marks defined in normal versus tumour tissue as well as between tissue and cell lines. The majority of SNP heritability lies in regions marked by H3k27 acetylation in prostate adenoc7arcinoma cell line (LNCaP) or by DNaseI hypersensitive sites in cancer cell lines. We find a high degree of similarity between European and African American ancestries suggesting a similar genetic architecture from common variation underlying PrCa risk. Our findings showcase the power of integrating functional annotation with genetic data to understand the genetic basis of PrCa. PMID:27052111

  4. Prostate cancer

    International Nuclear Information System (INIS)

    This work is about diagnosis, treatment and monitoring of prostate cancer. The techniques used are: transrectal ultrasound, laparascopy, bone scan, chest x-ray, radiography, chemoterapy and radiotherapy

  5. Quercetin inhibits angiogenesis mediated human prostate tumor growth by targeting VEGFR- 2 regulated AKT/mTOR/P70S6K signaling pathways.

    Directory of Open Access Journals (Sweden)

    Poyil Pratheeshkumar

    Full Text Available Angiogenesis is a crucial step in the growth and metastasis of cancers, since it enables the growing tumor to receive oxygen and nutrients. Cancer prevention using natural products has become an integral part of cancer control. We studied the antiangiogenic activity of quercetin using ex vivo, in vivo and in vitro models. Rat aortic ring assay showed that quercetin at non-toxic concentrations significantly inhibited microvessel sprouting and exhibited a significant inhibition in the proliferation, migration, invasion and tube formation of endothelial cells, which are key events in the process of angiogenesis. Most importantly, quercetin treatment inhibited ex vivo angiogenesis as revealed by chicken egg chorioallantoic membrane assay (CAM and matrigel plug assay. Western blot analysis showed that quercetin suppressed VEGF induced phosphorylation of VEGF receptor 2 and their downstream protein kinases AKT, mTOR, and ribosomal protein S6 kinase in HUVECs. Quercetin (20 mg/kg/d significantly reduced the volume and the weight of solid tumors in prostate xenograft mouse model, indicating that quercetin inhibited tumorigenesis by targeting angiogenesis. Furthermore, quercetin reduced the cell viability and induced apoptosis in prostate cancer cells, which were correlated with the downregulation of AKT, mTOR and P70S6K expressions. Collectively the findings in the present study suggest that quercetin inhibits tumor growth and angiogenesis by targeting VEGF-R2 regulated AKT/mTOR/P70S6K signaling pathway, and could be used as a potential drug candidate for cancer therapy.

  6. A miR-590/Acvr2a/Rad51b Axis Regulates DNA Damage Repair during mESC Proliferation

    Directory of Open Access Journals (Sweden)

    Qidong Liu

    2014-12-01

    Full Text Available Embryonic stem cells (ESCs enable rapid proliferation that also causes DNA damage. To maintain genomic stabilization during rapid proliferation, ESCs must have an efficient system to repress genotoxic stress. Here, we show that withdrawal of leukemia inhibitory factor (LIF, which maintains the self-renewal capability of mouse ESCs (mESCs, significantly inhibits the cell proliferation and DNA damage of mESCs and upregulates the expression of miR-590. miR-590 promotes single-strand break (SSB and double-strand break (DSB damage repair, thus slowing proliferation of mESCs without influencing stemness. miR-590 directly targets Activin receptor type 2a (Acvr2a to mediate Activin signaling. We identified the homologous recombination-mediated repair (HRR gene, Rad51b, as a downstream molecule of the miR-590/Acvr2a pathway regulating the SSB and DSB damage repair and cell cycle. Our study shows that a miR-590/Acvr2a/Rad51b signaling axis ensures the stabilization of mESCs by balancing DNA damage repair and rapid proliferation during self-renewal.

  7. Taurine and pioglitazone attenuate diabetes-induced testicular damage by abrogation of oxidative stress and up-regulation of the pituitary-gonadal axis.

    Science.gov (United States)

    Abd El-Twab, Sanaa M; Mohamed, Hanaa M; Mahmoud, Ayman M

    2016-06-01

    Chronic hyperglycemia is associated with impairment of testicular function. The current study aimed to investigate the protective effects and the possible mechanisms of taurine and pioglitazone against diabetes-induced testicular dysfunction in rats. Diabetes was induced by streptozotocin injection. Both normal and diabetic rats received taurine (100 mg/kg) or pioglitazone (10 mg/kg) orally and daily for 6 weeks. Diabetic rats showed a significant (P diabetic rats. Taurine and pioglitazone alleviated hyperglycemia, decreased pro-inflammatory cytokines, and increased circulating levels of insulin, testosterone, LH, and FSH. Gene and protein expression of LH and FSH receptors and cytochrome P450 17α-hydroxylase (CYP17) was significantly (P diabetic rats, an effect which was significantly increased after administration of taurine and pioglitazone. In addition, taurine and pioglitazone significantly decreased lipid peroxidation and DNA damage, and enhanced activity of the antioxidant enzymes in testes of diabetic rats. In conclusion, taurine and pioglitazone exerted protective effects against diabetes-induced testicular damage through attenuation of hyperglycemia, inflammation, oxidative stress and DNA damage, and up-regulation of the pituitary/gonadal axis. PMID:27089006

  8. A post-translational modification cascade employing HDAC9-PIASy-RNF4 axis regulates chondrocyte hypertrophy by modulating Nkx3.2 protein stability.

    Science.gov (United States)

    Choi, Hye-Jeong; Kwon, Seongran; Kim, Dae-Won

    2016-09-01

    While Nkx3.2/Bapx1 promotes chondrogenic differentiation and plays a role in maintaining chondrocyte viability and suppressing chondrocyte hypertrophy, the regulatory mechanisms of Nkx3.2 remain poorly understood. Here we show that p300- and HDAC9-induced Nkx3.2 acetylation and de-acetylation, respectively, play critical roles in controlling Nkx3.2 protein stability. In addition, we also found that HDAC9-dependent de-acetylation of Nkx3.2 triggers PIASy-mediated sumoylation and subsequent RNF4-mediated SUMO-targeted ubiquitination. Furthermore, we demonstrate that Nkx3.2 regulation by HDAC9 can be linked to the management of chondrocyte survival and hypertrophic maturation during cartilage development. Finally, our results together reveal a novel mechanism of protein stability control involving complex interplay between acetylation, de-acetylation, sumoylation, and ubiquitination, and suggest that this post-translational modification of Nkx3.2 employing HDAC9-PIASy-RNF4 axis plays a crucial role in controlling chondrocyte viability and hypertrophic maturation during skeletal development in vertebrates. PMID:27312341

  9. Fucoidan Elevates MicroRNA-29b to Regulate DNMT3B-MTSS1 Axis and Inhibit EMT in Human Hepatocellular Carcinoma Cells

    Directory of Open Access Journals (Sweden)

    Ming-De Yan

    2015-09-01

    Full Text Available Accumulating evidence has revealed that fucoidan exhibits anti-tumor activities by arresting cell cycle and inducing apoptosis in many types of cancer cells including hepatocellular carcinoma (HCC. Exploring its effect on microRNA expression, we found that fucoidan markedly upregulated miR-29b of human HCC cells. The induction of miR-29b was accompanied with suppression of its downstream target DNMT3B in a dose-dependent manner. The reduction of luciferase activity of DNMT3B 3′-UTR reporter by fucoidan was as markedly as that by miR-29b mimic, indicating that fucoidan induced miR-29b to suppress DNMT3B. Accordingly, the mRNA and protein levels of MTSS1 (metastasis suppressor 1, a target silenced by DNMT3B, were increased after fucoidan treatment. Furthermore, fucoidan also down-regulated TGF-β receptor and Smad signaling of HCC cells. All these effects leaded to the inhibition of EMT (increased E-cadherin and decreased N-cadherin and prevention of extracellular matrix degradation (increased TIMP-1 and decreased MMP2, 9, by which the invasion activity of HCC cells was diminished. Our results demonstrate the profound effect of fucoidan not only on the regulation of miR-29b-DNMT3B-MTSS1 axis but also on the inhibition of TGF-β signaling in HCC cells, suggesting the potential of using fucoidan as integrative therapeutics against invasion and metastasis of HCC.

  10. Essential function for PDLIM2 in cell polarization in three-dimensional cultures by feedback regulation of the β1-integrin-RhoA signaling axis.

    Science.gov (United States)

    Deevi, Ravi Kiran; Cox, Orla T; O'Connor, Rosemary

    2014-05-01

    PDLIM2 is a cytoskeletal and nuclear PDZ-LIM domain protein that regulates the stability of Nuclear Factor kappa-B (NFκB) and other transcription factors, and is required for polarized cell migration. PDLIM2 expression is suppressed by methylation in different cancers, but is strongly expressed in invasive breast cancer cells that have undergone an Epithelial Mesenchymal Transition (EMT). PDLIM2 is also expressed in non-transformed breast myoepithelial MCF10A cells and here we asked whether it is important for maintaining the polarized, epithelial phenotype of these cells. Suppression of PDLIM2 in MCF10A cells was sufficient to disrupt cell polarization and acini formation with increased proliferation and reduced apoptosis in the luminal space compared to control acini with hollow lumina. Spheroids with suppressed PDLIM2 exhibited increased expression of cell-cell and cell-matrix adhesion proteins including beta 1 (β1) integrin. Interestingly, levels of the Insulin-like growth factor 1 receptor (IGF-1 R) and Receptor of activated protein kinase C 1 (RACK1), which scaffolds IGF-1R to β1 integrin, were also increased, indicating a transformed phenotype. Focal Adhesion Kinase (FAK) and cofilin phosphorylation, and RhoA Guanosine Triphosphatase (GTPase) activity were all enhanced in these spheroids compared to control acini. Importantly, inhibition of either FAK or Rho Kinase (ROCK) was sufficient to rescue the polarity defect. We conclude that PDLIM2 expression is essential for feedback regulation of the β1-integrin-RhoA signalling axis and integration of cellular microenvironment signals with gene expression to control the polarity of breast epithelial acini structures. This is a mechanism by which PDLIM2 could mediate tumour suppression in breast epithelium. PMID:24863845

  11. Essential Function for PDLIM2 in Cell Polarization in Three-Dimensional Cultures by Feedback Regulation of the β1-Integrin–RhoA Signaling Axis

    Directory of Open Access Journals (Sweden)

    Ravi Kiran Deevi

    2014-05-01

    Full Text Available PDLIM2 is a cytoskeletal and nuclear PDZ-LIM domain protein that regulates the stability of Nuclear Factor kappa-B (NFκB and other transcription factors, and is required for polarized cell migration. PDLIM2 expression is suppressed by methylation in different cancers, but is strongly expressed in invasive breast cancer cells that have undergone an Epithelial Mesenchymal Transition (EMT. PDLIM2 is also expressed in non-transformed breast myoepithelial MCF10A cells and here we asked whether it is important for maintaining the polarized, epithelial phenotype of these cells. Suppression of PDLIM2 in MCF10A cells was sufficient to disrupt cell polarization and acini formation with increased proliferation and reduced apoptosis in the luminal space compared to control acini with hollow lumina. Spheroids with suppressed PDLIM2 exhibited increased expression of cell-cell and cell-matrix adhesion proteins including beta 1 (β1 integrin. Interestingly, levels of the Insulin-like growth factor 1 receptor (IGF-1 R and Receptor of activated protein kinase C 1 (RACK1, which scaffolds IGF-1R to β1 integrin, were also increased, indicating a transformed phenotype. Focal Adhesion Kinase (FAK and cofilin phosphorylation, and RhoA Guanosine Triphosphatase (GTPase activity were all enhanced in these spheroids compared to control acini. Importantly, inhibition of either FAK or Rho Kinase (ROCK was sufficient to rescue the polarity defect. We conclude that PDLIM2 expression is essential for feedback regulation of the β1-integrin-RhoA signalling axis and integration of cellular microenvironment signals with gene expression to control the polarity of breast epithelial acini structures. This is a mechanism by which PDLIM2 could mediate tumour suppression in breast epithelium.

  12. Androgen receptor and its splice variant, AR-V7, differentially regulate FOXA1 sensitive genes in LNCaP prostate cancer cells.

    Science.gov (United States)

    Krause, William C; Shafi, Ayesha A; Nakka, Manjula; Weigel, Nancy L

    2014-09-01

    Prostate cancer (PCa) is an androgen-dependent disease, and tumors that are resistant to androgen ablation therapy often remain androgen receptor (AR) dependent. Among the contributors to castration-resistant PCa are AR splice variants that lack the ligand-binding domain (LBD). Instead, they have small amounts of unique sequence derived from cryptic exons or from out of frame translation. The AR-V7 (or AR3) variant is constitutively active and is expressed under conditions consistent with CRPC. AR-V7 is reported to regulate a transcriptional program that is similar but not identical to that of AR. However, it is unknown whether these differences are due to the unique sequence in AR-V7, or simply to loss of the LBD. To examine transcriptional regulation by AR-V7, we have used lentiviruses encoding AR-V7 (amino acids 1-627 of AR with the 16 amino acids unique to the variant) to prepare a derivative of the androgen-dependent LNCaP cells with inducible expression of AR-V7. An additional cell line was generated with regulated expression of AR-NTD (amino acids 1-660 of AR); this mutant lacks the LBD but does not have the AR-V7 specific sequence. We find that AR and AR-V7 have distinct activities on target genes that are co-regulated by FOXA1. Transcripts regulated by AR-V7 were similarly regulated by AR-NTD, indicating that loss of the LBD is sufficient for the observed differences. Differential regulation of target genes correlates with preferential recruitment of AR or AR-V7 to specific cis-regulatory DNA sequences providing an explanation for some of the observed differences in target gene regulation.

  13. Biomarkers in Prostate Cancer Epidemiology

    Directory of Open Access Journals (Sweden)

    Mudit Verma

    2011-09-01

    Full Text Available Understanding the etiology of a disease such as prostate cancer may help in identifying populations at high risk, timely intervention of the disease, and proper treatment. Biomarkers, along with exposure history and clinical data, are useful tools to achieve these goals. Individual risk and population incidence of prostate cancer result from the intervention of genetic susceptibility and exposure. Biochemical, epigenetic, genetic, and imaging biomarkers are used to identify people at high risk for developing prostate cancer. In cancer epidemiology, epigenetic biomarkers offer advantages over other types of biomarkers because they are expressed against a person’s genetic background and environmental exposure, and because abnormal events occur early in cancer development, which includes several epigenetic alterations in cancer cells. This article describes different biomarkers that have potential use in studying the epidemiology of prostate cancer. We also discuss the characteristics of an ideal biomarker for prostate cancer, and technologies utilized for biomarker assays. Among epigenetic biomarkers, most reports indicate GSTP1 hypermethylation as the diagnostic marker for prostate cancer; however, NKX2-5, CLSTN1, SPOCK2, SLC16A12, DPYS, and NSE1 also have been reported to be regulated by methylation mechanisms in prostate cancer. Current challenges in utilization of biomarkers in prostate cancer diagnosis and epidemiologic studies and potential solutions also are discussed.

  14. Inhibitory effect of triptolide on lymph node metastasis in patients with non-Hodgkin lymphoma by regulating SDF-1/CXCR4 axis in vitro

    Institute of Scientific and Technical Information of China (English)

    Chun ZHANG; Guo-hui CUI; Fang LIU; Qiu-ling WU; Yan CHEN

    2006-01-01

    Aim: To investigate the antiproliferative effect of triptolide on B-NHL cell line Raji cells, to study its effect on lymph node metastasis in patients with non-Hodgkin's lymphoma (NHL) in vitro, and to explore the underlying mechanism regulating SDF-1/CXCR4 axis. Methods: The effects of triptolide on the growth of Raji cells were studied by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium (MTT) assay. The effects of triptolide on SDF-1 mRNA expression in lymph node stromal cells from patients with NHL were determined by reverse transcriptase-polymerase chain reaction (RT-PCR). The effects of triptolide on CXCR4 expression on lymphoma cells freshly isolated from the lymph nodes of these patients were studied by flow cytometric analysis. Chemotaxis assays were performed to observe the effects of triptolide on migration of primary lymphoma cells towards recombinant human SDF-la (rhSDF-1α) or cultured lymph node stromal cells in vitro. Results: Triptolide inhibited the proliferation of B-NHL cell line Raji cells in a dose- and time-dependent manner with a 24-h IC50 value of 43.06 nmol/L and a 36-h IC50 value of 25.08 nmol/L. The expression of SDF-la mRNA in lymph node stromal cells obtained from patients with NHL was decreased after treatment by triptolide at concentrations of 25 and 50 nmol/L for 24 h. Flow cytometry analysis showed that the CXCR4 expression on primary lymphoma cells were downregulated gradually in a dose-dependent manner following triptolide treatment. Chemotaxis assays revealed that the migration of freshly isolated lymphoma cells towards either rhSDF-1 or cultured lymph node stromal cells was markedly inhibited by the addition of triptolide in vitro, and the inhibition was dose-dependent. Conclusion: Triptolide can inhibit the proliferation of B-NHL cell line Raji cells. Moreover, triptolide is able to inhibit the migration of lymphoma cells via lymph nodes in vitro. The potential antitumor mechanisms of triptolide are related to the

  15. Inflammatory Genetic Markers of Prostate Cancer Risk

    Energy Technology Data Exchange (ETDEWEB)

    Tindall, Elizabeth A.; Hayes, Vanessa M. [Cancer Genetics Group, Children’s Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, University of New South Wales, PO Box 81, Randwick, NSW 2031 (Australia); University of New South Wales, Kensington Campus, Sydney, NSW 2052 (Australia); Petersen, Desiree C., E-mail: dpetersen@ccia.unsw.edu.au [Cancer Genetics Group, Children’s Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, University of New South Wales, PO Box 81, Randwick, NSW 2031 (Australia)

    2010-06-08

    Prostate cancer is the most common cancer in Western society males, with incidence rates predicted to rise with global aging. Etiology of prostate cancer is however poorly understood, while current diagnostic tools can be invasive (digital rectal exam or biopsy) and/or lack specificity for the disease (prostate-specific antigen (PSA) testing). Substantial histological, epidemiological and molecular genetic evidence indicates that inflammation is important in prostate cancer pathogenesis. In this review, we summarize the current status of inflammatory genetic markers influencing susceptibility to prostate cancer. The focus will be on inflammatory cytokines regulating T-helper cell and chemokine homeostasis, together with the Toll-like receptors as key players in the host innate immune system. Although association studies indicating a genetic basis for prostate cancer are presently limited mainly due to lack of replication, larger and more ethnically and clinically defined study populations may help elucidate the true contribution of inflammatory gene variants to prostate cancer risk.

  16. Inflammatory Genetic Markers of Prostate Cancer Risk

    International Nuclear Information System (INIS)

    Prostate cancer is the most common cancer in Western society males, with incidence rates predicted to rise with global aging. Etiology of prostate cancer is however poorly understood, while current diagnostic tools can be invasive (digital rectal exam or biopsy) and/or lack specificity for the disease (prostate-specific antigen (PSA) testing). Substantial histological, epidemiological and molecular genetic evidence indicates that inflammation is important in prostate cancer pathogenesis. In this review, we summarize the current status of inflammatory genetic markers influencing susceptibility to prostate cancer. The focus will be on inflammatory cytokines regulating T-helper cell and chemokine homeostasis, together with the Toll-like receptors as key players in the host innate immune system. Although association studies indicating a genetic basis for prostate cancer are presently limited mainly due to lack of replication, larger and more ethnically and clinically defined study populations may help elucidate the true contribution of inflammatory gene variants to prostate cancer risk

  17. TGF-β regulates DNA methyltransferase expression in prostate cancer, correlates with aggressive capabilities, and predicts disease recurrence.

    Directory of Open Access Journals (Sweden)

    Qiang Zhang

    Full Text Available BACKGROUND: DNA methyltransferase (DNMT is one of the major factors mediating the methylation of cancer related genes such as TGF-β receptors (TβRs. This in turn may result in a loss of sensitivity to physiologic levels of TGF-β in aggressive prostate cancer (CaP. The specific mechanisms of DNMT's role in CaP remain undetermined. In this study, we describe the mechanism of TGF-β-mediated DNMT in CaP and its association with clinical outcomes following radical prostatectomy. METHODOLOGY/PRINCIPAL FINDINGS: We used human CaP cell lines with varying degrees of invasive capability to describe how TGF-β mediates the expression of DNMT in CaP, and its effects on methylation status of TGF-β receptors and the invasive capability of CaP in vitro and in vivo. Furthermore, we determined the association between DNMT expression and clinical outcome after radical prostatectomy. We found that more aggressive CaP cells had significantly higher TGF-β levels, increased expression of DNMT, but reduced TβRs when compared to benign prostate cells and less aggressive prostate cancer cells. Blockade of TGF-β signaling or ERK activation (p-ERK was associated with a dramatic decrease in the expression of DNMT, which results in a coincident increase in the expression of TβRs. Blockade of either TGF-β signaling or DNMT dramatically decreased the invasive capabilities of CaP. Inhibition of TGF-β in an TRAMP-C2 CaP model in C57BL/6 mice using 1D11 was associated with downregulation of DNMTs and p-ERK and impairment in tumor growth. Finally, independent of Gleason grade, increased DNMT1 expression was associated with biochemical recurrence following surgical treatment for prostate cancer. CONCLUSIONS AND SIGNIFICANCE: Our findings demonstrate that CaP derived TGF-β may induce the expression of DNMTs in CaP which is associated with methylation of its receptors and the aggressive potential of CaP. In addition, DNMTs is an independent predictor for disease

  18. Prostate Cancer (Radiation Therapy)

    Science.gov (United States)

    ... Physician Resources Professions Site Index A-Z Prostate Cancer Treatment Prostate cancer overview? What are my treatment options? What ... any new developments in treating my disease? Prostate cancer overview Prostate cancer is the most common form of cancer ...

  19. What is Prostate Cancer?

    Science.gov (United States)

    ... Research Get Involved Find Local ACS Learn About Cancer » Prostate Cancer » Detailed Guide » What is prostate cancer? Share ... how cancers start and spread, see What Is Cancer? Prostate cancer begins when cells in the prostate gland ...

  20. Cryotherapy for prostate cancer

    Science.gov (United States)

    Cryosurgery-prostate cancer; Cryoablation-prostate cancer ... Prostate Cancer. American Cancer Society. www.cancer.org/cancer/prostatecancer/detailedguide/prostate-cancer-treating-cryosurgery. Accessed August 31, 2015. Horwich ...

  1. AMP-Activated Protein Kinase Suppresses Autoimmune Central Nervous System Disease by Regulating M1-Type Macrophage-Th17 Axis.

    Science.gov (United States)

    Mangalam, Ashutosh K; Rattan, Ramandeep; Suhail, Hamid; Singh, Jaspreet; Hoda, Md Nasrul; Deshpande, Mandar; Fulzele, Sadanand; Denic, Alexander; Shridhar, Viji; Kumar, Ashok; Viollet, Benoit; Rodriguez, Moses; Giri, Shailendra

    2016-08-01

    The AMP-activated protein kinase, AMPK, is an energy-sensing, metabolic switch implicated in various metabolic disorders; however, its role in inflammation is not well defined. We have previously shown that loss of AMPK exacerbates experimental autoimmune encephalomyelitis (EAE) disease severity. In this study, we investigated the mechanism through which AMPK modulates inflammatory disease like EAE. AMPKα1 knockout (α1KO) mice with EAE showed severe demyelination and inflammation in the brain and spinal cord compared with wild-type due to higher expression of proinflammatory Th17 cytokines, including IL-17, IL-23, and IL-1β, impaired blood-brain barrier integrity, and increased infiltration of inflammatory cells in the CNS. Infiltrated CD4 cells in the brains and spinal cords of α1KO with EAE were significantly higher compared with wild-type EAE and were characterized as IL-17 (IL-17 and GM-CSF double-positive) CD4 cells. Increased inflammatory response in α1KO mice was due to polarization of macrophages (Mϕ) to proinflammatory M1 type phenotype (IL-10(low)IL-23/IL-1β/IL-6(high)), and these M1 Mϕ showed stronger capacity to induce allogenic as well as Ag-specific (myelin oligodendrocyte glycoprotein [MOG]35-55) T cell response. Mϕ from α1KO mice also enhanced the encephalitogenic property of MOG35-55-primed CD4 T cells in B6 mice. The increased encephalitogenic MOG-restricted CD4(+) T cells were due to an autocrine effect of IL-1β/IL-23-mediated induction of IL-6 production in α1KO Mϕ, which in turn induce IL-17 and GM-CSF production in CD4 cells. Collectively, our data indicate that AMPK controls the inflammatory disease by regulating the M1 phenotype-Th17 axis in an animal model of multiple sclerosis. PMID:27354217

  2. Zinc regulates expression of IL-23 p19 mRNA via activation of eIF2α/ATF4 axis in HAPI cells.

    Science.gov (United States)

    Doi, Takuya; Hara, Hirokazu; Kajita, Miho; Kamiya, Tetsuro; Adachi, Tetsuo

    2015-10-01

    Zinc (Zn(2+)) is considered to be one of the factors aggravating brain damage after cerebral ischemia. Since Zn(2+) activates microglia, immune cells in the brain, this metal is proposed to modulate neuroinflammatory responses in the post-ischemic brain. Interleukin (IL)-23 is a heterodimeric cytokine composed of the p19 subunit unique to IL-23 and the p40 subunit common to IL-12. IL-23 has been shown to play a critical role in the progression of ischemic brain injury. However, whether Zn(2+) participates in the expression of IL-23 in microglia remains unknown. In this study, we examined the effect of Zn(2+) on IL-23 p19 mRNA expression using rat immortalized microglia HAPI cells. Exposure to Zn(2+) dose- and time-dependently induced the expression of IL-23 p19 mRNA in HAPI cells. Inhibitors of MAPK and NF-κB pathways failed to suppress this induction. Interestingly, we found that Zn(2+) stimulated the phosphorylation of eIF2α and promoted the nuclear accumulation of activating transcription factor 4 (ATF4). Treatment with salubrinal, an eIF2α dephosphorylation inhibitor, enhanced Zn(2+)-induced ATF4 accumulation and IL-23 p19 mRNA expression. In addition, reporter assay using the IL-23 p19 promoter region revealed that ATF4 directly transactivated IL-23 p19 promoter and that dominant-negative ATF4 suppressed Zn(2+)-induced activation of IL-23 p19 promoter. Taken together, these findings suggest that Zn(2+) up-regulates expression of the IL-23 p19 gene via the eIF2α/ATF4 axis in HAPI cells. PMID:26174742

  3. 针灸调控下丘脑-垂体-肾上腺轴抗抑郁的机理分析%Mechanism Analysis of the Antidepressant Effect of Acupuncture by Regulating the HPA Axis

    Institute of Scientific and Technical Information of China (English)

    肖夏; 魏京金; 李维靖; 曾晓春; 沈晓炜; 冷金成; 周奇志

    2016-01-01

    研究发现抑郁症与下丘脑-垂体-肾上腺(hypothalamic-pituitary-adrenocortical,HPA)轴功能亢进密切相关,具体表现为 HPA 轴相关激素 CRH、ACTH 及 CORT 含量的增加。针灸可良性下调 HPA 轴水平而达到显著抗抑郁效果。然而目前尚未见针刺抗抑郁的 HPA 轴机理分析,故拟从抑郁症与 HPA 轴的关系和针刺调控 HPA 轴抗抑郁的临床、动物实验机理研究这两方面分析,为临床上针灸治疗抑郁症提供更有力的科学依据和进一步深入研究的思路。%Studies have found that depression is closely related to the hyperactivity of the hypothalamo–pituitary–adrenal (HPA) axis, which is manifested in increases in HPA axis-related hormones CRH, ACTH and CORT contents. Traditional Chinese medical acupuncture can down-regulate HPA axis levels to produce a marked antidepressant effect. However, at present there is no HPA axis mechanism analysis of the antidepressant effect of acupuncture. From two aspects: the relationship between depression and HPA axis, and clinical and animal mechanism studies of the antidepressant effect of acupuncture by regulating the HPA axis, an analysis has been made to provide a more powerful scientific basis and the idea of further in-depth study for clinical acupuncture treatment of depression.

  4. Prostatic melanosis

    Directory of Open Access Journals (Sweden)

    Kemal DENİZ

    2007-09-01

    Full Text Available Prostatic melanosis is a rare lesion that is characterized by melanin-containing spindle cells mainly located in the stroma of the prostate gland. This lesion is certainly benign and not a precursor of malignant melanoma. However, differential diagnosis of melanosis with primary and metastatic malignant melanoma is extremely important because of the different biological nature and clinical behavior of these two entities. Recognition of the spectrum of pigmented lesions in the prostate gland is essential to take into consideration of the diagnosis of melanocytic lesions.In this paper, a case of melanosis

  5. Oridonin Up-regulates Expression of P21 and Induces Autophagy and Apoptosis in Human Prostate Cancer Cells

    Directory of Open Access Journals (Sweden)

    Xiang Li, Xiang Li, Jiaxiong Wang, Zaiyuan Ye, Ji-Cheng Li

    2012-01-01

    Full Text Available Background: Oridonin (ORI could inhibit the proliferation and induce apoptosis in various cancer cell lines. However, the mechanism is not fully understood.Methods: Human prostate cancer (HPC cells were cultured in vitro and cell viability was detected by the CCK-8 assay. The ultrastructure changes were observed under transmission electron microscope (TEM. Chemical staining with acridine orange (AO, MDC or DAPI was used to detect acidic vesicular organelles (AVOs and alternation of DNA. Expression of LC3 and P21 was detected by Western Blot. Apoptotic rates and cell cycle arrest were detected by FACS.Results: Our study demonstrated that after ORI treatment, the proliferations of human prostate cancer (HPC cell lines PC-3 and LNCaP were inhibited in a concentration and time-dependent manner. ORI induced cell cycle arrest at the G2/M phase. A large number of autophagosomes with double-membrane structure and acidic vesicular organelles (AVOs were detected in the cytoplasm of HPC cells treated with ORI for 24 hours. ORI resulted in the conversion of LC3-I to LC3-II and recruitment of LC3-II to the autophagosomal membranes. Autophagy inhibitor 3-methyladenine (3-MA reduced AVOs formation and inhibited LC3-I to LC3-II conversion. At 48 h, DNA fragmentation, chromatin condensation and disappearance of surface microvilli were detected in ORI-treated cells. ORI induced a significant increase in the number of apoptotic cells (PC-3: 5.4% to 27.0%, LNCaP: 5.3% to 31.0%. Promoting autophagy by nutrient starvation increased cell viability, while inhibition of autophagy by 3-MA promoted cell death. The expression of P21 was increased by ORI, which could be completely reversed by the inhibition of autophagy.Conclusions: Our findings indicated that autophagy occurred before the onset of apoptosis and protected cancer cells in ORI-treated HPC cells. P21 was involved in ORI-induced autophagy and apoptosis. Our results provide an experimental basis for understand

  6. Benign prostate hyperplasia (BPH) - resources

    Science.gov (United States)

    Resources - benign prostatic hyperplasia (BPH); Prostate enlargement resources; BPH resources ... The following organizations provide information on benign prostatic hyperplasia ( prostate enlargement ... Urology Care Foundation -- www. ...

  7. Toll-like Receptor 3 Regulates Angiogenesis and Apoptosis in Prostate Cancer Cell Lines through Hypoxia-Inducible Factor 1α

    Directory of Open Access Journals (Sweden)

    Alessio Paone

    2010-07-01

    Full Text Available Toll-like receptors (TLRs recognize microbial/viral-derived components that trigger innate immune response and conflicting data implicate TLR agonists in cancer, either as protumor or antitumor agents. We previously demonstrated that TLR3 activation mediated by its agonist poly(I:C induces antitumor signaling, leading to apoptosis of prostate cancer cells LNCaP and PC3 with much more efficiency in the former than in the second more aggressive line. The transcription factor hypoxia-induciblefactor 1 (HIF-1regulates several cellular processes, includingapoptosis, in response to hypoxia and to other stimuli also in normoxic conditions. Here we describe a novel protumor machinery triggered by TLR3 activation in PC3 cells consisting of increased expression of the specific 1.3 isoform of HIF-1α and nuclear accumulation of HIF-1 complex in normoxia, resulting in reduced apoptosis and in secretion of functional vascular endothelial growth factor (VEGF. Moreover, we report that, in the less aggressive LNCaP cells, TLR3 activation fails to induce nuclear accumulation of HIF-1α. However, the transfection of 1.3 isoform of hif-1α in LNCaP cells allows poly(I:CI-induced HIF-1 activation, resulting in apoptosis protection and VEGF secretion. Altogether, our findings demonstrate that differences in the basal level of HIF-1α expression in different prostate cancer cell lines underlie their differential response to TLR3 activation, suggesting a correlation between different stages of malignancy, hypoxic gene expression, and beneficial responsiveness to TLR agonists.

  8. Toll-like receptor 3 regulates angiogenesis and apoptosis in prostate cancer cell lines through hypoxia-inducible factor 1 alpha.

    Science.gov (United States)

    Paone, Alessio; Galli, Roberta; Gabellini, Chiara; Lukashev, Dmitriy; Starace, Donatella; Gorlach, Agnes; De Cesaris, Paola; Ziparo, Elio; Del Bufalo, Donatella; Sitkovsky, Michail V; Filippini, Antonio; Riccioli, Anna

    2010-07-01

    Toll-like receptors (TLRs) recognize microbial/viral-derived components that trigger innate immune response and conflicting data implicate TLR agonists in cancer, either as protumor or antitumor agents. We previously demonstrated that TLR3 activation mediated by its agonist poly(I:C) induces antitumor signaling, leading to apoptosis of prostate cancer cells LNCaP and PC3 with much more efficiency in the former than in the second more aggressive line. The transcription factor hypoxia-inducible factor 1 (HIF-1) regulates several cellular processes, including apoptosis, in response to hypoxia and to other stimuli also in normoxic conditions. Here we describe a novel protumor machinery triggered by TLR3 activation in PC3 cells consisting of increased expression of the specific I.3 isoform of HIF-1 alpha and nuclear accumulation of HIF-1 complex in normoxia, resulting in reduced apoptosis and in secretion of functional vascular endothelial growth factor (VEGF). Moreover, we report that, in the less aggressive LNCaP cells, TLR3 activation fails to induce nuclear accumulation of HIF-1 alpha. However, the transfection of I.3 isoform of hif-1 alpha in LNCaP cells allows poly(I:C)-induced HIF-1 activation, resulting in apoptosis protection and VEGF secretion. Altogether, our findings demonstrate that differences in the basal level of HIF-1 alpha expression in different prostate cancer cell lines underlie their differential response to TLR3 activation, suggesting a correlation between different stages of malignancy, hypoxic gene expression, and beneficial responsiveness to TLR agonists. PMID:20651983

  9. Toll-like Receptor 3 Regulates Angiogenesis and Apoptosis in Prostate Cancer Cell Lines through Hypoxia-Inducible Factor 1α1

    Science.gov (United States)

    Paone, Alessio; Galli, Roberta; Gabellini, Chiara; Lukashev, Dmitriy; Starace, Donatella; Gorlach, Agnes; De Cesaris, Paola; Ziparo, Elio; Del Bufalo, Donatella; Sitkovsky, Michail V; Filippini, Antonio; Riccioli, Anna

    2010-01-01

    Toll-like receptors (TLRs) recognize microbial/viral-derived components that trigger innate immune response and conflicting data implicate TLR agonists in cancer, either as protumor or antitumor agents. We previously demonstrated that TLR3 activation mediated by its agonist poly(I:C) induces antitumor signaling, leading to apoptosis of prostate cancer cells LNCaP and PC3 with much more efficiency in the former than in the second more aggressive line. The transcription factor hypoxia-inducible factor 1 (HIF-1) regulates several cellular processes, including apoptosis, in response to hypoxia and to other stimuli also in normoxic conditions. Here we describe a novel protumor machinery triggered by TLR3 activation in PC3 cells consisting of increased expression of the specific I.3 isoform of HIF-1α and nuclear accumulation of HIF-1 complex in normoxia, resulting in reduced apoptosis and in secretion of functional vascular endothelial growth factor (VEGF). Moreover, we report that, in the less aggressive LNCaP cells, TLR3 activation fails to induce nuclear accumulation of HIF-1α. However, the transfection of I.3 isoform of hif-1α in LNCaP cells allows poly(I:C)-induced HIF-1 activation, resulting in apoptosis protection and VEGF secretion. Altogether, our findings demonstrate that differences in the basal level of HIF-1α expression in different prostate cancer cell lines underlie their differential response to TLR3 activation, suggesting a correlation between different stages of malignancy, hypoxic gene expression, and beneficial responsiveness to TLR agonists. PMID:20651983

  10. Hypoxia-Responsive Mir-301a and Mir-301b Promote Radioresistance of Prostate Cancer Cells via Downregulating NDRG2.

    Science.gov (United States)

    Wang, Wei; Liu, Mingbo; Guan, Yawei; Wu, Qingwu

    2016-01-01

    BACKGROUND MiR-301a and miR-301b are 2 oncomiRs involved in multiple types of cancer. In this study, we explored the expression change of miR-301a and miR-301b in prostate cancer cells in hypoxia and studied their regulation of autophagy and radiosensitivity of prostate cancer cells. MATERIAL AND METHODS QRT-PCR was performed to quantify the expression change of miR-301a and miR-301b in hypoxia. Their effects on autophagy were measured by Western blot analysis, and their effects on radiosensitivity were measured by clonogenic assay and flow cytometry. In addition, the regulation of miR-301a and miR-301b on NDRG2, a tumor-suppressor gene in prostate cancer, was also studied. The effect of miR-301a/b-NDRG2 axis on autophagy and radiosensitivity of prostate cancer cells was further investigated. RESULTS MiR-301a and miR-301b are 2 hypoxia responsive miRNAs that are significantly upregulated in hypoxia in prostate cancer cells. Higher level of miR-301a and miR-301b expression results in elevated autophagy and increased radioresistance in LNCaP cells. MiR-301a and miR-301b simultaneously target NDRG2 and decrease its expression. Knockdown of NDRG2 leads to increased autophagy and radioresistance. CONCLUSIONS MiR-301a and miR-301b are 2 hypoxia-responsive miRNAs that decrease autophagy of prostate cancer cells in hypoxia by targeting NDRG2. Through downregulating NDRG2, miR-301a and miR-301b can promote radioresistance of prostate cancer cells. PMID:27327120

  11. Prostatitis - acute

    Science.gov (United States)

    ... bladder, such as alcohol, caffeinated foods and drinks, citrus juices, and hot or spicy foods. Drink more ... A.D.A.M. Editorial team. Related MedlinePlus Health Topics Prostate Diseases Browse the Encyclopedia A.D. ...

  12. Prostate cancer

    DEFF Research Database (Denmark)

    Chabanova, Elizaveta; Balslev, Ingegerd; Logager, Vibeke;

    2011-01-01

    To investigate diagnostic accuracy of detection of prostate cancer by magnetic resonance: to evaluate the performance of T2WI, DCEMRI and CSI and to correlate the results with biopsy and radical prostatectomy histopathological data....

  13. Prostate cancer

    DEFF Research Database (Denmark)

    Chabanova, Elizaveta; Balslev, Ingegerd; Logager, Vibeke;

    2011-01-01

    To investigate diagnostic accuracy of detection of prostate cancer by magnetic resonance: to evaluate the performance of T2WI, DCEMRI and CSI and to correlate the results with biopsy and radical prostatectomy histopathological data.......To investigate diagnostic accuracy of detection of prostate cancer by magnetic resonance: to evaluate the performance of T2WI, DCEMRI and CSI and to correlate the results with biopsy and radical prostatectomy histopathological data....

  14. The genomic landscape of prostate cancer

    Directory of Open Access Journals (Sweden)

    Sylvan eBaca

    2012-05-01

    Full Text Available Prostate cancer is a common malignancy in men, with a markedly variable clinical course. Somatic alterations in DNA drive the growth of prostate cancers and may underlie the behavior of aggressive versus indolent tumors. The accelerating application of genomic technologies over the last two decades has identified mutations that drive prostate cancer formation, progression, and therapeutic resistance. Here, we discuss exemplary somatic mutations in prostate cancer, and highlight mutated cellular pathways with biological and possible therapeutic importance. Examples include mutated genes involved in androgen signaling, cell cycle regulation, signal transduction and development. Some genetic alterations may also predict the clinical course of disease or response to therapy, although the molecular heterogeneity of prostate tumors poses challenges to genomic biomarker identification. The widespread application of massively parallel sequencing technology to the analysis of prostate cancer genomes should continue to advance both discovery-oriented and diagnostic avenues.

  15. Androgen and prostatic stroma

    Institute of Scientific and Technical Information of China (English)

    Yuan-JieNIU; Teng-XiangMA; IuZHANG; YongXU; Rui-FaHAN; GuangSUN

    2003-01-01

    90,The expression of ER remained unchanged in the whole course.The prostatic stromal cells,including SMCs and fibroblasts,diminished and underwent serial pathological changes of atrophy and apoptosis after castration.The atrophic cells were filled with huge intracellular lipofuscin.The expression of SMC myosin declined after castration,coincident with the increase in TGFβ mRNA level and decline in bFGF mRNA level.In vitro,DHT caused a weak increase in the proliferation and expression of SMC-specific proteins(P<0.05).However,DHT and bFGF together stimulated the proliferation of stromal cells significantly more than either agent alone(P<0.01).The combination of DHT and TGFβgreatly enhanced the expression of SMC-specific proteins(P<0.01)more strongly than either alone(P<0.01.Conclusions:The whole prostate gland is an androgen-sensitive organ with both the epithelium and stroma under the control of androgen.Androgen may direct the proliferation,differentiation and regression of stromal cells by regulating the expression of TGFβ,bFGF ,AR and smooth muscle cell specific proteins.

  16. Suppression of casein kinase 2 sensitizes tumor cells to antitumor TRAIL therapy by regulating the phosphorylation and localization of p65 in prostate cancer.

    Science.gov (United States)

    Gang, Xiaokun; Wang, Yao; Wang, Yingdi; Zhao, Yu; Ding, Liya; Zhao, Jingwen; Sun, Lin; Wang, Guixia

    2015-09-01

    In the United States, prostate cancer (PCa) is the most commonly diagnosed cancer in males. For PCa at the late hormone-refractory stage, substantial improvement in treatment strategies is critically needed. TNF-related apoptosis-inducing ligand (TRAIL) is a promising anticancer agent, but both intrinsic and acquired resistance to TRAIL poses a huge problem in establishing clinically effective TRAIL therapies. In the present study, we examined the role played by casein kinase 2 (CK2) in the TRAIL‑induced nuclear factor κ-light-chain-enhancer of activated B cell (NF-κB) pathway in a PCa cell line. Downregulation of CK2 combined with a sub-dose of TRAIL suppressed p65 phosphorylation at serine 536. The combination treatment of TRAIL and the CK2 inhibitor decreased p65 nuclear translocation. Under the treatment of a sub-dose of TRAIL, downregulation of CK2, using both genetic and pharmacological approaches, decreased the transcriptional activity of NF-κB and the expression of NF-κB downstream anti-apoptosis genes. Therefore, we provided novel molecular mechanistic insight reporting that CK2 regulates the sensitivity of PCa cells to the antitumor effect of TRAIL. This is important for understanding how the TRAIL pathway is disrupted in PCa and may help to develop an effective combinatorial therapy for PCa.

  17. Up-regulation of Bcl-2 is required for the progression of prostate cancer cells from an androgen-dependent to an androgen-independent growth stage

    Institute of Scientific and Technical Information of China (English)

    Yuting Lin; Junichi Fukuchi; Richard A Hiipakka; John M Kokontis; Jialing Xiang

    2007-01-01

    Bcl-2 is an anti-apoptotic oncoprotein and its protein levels are inversely correlated with prognosis in many cancers.However, the role of Bcl-2 in the progression of prostate cancer is not clear. Here we report that Bcl-2 is required for the progression of LNCaP prostate cancer cells from an androgen-dependent to an androgen-independent growth stage. The mRNA and protein levels of Bcl-2 are significantly increased in androgen-independent prostate cancer cells, shRNA-mediated gene silencing of Bcl-2 in androgen-independent prostate cancer cells promotes UV-induced apoptosis and suppresses the growth of prostate tumors in vivo. Growing androgen-dependent cells under androgen-deprivation conditions results in formation of androgen-independent colonies; and the transition from androgen-dependent to androgen-independent growth is blocked by ectopic expression of the Bcl-2 antagonist Bax or Bcl-2 shRNA. Thus, our results demonstrate that Bcl-2 is not only critical for the survival of androgen-independent prostate cancer cells, but is also required for the progression of prostate cancer cells from an androgen-dependent to an androgen-independent growth stage.

  18. Risk factors for prostatic inflammation extent and infection in benign prostatic hyperplasia

    Institute of Scientific and Technical Information of China (English)

    Fa-Xian Yi; Qiang Wei; Hong Li; Xiang Li; Ming Shi; Qiang Dong; Yu-Ru Yang

    2006-01-01

    Aim: To investigate the risk factors for prostatic inflammation extent and infection in patients with benign prostatic hyperplasia (BPH) so as to manage prostatic inflammation more efficiently. Methods: Sixty patients with BPH undergoing TURP between September 2005 and December 2005 in West China Hospital of Sichuan University were studied. Prostate fluid (PF) was collected for the measurement of secretory IgA (SIgA) and complement 3 (C3).Prostate tissue were collected for testing bacterial 16S rDNA by real-time PCR, examining SIgA in the tissue and examining the inflammation. The possible clinical and immune risk factors for prostatic inflammation or infection were analyzed by using the logistic regression method. Results: Abnormal white blood cell count in urinalysis, prostatic infection and a high concentration of C3 in PF are the risk factors for prostatic inflammation extent (P = 0.025, 0.034 and 0.035, respectively and odds ratio [OR] = 18.269, 8.284 and 1.508, respectively). Risk factors for prostatic infection include the C3 concentration and the concentration of S IgA in PF (P = 0.003 and 0.013, respectively, and OR= 1.645 and 0.993, respectively). Conclusion: The present study suggests that prostatic inflammation is associated with urinary tract infection, prostatic infection and the activated complement and that prostatic infection is associated with the activated complement and downregulated mucosal immunity in prostates of the patients with BPH. It is also suggested that individual immune regulation should be considered in the treatment of prostatic inflammation and infection of patients with BPH.

  19. BMP and retinoic acid regulate anterior–posterior patterning of the non-axial mesoderm across the dorsal–ventral axis

    Science.gov (United States)

    Naylor, Richard W.; Skvarca, Lauren Brilli; Thisse, Christine; Thisse, Bernard; Hukriede, Neil A.; Davidson, Alan J.

    2016-01-01

    Despite the fundamental importance of patterning along the dorsal–ventral (DV) and anterior–posterior (AP) axes during embryogenesis, uncertainty exists in the orientation of these axes for the mesoderm. Here we examine the origin and formation of the zebrafish kidney, a ventrolateral mesoderm derivative, and show that AP patterning of the non-axial mesoderm occurs across the classic gastrula stage DV axis while DV patterning aligns along the animal–vegetal pole. We find that BMP signalling acts early to establish broad anterior and posterior territories in the non-axial mesoderm while retinoic acid (RA) functions later, but also across the classic DV axis. Our data support a model in which RA on the dorsal side of the embryo induces anterior kidney fates while posterior kidney progenitors are protected ventrally by the RA-catabolizing enzyme Cyp26a1. This work clarifies our understanding of vertebrate axis orientation and establishes a new paradigm for how the kidney and other mesodermal derivatives arise during embryogenesis. PMID:27406002

  20. Endogenous opioids participate in the regulation of the hypothalamus-pituitary-luteinizing hormone axis and testosterone's negative feedback control of luteinizing hormone.

    Science.gov (United States)

    Cicero, T J; Schainker, B A; Meyer, E R

    1979-05-01

    Two narcotic antagonists, naloxone and naltrexone, significantly elevated serum LH levels in male rats within minutes after their sc injection. The peak increase in serum LH occurred 20 min after the injection. Naloxone increased LH levels up to a dose of 1 mg/kg, after which no further increases were found. A dose of 0.35 mg/kg produced a half-maximal response. The exogenous opioid morphine blocked the increase in LH produced by naloxone in a dose-dependent fashion, suggesting that the specific receptor-blocking effects of the antagonist could account for its enhancement of serum LH levels. The locus of action of naloxone within the hypothalamic-pituitary-LH axis appeared to be at the level of the hypothalamus since the drug had no effect on LHRH-stimulated release of LH by the anterior pituitary and did not block dihydrotestosterone's suppression of pituitary LH release in vitro. Naloxone also prevented testosterone's negative feedback inhibition of serum LH in the castrated male rat. The results of these studies suggest that endogenous opioids exist in brain tissue which normally inhibit activity in the hypothalamic-pituitary-LH axis and participate in the androgen-dependent feedback control of LH elaboration by this axis. PMID:374068

  1. Principles of the prolactin/vasoinhibin axis.

    Science.gov (United States)

    Triebel, Jakob; Bertsch, Thomas; Bollheimer, Cornelius; Rios-Barrera, Daniel; Pearce, Christy F; Hüfner, Michael; Martínez de la Escalera, Gonzalo; Clapp, Carmen

    2015-11-15

    The hormonal family of vasoinhibins, which derive from the anterior pituitary hormone prolactin, are known for their inhibiting effects on blood vessel growth, vasopermeability, and vasodilation. As pleiotropic hormones, vasoinhibins act in multiple target organs and tissues. The generation, secretion, and regulation of vasoinhibins are embedded into the organizational principle of an axis, which integrates the hypothalamus, the pituitary, and the target tissue microenvironment. This axis is designated as the prolactin/vasoinhibin axis. Disturbances of the prolactin/vasoinhibin axis are associated with the pathogenesis of retinal and cardiac diseases and with diseases occurring during pregnancy. New phylogenetical, physiological, and clinical implications are discussed.

  2. Prostate cancer - treatment

    Science.gov (United States)

    ... this page: //medlineplus.gov/ency/patientinstructions/000403.htm Prostate cancer - treatment To use the sharing features on this ... a combination of drugs is recommended. References National Cancer Institute. Prostate cancer treatment (PDQ): Stages of prostate cancer. Updated ...

  3. Cancer of the Prostate

    Science.gov (United States)

    ... will die of this disease. Who Gets This Cancer? Prostate cancer occurs only in men, and it is ... Percent of New Cases by Age Group: Prostate Cancer Prostate cancer is most frequently diagnosed among men aged ...

  4. What Is Prostate Cancer?

    Medline Plus

    Full Text Available ... no such thing as one type of prostate cancer. Prostate cancer is really a spectrum of diseases where on ... very benevolent in its behavior. Men will develop prostate cancer and live the rest of their lives -- 20, ...

  5. Localized Prostate Cancer

    Science.gov (United States)

    ... a decision aid for men with clinically localized prostate cancer (available at http://effectivehealthcare.ahrq.gov/prostate_da) ... A Decision Aid for Men With Clinically Localized Prostate Cancer Page 1 of 24 Introduction Men with clinically ...

  6. Prostate Cancer Foundation

    Science.gov (United States)

    ... P 2 rovocative Questions PCCTC Scientific Retreat Coffey-Holden Research News Faces of Prostate Cancer [4] Survivors ... Foundation News The Prostate Cancer Foundation’s 2016 Coffey-Holden Prostate Cancer Academy Meeting accelerates advances in the ...

  7. Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Scott Eggener

    2011-01-01

    Full Text Available Prostate cancer continues to be a significant public health issue worldwide, particularly in countries where men have life expectancies long enough to clinically manifest the disease. In many countries, it remains one of the leading causes of cancer-related morbidity and mortality.

  8. ETS fusion genes in prostate cancer.

    Science.gov (United States)

    Gasi Tandefelt, Delila; Boormans, Joost; Hermans, Karin; Trapman, Jan

    2014-06-01

    Prostate cancer is very common in elderly men in developed countries. Unravelling the molecular and biological processes that contribute to tumor development and progressive growth, including its heterogeneity, is a challenging task. The fusion of the genes ERG and TMPRSS2 is the most frequent genomic alteration in prostate cancer. ERG is an oncogene that encodes a member of the family of ETS transcription factors. At lower frequency, other members of this gene family are also rearranged and overexpressed in prostate cancer. TMPRSS2 is an androgen-regulated gene that is preferentially expressed in the prostate. Most of the less frequent ETS fusion partners are also androgen-regulated and prostate-specific. During the last few years, novel concepts of the process of gene fusion have emerged, and initial experimental results explaining the function of the ETS genes ERG and ETV1 in prostate cancer have been published. In this review, we focus on the most relevant ETS gene fusions and summarize the current knowledge of the role of ETS transcription factors in prostate cancer. Finally, we discuss the clinical relevance of TMRPSS2-ERG and other ETS gene fusions in prostate cancer.

  9. Carvacrol Alleviates Prostate Cancer Cell Proliferation, Migration, and Invasion through Regulation of PI3K/Akt and MAPK Signaling Pathways

    Science.gov (United States)

    Luo, Yun; Wu, Jie-Ying; Lu, Min-Hua; Shi, Zhi

    2016-01-01

    TRPM7 is a potential therapeutic target for treatment of prostate cancer. In this study, we investigated the effects of nonselective TRPM7 inhibitor carvacrol on cell proliferation, migration, and invasion of prostate cancer PC-3 and DU145 cells. Our results showed that carvacrol blocked TRPM7-like currents in PC-3 and DU145 cells and reduced their proliferation, migration, and invasion. Moreover, carvacrol treatment significantly decreased MMP-2, p-Akt, and p-ERK1/2 protein expression and inhibited F-actin reorganization. Furthermore, consistently, TRPM7 knockdown reduced prostate cancer cell proliferation, migration, and invasion as well. Our study suggests that carvacrol may have therapeutic potential for the treatment of prostate cancer through its inhibition of TRPM7 channels and suppression of PI3K/Akt and MAPK signaling pathways. PMID:27803760

  10. Zyflamend, a polyherbal mixture, down regulates class I and class II histone deacetylases and increases p21 levels in castrate-resistant prostate cancer cells

    OpenAIRE

    Huang, E-Chu; Zhao, Yi; Chen, Guoxun; Baek, Seung Joon; McEntee, Michael F.; Minkin, Steven; Biggerstaff, John P.; Whelan, Jay

    2014-01-01

    Background Zyflamend, a mixture containing extracts of ten herbs, has shown promise in a variety of preclinical cancer models, including prostate cancer. The current experiments were designed to investigate the effects of Zyflamend on the expression of class I and II histone deacetylases, a family of enzymes known to be over expressed in a variety of cancers. Methods CWR22Rv1 cells, a castrate-resistant prostate cancer cell line, were treated with Zyflamend and the expression of class I and I...

  11. Vitamin D, Sunlight and Prostate Cancer Risk

    Directory of Open Access Journals (Sweden)

    Krishna Vanaja Donkena

    2011-01-01

    Full Text Available Prostate cancer is the second common cancer in men worldwide. The prevention of prostate cancer remains a challenge to researchers and clinicians. Here, we review the relationship of vitamin D and sunlight to prostate cancer risk. Ultraviolet radiation of the sunlight is the main stimulator for vitamin D production in humans. Vitamin D's antiprostate cancer activities may be involved in the actions through the pathways mediated by vitamin D metabolites, vitamin D metabolizing enzymes, vitamin D receptor (VDR, and VDR-regulated genes. Although laboratory studies including the use of animal models have shown that vitamin D has antiprostate cancer properties, whether it can effectively prevent the development and/or progression of prostate cancer in humans remains to be inconclusive and an intensively studied subject. This review will provide up-to-date information regarding the recent outcomes of laboratory and epidemiology studies on the effects of vitamin D on prostate cancer prevention.

  12. PAK6对前列腺癌的双向调控作用%The bidirectional regulation effect that PAK6 exerts in prostate cancer

    Institute of Scientific and Technical Information of China (English)

    唐诣超; 陈思蕾; 刘彤

    2016-01-01

    Prostate cancer (PCa)is a type of cancer with high male prevalence.Due to the restrictions of the mecha-nism awareness and limitations of current therapeutic modalities,PCa is the leading diagnosed malignancy in western European and American men.With the continuous progress of scientific research,the role that the PAK protein family play in cancer has been surfaced out of water.PAK6 was primarily an androgen receptor interacting protein recognized by yeast double -hybrid,amino acid sequence 629 ~919 in ligand binding domain (LBD)of androgen receptor.An-drogen and androgen receptor plays a crucial role in the development and growth of prostate malignancies,which makes PAK6 protein an attractive new therapeutic target in prostate cancer.The article mainly focuses on the double-action that PAK6 takes in PCa,including inhibition of the cancer by phosphorylating AR thus inhibits the AR's translocation into nucleus,and promotion of the cancer by inhibiting BAD apoptosis pathway,interfering with growth cycle of PCa cells,and promoting the PCa cells remove from cell colonies.At the same time,the expression level of PAK6 and the regulation of kinase activity also of great significance for PAK6 to affect prostate cancer.This paper ar-gues hormone and growth factor together with reticulum stress are two possible ways in increasing PAK6 expression and im-proving kinase activity.The role PAK6 plays in PCa and the regulatory mechanism between its expression level and ki-nase activity is of great importance to the research of PCa therapeutic modalities and target objectives of medication.%前列腺癌为一类男性患病率较高的癌症,对该癌症机制的认识以及治疗手段非常有限,在西欧和美洲男性中是一类致死率较高的癌症。随着科学研究的不断进展,p21活化激酶(PAK)蛋白家族在癌症中发挥的作用开始进入人们的视野。p21活化激酶6(PAK6)最初是以雄激素受体的配体结合

  13. Uric acid: a modulator of prostate cells and activin sensitivity.

    Science.gov (United States)

    Sangkop, Febbie; Singh, Geeta; Rodrigues, Ely; Gold, Elspeth; Bahn, Andrew

    2016-03-01

    Elevated serum uric acid (SUA) or urate is associated with inflammation and gout. Recent evidence has linked urate to cancers, but little is known about urate effects in prostate cancer. Activins are inflammatory cytokines and negative growth regulators in the prostate. A hallmark of prostate cancer progression is activin insensitivity; however, mechanisms underlying this are unclear. We propose that elevated SUA is associated with prostate cancer counteracting the growth inhibitory effects of activins. The expression of activins A and B, urate transporter GLUT9 and tissue urate levels were examined in human prostate disease. Intracellular and secreted urate and GLUT9 expression were assessed in human prostate cancer cell lines. Furthermore, the effects of urate and probenecid, a known urate transport inhibitor, were determined in combination with activin A. Activin A expression was increased in low-grade prostate cancer, whereas activin B expression was reduced in high-grade prostate cancer. Intracellular urate levels decreased in all prostate pathologies, while GLUT9 expression decreased in benign prostatic hyperplasia, prostatitis and high-grade prostate cancer. Activin responsive LNCaP cells had higher intracellular and lower secreted urate levels than activin-insensitive PC3 cells. GLUT9 expression in prostate cancer cells was progressively lower than in prostate epithelial cells. Elevated extracellular urate was growth promoting in vitro, which was abolished by the gout medication probenecid, and it antagonized the growth inhibitory effects of activins. This study shows for the first time that a change in plasma or intracellular urate levels, possibly involving GLUT9 and a urate efflux transporter, has an impact on prostate cancer cell growth, and that lowering SUA levels in prostate cancer is likely to be therapeutically beneficial. PMID:26910779

  14. cDNA macroarray for analysis of gene expression profiles in prostate cancer

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    Background Early diagnosis and timely treatment are important for improving therapeutic efficiency of prostate cancer. DNA array is a new bio-technology for disease diagnosis. This study was conducted to diagnose prostate cancer with cDNA macroarray and analysis gene expression profiles of some selective genes in prostate cancer.Methods Total RNA was isolated from patients with prostate cancer and from normal people, and poly(A) RNA was further purified. Then it was analyzed for differentially expressed genes in prostate cancer and normal prostate by cDNA macroarray system.Results There were different expressions in the nine prostate-associated specific genes in prostate cancer as compared with normal prostate, in which, 7 were significantly upregulated and 2 were down-regulated.Conclusion As a diagnostic approach at molecular level, the cDNA macroarray is an effectively diagnostic method for prostate cancer.

  15. Gut Microbiota-brain Axis

    Science.gov (United States)

    Wang, Hong-Xing; Wang, Yu-Ping

    2016-01-01

    Objective: To systematically review the updated information about the gut microbiota-brain axis. Data Sources: All articles about gut microbiota-brain axis published up to July 18, 2016, were identified through a literature search on PubMed, ScienceDirect, and Web of Science, with the keywords of “gut microbiota”, “gut-brain axis”, and “neuroscience”. Study Selection: All relevant articles on gut microbiota and gut-brain axis were included and carefully reviewed, with no limitation of study design. Results: It is well-recognized that gut microbiota affects the brain's physiological, behavioral, and cognitive functions although its precise mechanism has not yet been fully understood. Gut microbiota-brain axis may include gut microbiota and their metabolic products, enteric nervous system, sympathetic and parasympathetic branches within the autonomic nervous system, neural-immune system, neuroendocrine system, and central nervous system. Moreover, there may be five communication routes between gut microbiota and brain, including the gut-brain's neural network, neuroendocrine-hypothalamic-pituitary-adrenal axis, gut immune system, some neurotransmitters and neural regulators synthesized by gut bacteria, and barrier paths including intestinal mucosal barrier and blood-brain barrier. The microbiome is used to define the composition and functional characteristics of gut microbiota, and metagenomics is an appropriate technique to characterize gut microbiota. Conclusions: Gut microbiota-brain axis refers to a bidirectional information network between the gut microbiota and the brain, which may provide a new way to protect the brain in the near future. PMID:27647198

  16. Pharmacological treatment of the benign prostatic hyperplasia

    International Nuclear Information System (INIS)

    Benign prostatic hyperplasia is a common disease in over 50 years-old men consisting in uncontrolled and benign growth of prostatic gland that leads to lower urinary tract symptoms. The etiology of benign prostatic hyperplasia is multifactoral involving the increased conversion of testosterone in dihydrotestosterone by the prostatic 5α-reductase action, which brought about events that encourage the prostate growth (static component) and the increase of the bladder and prostate smooth muscle tone (dynamic component) regulated by the aα1 -adrenoceptors (ADR). The pharmacological treatment of the benign prostatic hyperplasia includes the prostatic 5aα-reductase inhibitors, the aα1-adrenoreceptor blockers, their combined therapy and the phytotherapy. This paper was aimed at presenting the most relevant aspects of the pharmacology of drugs used for treating the benign prostatic hyperplasia, and providing elements to analyze their efficacy, safety and tolerability. To this end, a review was made of the different drugs for the treatment of this pathology and they were grouped according to their mechanism of action. Natural products were included as lipid extracts from Serenoa repens and Pygeum africanum as well as D-004, a lipid extract from Roystonea regia fruits, with proved beneficial effects on the main etiological factors of benign prostatic hyperplasia. D-004 is a prostatic 5a-reductase inhibitor, an aα1-adrenoceptor antagonist, aα 5-lipooxygenase inhibitor and has antioxidant action, all of which reveals a multifactoral mechanism. The results achieved till now indicate that D-004 is a safe and well-tolerated product

  17. Fetal and Neonatal HPA Axis.

    Science.gov (United States)

    Wood, Charles E; Walker, Claire-Dominique

    2015-01-01

    Stress is an integral part of life. Activation of the hypothalamus-pituitary-adrenal (HPA) axis in the adult can be viewed as mostly adaptive to restore homeostasis in the short term. When stress occurs during development, and specifically during periods of vulnerability in maturing systems, it can significantly reprogram function, leading to pathologies in the adult. Thus, it is critical to understand how the HPA axis is regulated during developmental periods and what are the factors contributing to shape its activity and reactivity to environmental stressors. The HPA axis is not a passive system. It can actively participate in critical physiological regulation, inducing parturition in the sheep for instance or being a center stage actor in the preparation of the fetus to aerobic life (lung maturation). It is also a major player in orchestrating mental function, metabolic, and cardiovascular function often reprogrammed by stressors even prior to conception through epigenetic modifications of gametes. In this review, we review the ontogeny of the HPA axis with an emphasis on two species that have been widely studied-sheep and rodents-because they each share many similar regulatory mechanism applicable to our understanding of the human HPA axis. The studies discussed in this review should ultimately inform us about windows of susceptibility in the developing brain and the crucial importance of early preconception, prenatal, and postnatal interventions designed to improve parental competence and offspring outcome. Only through informed studies will our public health system be able to curb the expansion of many stress-related or stress-induced pathologies and forge a better future for upcoming generations.

  18. Activation of the HPA axis and depression of feeding behavior induced by restraint stress are separately regulated by PACAPergic neurotransmission in the mouse.

    Science.gov (United States)

    Jiang, Sunny Zhihong; Eiden, Lee E

    2016-07-01

    We measured serum CORT elevation in wild-type and PACAP-deficient C57BL/6N male mice after acute (1 h) or prolonged (2-3 h) daily restraint stress for 7 d. The PACAP dependence of CORT elevation was compared to that of stress-induced hypophagia. Daily restraint induced unhabituated peak CORT elevation, and hypophagia/weight loss, of similar magnitude for 1, 2, and 3 h of daily restraint, in wild-type mice. Peak CORT elevation, and hypophagia, were both attenuated in PACAP-deficient mice for 2 and 3 h daily restraint. Hypophagia induced by 1-h daily restraint was also greatly reduced in PACAP-deficient mice, however CORT elevation, both peak and during recovery from stress, was unaffected. Thus, hypothalamic PACAPergic neurotransmission appears to affect CRH gene transcription and peptide production, but not CRH release, in response to psychogenic stress. A single exposure to restraint sufficed to trigger hypophagia over the following 24 h. PACAP deficiency attenuated HPA axis response (CORT elevation) to prolonged (3 h) but not acute (1 h) single-exposure restraint stress, while hypophagia induced by either a single 1 h or a single 3 h restraint were both abolished in PACAP-deficient mice. These results suggest that PACAP's actions to promote suppression of food intake following an episode of psychogenic stress is unrelated to the release of CRH into the portal circulation to activate the pituitary-adrenal axis. Furthermore, demonstration of suppressed food intake after a single 1-h restraint stress provides a convenient assay for investigating the location of the synapses and circuits mediating the effects of PACAP on the behavioral sequelae of psychogenic stress.

  19. Genomic rearrangements of PTEN in prostate cancer

    Directory of Open Access Journals (Sweden)

    Sopheap ePhin

    2013-09-01

    Full Text Available The phosphatase and tensin homolog gene on chromosome 10q23.3 (PTEN is a negative regulator of the PIK3/Akt survival pathway and is the most frequently deleted tumor suppressor gene in prostate cancer. Monoallelic loss of PTEN is present in up to 60% of localized prostate cancers and complete loss of PTEN in prostate cancer is linked to metastasis and androgen independent progression. Studies on the genomic status of PTEN in prostate cancer initially used a two-color fluorescence in-situ hybridization (FISH assay for PTEN copy number detection in formalin fixed paraffin embedded tissue preparations. More recently, a four-color FISH assay containing two additional control probes flanking the PTEN locus with a lower false-positive rate was reported. Combined with the detection of other critical genomic biomarkers for prostate cancer such as ERG, AR, and MYC, the evaluation of PTEN genomic status has proven to be invaluable for patient stratification and management. Although less frequent than allelic deletions, point mutations in the gene and epigenetic silencing are also known to contribute to loss of PTEN function, and ultimately to prostate cancer initiation. Overall, it is clear that PTEN is a powerful biomarker for prostate cancer. Used as a companion diagnostic for emerging therapeutic drugs, FISH analysis of PTEN is promisingly moving human prostate cancer closer to more effective cancer management and therapies.

  20. Oxidative stress in prostate hypertrophy and carcinogenesis

    Directory of Open Access Journals (Sweden)

    Waldemar M. Przybyszewski

    2009-07-01

    Full Text Available Aging, significant impairment of the oxidation/reduction balance, infection, and inflammation are recognized risk factors of benign hyperplasia and prostate cancer. Chronic symptomatic and asymptomatic prostate inflammatory processes generate significantly elevated levels of reactive oxygen and nitrogen species, and halogenated compounds. Prostate cancer patients showed significantly higher lipid peroxidation and lower antioxidant levels in peripheral blood than healthy controls, whereas patients with prostate hyperplasia did not show such symptoms. Oxidative/nitrosative/halogenative stress causes DNA modifications leading to genome instability that may initiate carcinogenesis; however, it was shown that oxidative damage alone is not sufficient to initiate this process. Peroxidation products induced by reactive oxygen and nitrogen species seem to take part in epigenetic mechanisms regulating genome activity. One of the most common changes occurring in more than 90�0of all analyzed prostate cancers is the silencing of GSTP1 gene activity. The gene encodes glutathione transferase, an enzyme participating in detoxification processes. Prostate hyperplasia is often accompanied by chronic inflammation and such a relationship was not observed in prostate cancer. The participation of infection and inflammation in the development of hyperplasia is unquestionable and these factors probably also take part in initiating the early stages of prostate carcinogenesis. Thus it seems that therapeutic strategies that prevent genome oxidative damage in situations involving oxidative/nitrosative/halogenative stress, i.e. use of antioxidants, plant steroids, antibiotics, and non-steroidal anti-inflammatory drugs, could help prevent carcinogenesis.

  1. Endothelial Cells Can Regulate Smooth Muscle Cells in Contractile Phenotype through the miR-206/ARF6&NCX1/Exosome Axis

    OpenAIRE

    Lin, Xiao; He, Yu; Hou, Xue; Zhang, Zhenming; Wang, Rui; Wu, Qiong

    2016-01-01

    Active interactions between endothelial cells and smooth muscle cells (SMCs) are critical to maintaining the SMC phenotype. Exosomes play an important role in intercellular communication. However, little is known about the mechanisms that regulate endothelial cells and SMCs crosstalk. We aimed to determine the mechanisms underlying the regulation of the SMC phenotype by human umbilical vein endothelial cells (HUVECs) through exosomes. We found that HUVECs overexpressing miR-206 upregulated co...

  2. Resistance to docetaxel in prostate cancer is associated with androgen receptor activation and loss of KDM5D expression.

    Science.gov (United States)

    Komura, Kazumasa; Jeong, Seong Ho; Hinohara, Kunihiko; Qu, Fangfang; Wang, Xiaodong; Hiraki, Masayuki; Azuma, Haruhito; Lee, Gwo-Shu Mary; Kantoff, Philip W; Sweeney, Christopher J

    2016-05-31

    The androgen receptor (AR) plays an essential role in prostate cancer, and suppression of its signaling with androgen deprivation therapy (ADT) has been the mainstay of treatment for metastatic hormone-sensitive prostate cancer for more than 70 y. Chemotherapy has been reserved for metastatic castration-resistant prostate cancer (mCRPC). The Eastern Cooperative Oncology Group-led trial E3805: ChemoHormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer (CHAARTED) showed that the addition of docetaxel to ADT prolonged overall survival compared with ADT alone in patients with metastatic hormone-sensitive prostate cancer. This finding suggests that there is an interaction between AR signaling activity and docetaxel sensitivity. Here we demonstrate that the prostate cancer cell lines LNCaP and LAPC4 display markedly different sensitivity to docetaxel with AR activation, and RNA-seq analysis of these cell lines identified KDM5D (lysine-specific demethylase 5D) encoded on the Y chromosome as a potential mediator of this sensitivity. Knocking down KDM5D expression in LNCaP leads to docetaxel resistance in the presence of dihydrotestosterone. KDM5D physically interacts with AR in the nucleus, and regulates its transcriptional activity by demethylating H3K4me3 active transcriptional marks. Attenuating KDM5D expression dysregulates AR signaling, resulting in docetaxel insensitivity. KDM5D deletion was also observed in the LNCaP-derived CRPC cell line 104R2, which displayed docetaxel insensitivity with AR activation, unlike parental LNCaP. Dataset analysis from the Oncomine database revealed significantly decreased KDM5D expression in CRPC and poorer prognosis with low KDM5D expression. Taking these data together, this work indicates that KDM5D modulates the AR axis and that this is associated with altered docetaxel sensitivity. PMID:27185910

  3. Evidence that Human Prostate Cancer is a ZIP1-Deficient Malignancy that could be Effectively Treated with a Zinc Ionophore (Clioquinol) Approach

    OpenAIRE

    Costello, Leslie C; Franklin, Renty B; Zou, Jing; Naslund, Michael J

    2015-01-01

    Despite decades of research, no efficacious chemotherapy exists for the treatment of prostate cancer. Malignant prostate zinc levels are markedly decreased in all cases of prostate cancer compared to normal/benign prostate. ZIP1 zinc transporter down regulation decreases zinc to prevent its cytotoxic effects. Thus, prostate cancer is a “ZIP1-deficient” malignancy. A zinc ionophore (e.g. Clioquinol) treatment to increase malignant zinc levels is a plausible treatment of prostate cancer. Howeve...

  4. Novel flutamide regulated genes in the rat ventral prostate: differential modulation of their expression by castration and flutamide treatments%大鼠腹侧前列腺中受氟他胺调控的新基因:去势和氟他胺处理对其表达的调控

    Institute of Scientific and Technical Information of China (English)

    A. M. Limaye; I. Asangani; N. Bora; P. Kondaiah

    2007-01-01

    Aim: To identify flutamide regulated genes in the rat ventral prostate. Methods: Total RNA from ventral prostates of control and flutamide treated rats were isolated. Differentially expressed transcripts were identified using differential display reverse transcriptase polymerase chain reaction. The effect of castration on the expression of flutamideregulated transcripts was studied. Results: We have identified β2-microglobulin, cytoplasmic FMR1 interacting protein 2 and pumilio 1 as flutamide induced and spermine binding protein and ribophorin Ⅱ as flutamide repressed targets in the rat ventral prostate. Although flutamide treatment caused an induction of pumilio 1 mRNA, castration had no effect. Conclusion: Castration and flutamide treatments exert differential effects on gene expression. Flutamide might also have direct AR independent effects, which might have implications in the emergence of androgen independent prostate cancer and the failure of flutamide therapy.

  5. Prostate cancer stem cells

    OpenAIRE

    Tu, Shi-Ming; Lin, Sue-Hwa

    2011-01-01

    Stem cells have long been implicated in prostate glandular formation. The prostate undergoes regression after androgen deprivation and regeneration after testosterone replacement. Regenerative studies suggest that these cells are found in the proximal ducts and basal layer of the prostate. Many characteristics of prostate cancer indicate that it originates from stem cells. For example, the putative AR− status of prostate stem cells renders them inherently insensitive to androgen blockade ther...

  6. Regulation of tumor cell migration and invasion by the H19/let-7 axis is antagonized by metformin-induced DNA methylation.

    Science.gov (United States)

    Yan, L; Zhou, J; Gao, Y; Ghazal, S; Lu, L; Bellone, S; Yang, Y; Liu, N; Zhao, X; Santin, A D; Taylor, H; Huang, Y

    2015-06-01

    The imprinted, developmentally regulated H19 long noncoding RNA has been implicated in the pathogenesis of diverse human cancers, but the underlying mechanisms have remained poorly understood. Here, we report that H19 promotes tumor cell migration and invasion by inhibiting let-7, a potent tumor suppressor microRNA that functions to posttranscriptionally suppress the expression of oncogenes that regulate cell growth and motility. We show that H19 depletion impairs, whereas its overexpression enhances the motility and invasiveness of tumor cells. These phenomena occur, at least in part through affecting let-7-mediated regulation of metastasis-promoting genes, including Hmga2, c-Myc and Igf2bp3. This H19/let-7-dependent regulation is recapitulated in vivo where co-expressions of oncogenes and H19 exist in both primary human ovarian and endometrial cancers. Furthermore, we provide evidence that the anti-diabetic drug metformin inhibits tumor cell migration and invasion, partly by downregulating H19 via DNA methylation. Our results reveal a novel mechanism underpinning H19-mediated regulation in metastasis and may explain why in some cases increased let-7 expression unexpectedly correlates with poor prognosis, given the widely accepted role for let-7 as a tumor suppressor. Targeting this newly identified pathway might offer therapeutic opportunities. PMID:25088204

  7. Anti-proliferative effects of polyphenols from pomegranate rind (Punica granatum L.) on EJ bladder cancer cells via regulation of p53/miR-34a axis.

    Science.gov (United States)

    Zhou, Benhong; Yi, Huilan; Tan, Jun; Wu, Yue; Liu, Gang; Qiu, Zhenpeng

    2015-03-01

    miRNAs and their validated miRNA targets appear as novel effectors in biological activities of plant polyphenols; however, limited information is available on miR-34a mediated cytotoxicity of pomegranate rind polyphenols in cancer cell lines. For this purpose, cell viability assay, Realtime quantitative PCR for mRNA quantification, western blot for essential protein expression, p53 silencing by shRNA and miR-34a knockdown were performed in the present study. EJ cell treatment with 100 µg (GAE)/mL PRE for 48 h evoked poor cell viability and caspase-dependent pro-apoptosis appearance. PRE also elevated p53 protein and triggered miR-34a expression. The c-Myc and CD44 were confirmed as direct targets of miR-34a in EJ cell apoptosis induced by PRE. Our results provide sufficient evidence that polyphenols in PRE can be potential molecular clusters to suppress bladder cancer cell EJ proliferation via p53/miR-34a axis. PMID:25572695

  8. Regulation of Cell Proliferation and Migration by miR-203 via GAS41/miR-10b Axis in Human Glioblastoma Cells

    Science.gov (United States)

    Pal, Dhananjaya; Mukhopadhyay, Debasmita; Ramaiah, M. Janaki; Sarma, Pranjal; Bhadra, Utpal; Bhadra, Manika Pal

    2016-01-01

    Glioma amplified sequence 41(GAS41) is a potent transcription factor that play a crucial role in cell proliferation and survival. In glioblastoma, the expression of GAS41 at both transcriptional and post transcriptional level needs to be tightly maintained in response to cellular signals. Micro RNAs (miRNA) are small non coding RNA that act as important regulators for modulating the expression of various target genes. Studies have shown that several miRNAs play role in the post-transcriptional regulation of GAS41. Here we identified GAS41 as a novel target for endogenous miR-203 and demonstrate an inverse correlation of miR-203 expression with GAS41 in glioma cell lines (HNGC2 and U87). Over expression of miR-203 negatively regulates GAS41 expression in U87 and HNGC2 cell lines. Moreover, miR-203 restrained miR-10b action by suppressing GAS41. GAS41 is essential for repressing p53 in tumor suppressor pathway during cell proliferation. Enforced expression of GAS41 produced contradictory effect on miR-203 but was able to enhance p53 tumor suppressor pathway associated protein. It was also found that miR-203 maintains the stability of p53 as knock down of p53 expression using siRNA resulted in down regulation of pri-miR and mature miR-203 expression. Conversely reconstitution of miR-203 expression induced apoptosis and inhibited migratory property of glioma cells. Taken together, we show that miR-203 is a key negative regulator of GAS41 and acts as tumor suppressor microRNA in glioma. PMID:27467502

  9. Can Prostate Cancer Be Found Early?

    Science.gov (United States)

    ... Research Get Involved Find Local ACS Learn About Cancer » Prostate Cancer » Detailed Guide » Can prostate cancer be found ... and symptoms of prostate cancer Tests for prostate cancer Prostate cancer stages Survival rates for prostate cancer Previous ...

  10. Androgen regulation of aldehyde dehydrogenase 1A3 (ALDH1A3) in androgen responsive human prostate cancer cell LNCaP.

    Science.gov (United States)

    Previous gene array data from our laboratory identified the retinoic acid (RA) biosynthesis enzyme aldehyde dehydrogenase 1A3 (ALDH1A3) as a putative androgen-responsive gene in prostate cancer epithelial cells (LNCaP). In the present study we attempted to identify if any of the three ALDH1A/RA synt...

  11. Fenofibrate down-regulates the expressions of androgen receptor (AR) and AR target genes and induces oxidative stress in the prostate cancer cell line LNCaP

    Energy Technology Data Exchange (ETDEWEB)

    Zhao, Hu; Zhu, Chen; Qin, Chao [State Key Laboratory of Reproductive Medicine, Department of Urology, First Affiliated Hospital of Nanjing Medical University, Nanjing (China); Tao, Tao [Department of Neurosurgery, First Affiliated Hospital of Nanjing Medical University, Nanjing (China); Li, Jie; Cheng, Gong; Li, Pu; Cao, Qiang; Meng, Xiaoxin; Ju, Xiaobing; Shao, Pengfei; Hua, Lixin [State Key Laboratory of Reproductive Medicine, Department of Urology, First Affiliated Hospital of Nanjing Medical University, Nanjing (China); Gu, Min, E-mail: medzhao1980@163.com [State Key Laboratory of Reproductive Medicine, Department of Urology, First Affiliated Hospital of Nanjing Medical University, Nanjing (China); Yin, Changjun, E-mail: drcjyin@gmail.com [State Key Laboratory of Reproductive Medicine, Department of Urology, First Affiliated Hospital of Nanjing Medical University, Nanjing (China)

    2013-03-08

    Highlights: ► Fenofibrate induces cell cycle arrest in G1 phase and apoptosis in LNCaP cells. ► Fenofibrate reduces the expressions of androgen receptor in LNCaP cells. ► Fenofibrate induces oxidative stress in the prostate cancer cell line LNCaP. -- Abstract: Fenofibrate, a peroxisome proliferator-androgen receptor-alpha agonist, is widely used in treating different forms of hyperlipidemia and hypercholesterolemia. Recent reports have indicated that fenofibrate exerts anti-proliferative and pro-apoptotic properties. This study aims to investigate the effects of fenofibrate on the prostate cancer (PCa) cell line LNCaP. The effects of fenofibrate on LNCaP cells were evaluated by flow cytometry, reverse transcription-polymerase chain reaction, enzyme-linked immunosorbent assays, Western blot analysis, and dual-luciferase reporter assay. Fenofibrate induces cell cycle arrest in G1 phase and apoptosis in LNCaP cells, reduces the expressions of androgen receptor (AR) and AR target genes (prostate-specific antigen and TMPRSS2), and inhibits Akt phosphorylation. Fenofibrate can induce the accumulation of intracellular reactive oxygen species and malondialdehyde, and decrease the activities of total anti-oxidant and superoxide dismutase in LNCaP cells. Fenofibrate exerts an anti-proliferative property by inhibiting the expression of AR and induces apoptosis by causing oxidative stress. Therefore, our data suggest fenofibrate may have beneficial effects in fenofibrate users by preventing prostate cancer growth through inhibition of androgen activation and expression.

  12. Fenofibrate down-regulates the expressions of androgen receptor (AR) and AR target genes and induces oxidative stress in the prostate cancer cell line LNCaP

    International Nuclear Information System (INIS)

    Highlights: ► Fenofibrate induces cell cycle arrest in G1 phase and apoptosis in LNCaP cells. ► Fenofibrate reduces the expressions of androgen receptor in LNCaP cells. ► Fenofibrate induces oxidative stress in the prostate cancer cell line LNCaP. -- Abstract: Fenofibrate, a peroxisome proliferator-androgen receptor-alpha agonist, is widely used in treating different forms of hyperlipidemia and hypercholesterolemia. Recent reports have indicated that fenofibrate exerts anti-proliferative and pro-apoptotic properties. This study aims to investigate the effects of fenofibrate on the prostate cancer (PCa) cell line LNCaP. The effects of fenofibrate on LNCaP cells were evaluated by flow cytometry, reverse transcription-polymerase chain reaction, enzyme-linked immunosorbent assays, Western blot analysis, and dual-luciferase reporter assay. Fenofibrate induces cell cycle arrest in G1 phase and apoptosis in LNCaP cells, reduces the expressions of androgen receptor (AR) and AR target genes (prostate-specific antigen and TMPRSS2), and inhibits Akt phosphorylation. Fenofibrate can induce the accumulation of intracellular reactive oxygen species and malondialdehyde, and decrease the activities of total anti-oxidant and superoxide dismutase in LNCaP cells. Fenofibrate exerts an anti-proliferative property by inhibiting the expression of AR and induces apoptosis by causing oxidative stress. Therefore, our data suggest fenofibrate may have beneficial effects in fenofibrate users by preventing prostate cancer growth through inhibition of androgen activation and expression

  13. Regulation of the PKCθ-NF-κB Axis in T lymphocytes by the Tumor Necrosis Factor Receptor Family Member OX40

    Directory of Open Access Journals (Sweden)

    Takanori eSo

    2012-05-01

    Full Text Available Antigen primed T lymphocytes need to expand and persist to promote adaptive immunity. The growth and survival signals that control this are in large part provided by the NF-κB pathway in activated or effector/memory T cells. Although several membrane receptors impact NF-κB activation, signaling from OX40 (CD134, TNFRSF4, a member of the tumor necrosis factor receptor (TNFR superfamily, has proven to be important for T cell immunity and a strong contributor to NF-κB activity. PKCθ directs the TCR and CD28-dependent assembly of a CBM complex (CARMA1, BCL10, and MALT1 for efficient activation of NF-κB, raising the question of whether other membrane bound receptors that activate NF-κB also require this PKCθ-CBM axis to control TCR-independent T cell activity. We discuss here our recent data demonstrating that after ligation by OX40L (CD252, TNFSF4 expressed on antigen-presenting cells, OX40 translocates into detergent-insoluble membrane lipid microdomains (DIM or lipid rafts in T cells irrespective of TCR signals, and assembles into a novel signaling complex containing PKCθ, together with TRAF2, RIP1, the CBM complex, and the IKKα/β/γ complex. PKCθ is required for optimal NF-κB activation mediated by OX40 and thus works as an essential component of this OX40 signalosome. We also discuss the likelihood that other TNFR superfamily molecules might complex with PKCθ in T cells, and whether PKC isoforms may be critical to the function of TNFR molecules in general. 

  14. Hypothalamus-pituitary-thyroid axis disruption in rats with breast cancer is related to an altered endogenous oxytocin/insulin-regulated aminopeptidase (IRAP) system.

    Science.gov (United States)

    Carrera-González, María Pilar; Ramírez-Expósito, María Jesús; de Saavedra, Jose Manuel Arias; Sánchez-Agesta, Rafael; Mayas, María Dolores; Martínez-Martos, Jose Manuel

    2011-06-01

    Associations of breast cancer with diseases of the thyroid have been repeatedly reported, but the mechanism underlying this association remains to be elucidated. It has been reported that oxytocin (OXT) attenuates the thyroid-stimulating hormone (TSH) release in response to thyrotrophin-releasing hormone (TRH) and decreased plasma levels of TSH as well as the thyroid hormones by an effect mediated by the central nervous system. Oxytocinase (IRAP) is the regulatory proteolytic enzyme reported to hydrolyze OXT. Changes in IRAP activity have been reported in both human breast cancer and N-methyl-nitrosourea (NMU)-induced rat mammary tumours. Here, we measure IRAP activity fluorometrically using cystyl-β-naphthylamide as the substrate, in the hypothalamus-pituitary-thyroid axis together with the circulating levels of OXT, and its relationship with circulating levels of TSH and free thyroxine (fT4), as markers of thyroid function in control rats and rats with breast cancer induced by NMU. We found decreased thyroid function in rats with breast cancer induced by NMU, supported by the existence of lower serum circulating levels of both TSH and fT4 than their corresponding controls. Concomitantly, we found a decrease of hypothalamic IRAP activity and an increase in circulating levels of OXT. We propose that breast cancer increases OXT pituitary release by decreasing its hypothalamic catabolism through IRAP activity, probably due to the alteration of the estrogenic endocrine status. Thus, high circulating levels of OXT decreased TSH release from the pituitary, and therefore, of thyroid hormones from the thyroid, supporting the association between breast cancer and thyroid function disruption.

  15. mTORC2-PKBα/Akt1 Serine 473 phosphorylation axis is essential for regulation of FOXP3 Stability by chemokine CCL3 in psoriasis.

    Science.gov (United States)

    Chen, Ling; Wu, Jinjin; Pier, Eric; Zhao, Yun; Shen, Zhu

    2013-02-01

    The connection between infections and acute guttate psoriasis (AGP) outbreaks/chronic plaque psoriasis (CPP) exacerbation has been known for years. Impaired function of FOXP3+Tregs in psoriasis has been identified. However, the mechanisms behind these two observations have not been fully interpreted. In the present study, we provide evidence to support chemokine CCL3 as one of the vital links between infections and FOXP3 stability in the psoriatic microenvironment. We found that serum CCL3, strongly induced by microorganism infections including streptococcus, was closely correlated with FOXP3 levels in CD4+CD25+T cells of patients with psoriasis. CCL3 manipulated FOXP3 stability in a concentration-dependent bidirectional manner. High-concentration CCL3 decreased FOXP3 stability by promoting FOXP3's degradation through K48-linkage ubiquitination. This degradation was mainly dependent on upregulation of Serine 473 phosphorylation of the PKBα/Akt1 isoform, and almost independent of mTORC1 (mammalian target of rapamycin complex 1) activity. On the other hand, low-concentration CCL3 could enhance FOXP3 stability by the maintenance of the PKC pathway and the restriction of the PKB/Akt pathway. We further demonstrated that enhancing FOXP3 stability by low-concentration CCL3 attributed, at least partly, to the prevention of cytoplasmic Sin1, a vital component of mTORC2, nuclear translocation. Our results suggest vital roles for CCL3-mTORC2-isoform PKB/Akt1 S473 phosphorylation axis in FOXP3+Tregs and the development of psoriasis.

  16. Recent progress of orexin in the regulation of the hypothalamic-pituitary-adrenal axis%增食欲素调节下丘脑-垂体-肾上腺轴的研究进展

    Institute of Scientific and Technical Information of China (English)

    王露; 赵玉岩

    2010-01-01

    增食欲素A和增食欲素B是下丘脑神经肽,通过激活两种G蛋白耦联受体发挥作用.增食欲素及其受体表达于下丘脑室旁核和正中隆起,增食欲素受体还表达于脑垂体促皮质激素细胞、肾上腺皮质和髓质.增食欲素能调节摄食、能量代谢平衡、睡醒周期、血压等,还能调节下丘脑-垂体-肾上腺(HPA)轴.现就增食欲素及其受体在HPA轴中枢支和周围支(peripheral branches)的表达及作用机制作一综述.%Orexin A and orexin B are hypothalamic peptides that play roles via two G protein-cou-pled receptors. Orexins and their receptors are expressed in the hypothalamic paraventricular nucleus and me-dian eminence, orexins receptors also expressed in pituitary corticotrophs, adrenal cortex and medulla. Orexins regulate feeding, energy metabolic homeostasis, the sleep/wake cycle, blood pressure and so on, they also modulate the hypothalamic-pituitary-adrenal (HPA) axis. Expression and function of orexins and their recep-tors in the central and peripheral branches of the HPA axis are reviewed in this article.

  17. The Tumor-Promoting Flow of Cells Into, Within and Out of the Tumor Site: Regulation by the Inflammatory Axis of TNFα and Chemokines

    OpenAIRE

    Ben-Baruch, Adit

    2011-01-01

    Tumors are dynamic organs, in which active processes of cell motility affect disease course by regulating the composition of cells at the tumor site. While sub-populations of tumor-promoting leukocytes are recruited inward and endothelial cell migration stands in the basis of vascular branching throughout the tumor, cancer cells make their way out of the primary site towards specific metastatic sites. This review describes the independent and cross-regulatory roles of inflammatory chemokines ...

  18. Afatinib down-regulates MCL-1 expression through the PERK-eIF2α-ATF4 axis and leads to apoptosis in head and neck squamous cell carcinoma.

    Science.gov (United States)

    Liu, Xianfang; Lv, Zhenghua; Zou, Jidong; Liu, Xiuxiu; Ma, Juke; Wang, Jinhua; Sa, Na; Jing, Peihang; Xu, Wei

    2016-01-01

    Afatinib is the second generation of irreversible inhibitor of EGFR, HER2 and HER4, which has shown encouraging phase II and III clinical outcomes in the treatment of head and neck squamous cell carcinoma (HNSCC). However, the molecular mechanism of afatinib-induced apoptosis in HNSCC is poorly understood. In the present investigation, we discovered that down-regulation of MCL-1, an anti-apoptotic member of BCL-2 family, was responsible for afatinib-triggered apoptosis. And the inactivation of AKT-mTOR signaling caused by afatinib lead to translational inhibition of MCL-1 expression. As a crucial branch of ER stress, PERK-eIF2α-ATF4 axis was also stimulated in HNSCC cells after afatinib incubation. Silencing either eIF2α or ATF4 by siRNA transfection relieved afatinib-caused suppression of AKT-mTOR activity, attenuating MCL-1 down-regulation as well as subsequent apoptosis. Collectively, the results show that afatinib hampers AKT-mTOR activation by stimulating PERK-eIF2α-ATF4 signaling pathway, giving rise to MCL-1 down-regulation mediated apoptosis in HNSCC cells. Therefore, our findings reveal the elaborate molecular network of afatinib-induced apoptosis in HNSCC, which would provide substantial theoretical underpinnings for afatinib clinical application and highlight its promising prospect in HNSCC treatment. PMID:27648360

  19. PU.1 Is Identified as a Novel Metastasis Suppressor in Hepatocellular Carcinoma Regulating the miR-615-5p/IGF2 Axis.

    Science.gov (United States)

    Song, Li-Jie; Zhang, Wei-Jie; Chang, Zhi-Wei; Pan, Yan-Feng; Zong, Hong; Fan, Qing-Xia; Wang, Liu-Xing

    2015-01-01

    Invasion and metastasis is the major cause of tumor recurrence, difficulty for cure and low survival rate. Excavating key transcription factors, which can regulate tumor invasion and metastasis, are crucial to the development of therapeutic strategies for cancers. PU.1 is a master hematopoietic transcription factor and a vital regulator in life. Here, we report that, compared to adjacent non-cancerous tissues, expression of PU.1 mRNA in metastatic hepatocellular carcinoma (HCC), but not primary HCC, was significantly down-regulated. In addition, levels of PU.1 mRNA in metastatic hepatoma cell lines MHCC97L and MHCC97H were much lower than in non-metastatic Hep3B cells. Transwell invasion assays after PU.1 siRNA transfection showed that the invasion of hepatoma cell lines was increased markedly by PU.1 knockdown. Oppositely, overexpression of PU.1 suppressed the invasion of these cells. However, knockdown and overexpression of PU.1 did not influence proliferation. Finally, we tried to explore the potential mechanism of PU.1 suppressing hepatoma cell invasion. ChIP-qPCR analysis showed that PU.1 exhibited a high binding capacity with miR-615-5p promoter sequence. Overexpression of PU.1 caused a dramatic increase of pri-, pre- and mature miR-615-5p, as well as a marked decrease of miR-615-5p target gene IGF2. These data indicate that PU.1 inhibits invasion of human HCC through promoting miR-615-5p and suppressing IGF2. These findings improve our understanding of PU.1 regulatory roles and provided a potential target for metastatic HCC diagnosis and therapy.

  20. The microRNA-200/Zeb1 axis regulates ECM-dependent β1-integrin/FAK signaling, cancer cell invasion and metastasis through CRKL.

    Science.gov (United States)

    Ungewiss, Christin; Rizvi, Zain H; Roybal, Jonathon D; Peng, David H; Gold, Kathryn A; Shin, Dong-Hoon; Creighton, Chad J; Gibbons, Don L

    2016-01-01

    Tumor cell metastasis is a complex process that has been mechanistically linked to the epithelial-mesenchymal transition (EMT). The double-negative feedback loop between the microRNA-200 family and the Zeb1 transcriptional repressor is a master EMT regulator, but there is incomplete understanding of how miR-200 suppresses invasion. Our recent efforts have focused on the tumor cell-matrix interactions essential to tumor cell activation. Herein we utilized both our Kras/p53 mutant mouse model and human lung cancer cell lines to demonstrate that upon miR-200 loss integrin β1-collagen I interactions drive 3D in vitro migration/invasion and in vivo metastases. Zeb1-dependent EMT enhances tumor cell responsiveness to the ECM composition and activates FAK/Src pathway signaling by de-repression of the direct miR-200 target, CRKL. We demonstrate that CRKL serves as an adaptor molecule to facilitate focal adhesion formation, mediates outside-in signaling through Itgβ1 to drive cell invasion, and inside-out signaling that maintains tumor cell-matrix contacts required for cell invasion. Importantly, CRKL levels in pan-cancer TCGA analyses were predictive of survival and CRKL knockdown suppressed experimental metastases in vivo without affecting primary tumor growth. Our findings highlight the critical ECM-tumor cell interactions regulated by miR-200/Zeb1-dependent EMT that activate intracellular signaling pathways responsible for tumor cell invasion and metastasis. PMID:26728244

  1. [Leptin and hypothalamus-hypophysis-thyroid axis].

    Science.gov (United States)

    Riccioni, G; Menna, V; Lambo, M S; Della Vecchia, R; Di Ilio, C; De Lorenzo, A; D'Orazio, N

    2004-01-01

    The leptin system is a major regulator of food intake and metabolic rate. The leptin, an adipose tissue hormone whose plasma levels reflect energy stores, plays an important rule in the pathogenesis of such eating disorders like bulimia and anorexia. Thyroid hormones are major regulators of energy homeostasis. It is possible that leptin and thyroid hormone exert their actions on thermogenesis and energy metabolism via the same common effector patways. Leptin influences feedback regulation of the hypotalamic TRH-secreting neurons by thyroid hormone. Low serum levels of thyroid hormones reflect a dysfunction of the hypotalamic-pituitary-thyroid (HPT) and hypotalamic-pituitary-adrenal (HPA) axis in patients with nervosa anorexia. Neuroendocrine effects of leptin include effects on the HPT and HPA axis. The aim of this work is to evaluated the interactions between leptina and HPT axis on the basis of recent published works and reviews in literature. PMID:15147079

  2. The Tumor-Promoting Flow of Cells Into, Within and Out of the Tumor Site: Regulation by the Inflammatory Axis of TNFα and Chemokines.

    Science.gov (United States)

    Ben-Baruch, Adit

    2012-08-01

    Tumors are dynamic organs, in which active processes of cell motility affect disease course by regulating the composition of cells at the tumor site. While sub-populations of tumor-promoting leukocytes are recruited inward and endothelial cell migration stands in the basis of vascular branching throughout the tumor, cancer cells make their way out of the primary site towards specific metastatic sites. This review describes the independent and cross-regulatory roles of inflammatory chemokines and of the inflammatory cytokine tumor necrosis factor α (TNFα) in determining cell motility processes that eventually have profound effects on tumor growth and metastasis. First, the effects of inflammatory chemokines such as CCL2 (MCP-1), CCL5 (RANTES) and CXCL8 (IL-8) are described, regulating the inward flow of leukocyte sub-populations with pro-tumoral activities, such as tumor-associated macrophages (TAM), myeloid-derived suppressor cells (MDSC), tumor-associated neutrophils (TAN), Th17 cells and Tregs. Then, the ability of inflammatory chemokines to induce endothelial cell migration, sprouting and tube formation is discussed, with its implications on tumor angiogenesis. This part is followed by an in depth description of the manners by which TNFα potentiates the above activities of the inflammatory chemokines, alongside with its ability to directly induce migratory processes in the tumor cells thus promoting metastasis. Note worthy is the ability of TNFα to induce in the tumor cells the important process of epithelial-to-mesenchymal transition (EMT). Emphasis is given to the ability of TNFα to establish an inflammatory network with the chemokines, and in parallel to form a cell re-modeling network together with transforming growth factor β (TGFβ). The review concludes by discussing the implications of such networks on disease course, and on the future design of therapeutic measures in cancer. PMID:22190050

  3. IL-6/STAT3 axis initiated CAFs via up-regulating TIMP-1 which was attenuated by acetylation of STAT3 induced by PCAF in HCC microenvironment.

    Science.gov (United States)

    Zheng, Xin; Xu, Meng; Yao, Bowen; Wang, Cong; Jia, Yuli; Liu, Qingguang

    2016-09-01

    Aberrant tumor microenvironment is involved closely in tumor initiation and progression, in which cancer associated fibroblasts (CAFs) play a pivotal role. Both IL-6/STAT3 signaling and TIMP-1 have been found to modulate the crosstalk between tumor cells and CAFs in tumor microenvironment, however, the underlying mechanism remains unclear. Here, we showed that IL-6/STAT3 signaling was activated aberrantly in HCC tissues and correlated with poor post-surgical outcome. The in vitro experiments confirmed that activation of IL-6/STAT3 pathway enhanced TIMP-1 expression directly via phosphorylated STATs (p-STAT3)-binding with TIMP-1 promoter in Huh7 cells. Furthermore, activation of IL-6/STAT3 pathway in HCC cells was shown to induce the transformation from normal liver fibroblasts (LFs) to CAFs via up-regulating TIMP-1 expression. Co-culture with CAFs promoted the growth of Huh7 cells both in vitro and in vivo. Finally, by co-Immunoprecipitation and immunoblotting assessments, PCAF, a well-known acetyltransferase, was revealed to acetylate cytoplasmic STAT3 protein directly and regulate TIMP-1 expression negatively in Huh7 cells. In summary, this investigation indicated that there was a positive IL-6/TIMP-1 feedback loop controlling the crosstalk between HCC cells and its neighbouring fibroblasts. The data here also identified that PCAF repressed TIMP-1 expression via acetylation of STAT3. In conclusion, this investigation demonstrated that CAFs promoted HCC growth via IL-6/STAT3/AKT pathway and TIMP-1 over-expression driven by IL-6/STAT3 pathway in HCC cells brought in more CAFs through activating LFs. Finally, PCAF could block this positive feedback by acetylating STAT3 in HCC cells.

  4. Prostate cancer - resources

    Science.gov (United States)

    Resources - prostate cancer ... The following organizations are good resources for information on prostate cancer : American Cancer Society -- www.cancer.org/cancer/prostatecancer/index National Cancer Institute -- www.cancer.gov/cancertopics/ ...

  5. Detecting Prostate Cancer

    Medline Plus

    Full Text Available ... such as a trans-rectal ultrasound and a biopsy. Physician: Now, just relax -- the best thing to ... prostate gland. Usually these are accompanied by a biopsy -- a sampling of the prostate tissue with a ...

  6. Prostate cancer staging

    Science.gov (United States)

    ... this page: //medlineplus.gov/ency/patientinstructions/000397.htm Prostate cancer staging To use the sharing features on this ... trials you may be able to join How Prostate Cancer Staging is Done Initial staging is based on ...

  7. Prostate cancer screenings

    Science.gov (United States)

    ... this page: //medlineplus.gov/ency/patientinstructions/000846.htm Prostate cancer screenings To use the sharing features on this ... Intern Med . 2011;155(11):762-71. National Cancer Institute. Prostate Cancer Screening -- for health professionals. Revised April 2, ...

  8. Cryotherapy for prostate cancer

    Science.gov (United States)

    Cryotherapy uses very cold temperatures to freeze and kill prostate cancer cells. The goal of cryosurgery is ... Possible short-term side effects of cryotherapy for prostate ... of the penis or scrotum Problems controlling your bladder (more ...

  9. Detecting Prostate Cancer

    Medline Plus

    Full Text Available ... like to do is just do a rectal examination and feel that prostate. Narrator: The other necessary ... they do have an abnormality in their rectal examination does not mean that they have prostate cancer. ...

  10. Prostate cancer in Denmark

    DEFF Research Database (Denmark)

    Brasso, K; Friis, S; Kjaer, S K;

    1998-01-01

    To review the trends in prostate cancer (PC) incidence and mortality rates in Denmark during a 50-year period.......To review the trends in prostate cancer (PC) incidence and mortality rates in Denmark during a 50-year period....

  11. Prostate Cancer Prevention

    Science.gov (United States)

    ... prostate cancer increases as men get older. Family history of prostate cancer A man whose father, brother, ... some foods, such as green vegetables, beans and orange juice. Folic acid is a man-made form ...

  12. About the Prostate

    Science.gov (United States)

    ... DRE) is a useful screening test. Benign prostatic hypertrophy ( BPH ), a non-cancerous prostate condition, typically develops ... Under normal circumstances, the urinary sphincters (bands of muscle at the base of the bladder and at ...

  13. American cranberry (Vaccinium macrocarpon) extract affects human prostate cancer cell growth via cell cycle arrest by modulating expression of cell cycle regulators.

    Science.gov (United States)

    Déziel, Bob; MacPhee, James; Patel, Kunal; Catalli, Adriana; Kulka, Marianna; Neto, Catherine; Gottschall-Pass, Katherine; Hurta, Robert

    2012-05-01

    Prostate cancer is one of the most common cancers in the world, and its prevalence is expected to increase appreciably in the coming decades. As such, more research is necessary to understand the etiology, progression and possible preventative measures to delay or to stop the development of this disease. Recently, there has been interest in examining the effects of whole extracts from commonly harvested crops on the behaviour and progression of cancer. Here, we describe the effects of whole cranberry extract (WCE) on the behaviour of DU145 human prostate cancer cells in vitro. Following treatment of DU145 human prostate cancer cells with 10, 25 and 50 μg ml⁻¹ of WCE, respectively for 6 h, WCE significantly decreased the cellular viability of DU145 cells. WCE also decreased the proportion of cells in the G2-M phase of the cell cycle and increased the proportion of cells in the G1 phase of the cell cycle following treatment of cells with 25 and 50 μg ml⁻¹ treatment of WCE for 6 h. These alterations in cell cycle were associated with changes in cell cycle regulatory proteins and other cell cycle associated proteins. WCE decreased the expression of CDK4, cyclin A, cyclin B1, cyclin D1 and cyclin E, and increased the expression of p27. Changes in p16(INK4a) and pRBp107 protein expression levels also were evident, however, the changes noted in p16(INK4a) and pRBp107 protein expression levels were not statistically significant. These findings demonstrate that phytochemical extracts from the American cranberry (Vaccinium macrocarpon) can affect the behaviour of human prostate cancer cells in vitro and further support the potential health benefits associated with cranberries.

  14. Toll-like Receptor 3 Regulates Angiogenesis and Apoptosis in Prostate Cancer Cell Lines through Hypoxia-Inducible Factor 1α

    OpenAIRE

    Alessio Paone; Roberta Galli; Chiara Gabellini; Dmitriy Lukashev; Donatella Starace; Agnes Gorlach; Paola De Cesaris; Elio Ziparo; Donatella Del Bufalo; Sitkovsky, Michail V.; Antonio Filippini; Anna Riccioli

    2010-01-01

    Toll-like receptors (TLRs) recognize microbial/viral-derived components that trigger innate immune response and conflicting data implicate TLR agonists in cancer, either as protumor or antitumor agents. We previously demonstrated that TLR3 activation mediated by its agonist poly(I:C) induces antitumor signaling, leading to apoptosis of prostate cancer cells LNCaP and PC3 with much more efficiency in the former than in the second more aggressive line. The transcription factor hypoxia-inducible...

  15. Toll-like Receptor 3 Regulates Angiogenesis and Apoptosis in Prostate Cancer Cell Lines through Hypoxia-Inducible Factor 1α1

    OpenAIRE

    Paone, Alessio; Galli, Roberta; Gabellini, Chiara; Lukashev, Dmitriy; Starace, Donatella; Gorlach, Agnes; Cesaris, Paola; Ziparo, Elio; Del Bufalo, Donatella; Sitkovsky, Michail V.; Filippini, Antonio; Riccioli, Anna

    2010-01-01

    Toll-like receptors (TLRs) recognize microbial/viral-derived components that trigger innate immune response and conflicting data implicate TLR agonists in cancer, either as protumor or antitumor agents. We previously demonstrated that TLR3 activation mediated by its agonist poly(I:C) induces antitumor signaling, leading to apoptosis of prostate cancer cells LNCaP and PC3 with much more efficiency in the former than in the second more aggressive line. The transcription factor hypoxia-inducible...

  16. Enlarged prostate - after care

    Science.gov (United States)

    ... self-care; Benign prostatic hypertrophy - self-care; Benign prostatic hyperplasia - self-care ... Kaplan SA. Benign prostatic hyperplasia and prostatis. In: Goldman L, Schafer AI, eds. Goldman-Cecil Medicine . 25th ed. Philadelphia, PA: Elsevier Saunders; 2016:chap ...

  17. 饮食防治前列腺癌%Dietary intervention of prostatic cancer (literature review)

    Institute of Scientific and Technical Information of China (English)

    刘国栋; 刘晓; 马宝良

    2011-01-01

    流行病学及病理研究证实,前列腺癌的发生和发展与饮食习惯、生活方式明显相关.文献还证实,低脂肪饮食,尤其来源于鱼油的n-3脂肪酸,及蔬菜、水果和豆类中的多酚类、异黄酮、番茄红素、类胡萝卜素及没食子,通过调节性激素、胰岛素/IGF轴及基因,可降低前列腺癌细胞生长、异种移植癌生长、细胞增殖,并增加凋亡,从而达到抑制前列腺癌生长和发展的作用.对前列腺癌患者,进行低脂肪饮食干预,可提高生活质量,且可使PSA倍增时间延长,增加存活.此法有效、安全、省钱、易行,值得推广.%Epidemiological and pathological findings have validated that the genesis and progress of prostatic cancer is closely related to diet and living style. Low-fat diet, especially n-3 lipid acid from fish oil, polyphenols, isoflavone, lycoypene, carotenoid and nutgall from vegetables, fruits and beans, are able to inhibit the growth of prostatic cancer by regulating sexual hormones, insulin/ IFG axis and genes, thus restraining the growth of prostatic cancer cells, xenogenesis cancer cells and cell proliferation, and increasing apoptosis. Patients with prostatic cancer can improve life quality and survival rate by taking low-fat diet, which is effective, safe, economical and feasible.

  18. Transcriptional network of androgen receptor in prostate cancer progression.

    Science.gov (United States)

    Takayama, Ken-ichi; Inoue, Satoshi

    2013-08-01

    The androgen receptor belongs to the nuclear receptor superfamily and functions as a ligand-dependent transcription factor. It binds to the androgen responsive element and recruits coregulatory factors to modulate gene transcription. In addition, the androgen receptor interacts with other transcription factors, such as forkhead box A1, and other oncogenic signaling pathway molecules that bind deoxyribonucleic acid and regulate transcription. Androgen receptor signaling plays an important role in the development of prostate cancer. Prostate cancer cells proliferate in an androgen-dependent manner, and androgen receptor blockade is effective in prostate cancer therapy. However, patients often progress to castration-resistant prostate cancer with elevated androgen receptor expression and hypersensitivity to androgen. Recently, comprehensive analysis tools, such as complementary DNA microarray, chromatin immunoprecipitation-on-chip and chromatin immunoprecipitation-sequence, have described the androgen-mediated diverse transcriptional program and gene networks in prostate cancer. Furthermore, functional and clinical studies have shown that some of the androgen receptor-regulated genes could be prognostic markers and potential therapeutic targets for the treatment of prostate cancer, particularly castration-resistant prostate cancer. Thus, identifying androgen receptor downstream signaling events and investigating the regulation of androgen receptor activity is critical for understanding the mechanism of carcinogenesis and progression to castration-resistant prostate cancer.

  19. Tumor-Suppressive Activity of Lunatic Fringe in Prostate through Differential Modulation of Notch Receptor Activation

    Directory of Open Access Journals (Sweden)

    Shubing Zhang

    2014-02-01

    Full Text Available Elevated Notch ligand and receptor expression has been associated with aggressive forms of prostate cancer, suggesting a role for Notch signaling in regulation of prostate tumor initiation and progression. Here, we report a critical role for Lunatic Fringe (Lfng, which encodes an O-fucosylpeptide 3-ß-N-acetylglucosaminyltransferase known to modify epidermal growth factor repeats of Notch receptor proteins, in regulation of prostate epithelial differentiation and proliferation, as well as in prostate tumor suppression. Deletion of Lfng in mice caused altered Notch activation in the prostate, associated with elevated accumulation of Notch1, Notch2, and Notch4 intracellular domains, decreased levels of the putative Notch3 intracellular fragment, as well as increased expression of Hes1, Hes5, and Hey2. Loss of Lfng resulted in expansion of the basal layer, increased proliferation of both luminal and basal cells, and ultimately, prostatic intraepithelial neoplasia. The Lfng-null prostate showed down-regulation of prostatic tumor suppressor gene NKX3.1 and increased androgen receptor expression. Interestingly, expression of LFNG and NKX3.1 were positively correlated in publically available human prostate cancer data sets. Knockdown of LFNG in DU-145 prostate cancer cells led to expansion of CD44+CD24− and CD49f+CD24− stem/progenitor-like cell population associated with enhanced prostatosphere-forming capacity. Taken together, these data revealed a tumor-suppressive role for Lfng in the prostate through differential regulation of Notch signaling.

  20. Enlarged prostate - what to ask your doctor

    Science.gov (United States)

    ... body? What does the prostate gland do? What causes the prostate gland to enlarge? Do many other men have prostate problems? How do I know my problem is not prostate cancer? What are the symptoms of an enlarged prostate? ...

  1. Retraction: "Down-regulation of Notch-1 and Jagged-1 inhibits prostate cancer cell growth, migration and invasion, and induces apoptosis via inactivation of Akt, mTOR, and NF-κB signaling pathways" by Wang et al.

    Science.gov (United States)

    2016-08-01

    The above article, published online on January 5, 2010 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor in Chief, Gary S. Stein, and Wiley Periodicals, Inc. The retraction has been agreed following an investigation from Wayne State University involving the first author and the corresponding author that found Figure 5A to be inappropriately manipulated. REFERENCE Wang Z, Li Y, Banerjee S, Kong D, Ahmad A, Nogueira V, Hay N, Sarkar FH. 2010. Down-regulation of Notch-1 and Jagged-1 inhibits prostate cancer cell growth, migration and invasion, and induces apoptosis via inactivation of Akt, mTOR, and NF-κB signaling pathways. J Cell Biochem 109:726-736; doi: 10.1002/jcb.22451.

  2. Retraction: "Down-regulation of Notch-1 is associated with Akt and FoxM1 in inducing cell growth inhibition and apoptosis in prostate cancer cells" by Wang et al.

    Science.gov (United States)

    2016-08-01

    The above article, published online on July 23, 2010 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor in Chief, Gary S. Stein, and Wiley Periodicals, Inc. The retraction has been agreed following an investigation from Wayne State University involving the first author and the corresponding author that found Figures 1B and 3A to be inappropriately manipulated. REFERENCE Wang Z, Li Y, Ahmad A, Banerjee S, Azmi AS, Kong D, Wojewoda C, Miele L, Sarkar FH. 2011. Down-regulation of Notch-1 is associated with Akt and FoxM1 in inducing cell growth inhibition and apoptosis in prostate cancer cells. J Cell Biochem 112:78-88; doi: 10.1002/jcb.22770.

  3. Retraction: "Down-regulation of Notch-1 and Jagged-1 inhibits prostate cancer cell growth, migration and invasion, and induces apoptosis via inactivation of Akt, mTOR, and NF-κB signaling pathways" by Wang et al.

    Science.gov (United States)

    2016-08-01

    The above article, published online on January 5, 2010 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor in Chief, Gary S. Stein, and Wiley Periodicals, Inc. The retraction has been agreed following an investigation from Wayne State University involving the first author and the corresponding author that found Figure 5A to be inappropriately manipulated. REFERENCE Wang Z, Li Y, Banerjee S, Kong D, Ahmad A, Nogueira V, Hay N, Sarkar FH. 2010. Down-regulation of Notch-1 and Jagged-1 inhibits prostate cancer cell growth, migration and invasion, and induces apoptosis via inactivation of Akt, mTOR, and NF-κB signaling pathways. J Cell Biochem 109:726-736; doi: 10.1002/jcb.22451. PMID:27301887

  4. Retraction: "Down-regulation of Notch-1 is associated with Akt and FoxM1 in inducing cell growth inhibition and apoptosis in prostate cancer cells" by Wang et al.

    Science.gov (United States)

    2016-08-01

    The above article, published online on July 23, 2010 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor in Chief, Gary S. Stein, and Wiley Periodicals, Inc. The retraction has been agreed following an investigation from Wayne State University involving the first author and the corresponding author that found Figures 1B and 3A to be inappropriately manipulated. REFERENCE Wang Z, Li Y, Ahmad A, Banerjee S, Azmi AS, Kong D, Wojewoda C, Miele L, Sarkar FH. 2011. Down-regulation of Notch-1 is associated with Akt and FoxM1 in inducing cell growth inhibition and apoptosis in prostate cancer cells. J Cell Biochem 112:78-88; doi: 10.1002/jcb.22770. PMID:27301889

  5. Sex differences in the HPA axis.

    Science.gov (United States)

    Goel, Nirupa; Workman, Joanna L; Lee, Tiffany T; Innala, Leyla; Viau, Victor

    2014-07-01

    The hypothalamic-pituitary-adrenal (HPA) axis is a major component of the systems that respond to stress, by coordinating the neuroendocrine and autonomic responses. Tightly controlled regulation of HPA responses is critical for maintaining mental and physical health, as hyper- and hypo-activity have been linked to disease states. A long history of research has revealed sex differences in numerous components of the HPA stress system and its responses, which may partially form the basis for sex disparities in disease development. Despite this, many studies use male subjects exclusively, while fewer reports involve females or provide direct sex comparisons. The purpose of this article is to present sex comparisons in the functional and molecular aspects of the HPA axis, through various phases of activity, including basal, acute stress, and chronic stress conditions. The HPA axis in females initiates more rapidly and produces a greater output of stress hormones. This review focuses on the interactions between the gonadal hormone system and the HPA axis as the key mediators of these sex differences, whereby androgens increase and estrogens decrease HPA activity in adulthood. In addition to the effects of gonadal hormones on the adult response, morphological impacts of hormone exposure during development are also involved in mediating sex differences. Additional systems impinging on the HPA axis that contribute to sex differences include the monoamine neurotransmitters norepinephrine and serotonin. Diverse signals originating from the brain and periphery are integrated to determine the level of HPA axis activity, and these signals are, in many cases, sex-specific.

  6. Matrine inhibits the proliferation, invasion and migration of castration-resistant prostate cancer cells through regulation of the NF-κB signaling pathway.

    Science.gov (United States)

    Li, Qi; Lai, Yiming; Wang, Chengbin; Xu, Guibin; He, Zheng; Shang, Xiaohong; Sun, Yi; Zhang, Fan; Liu, Leyuan; Huang, Hai

    2016-01-01

    Matrine is a naturally occurring alkaloid extracted from the Chinese herb Sophora flavescens. It has been demonstrated to exhibit antiproliferative properties, promote apoptosis and inhibit cell invasion in a number of cancer cell lines. It has also been shown to improve the efficacy of chemotherapy when it is combined with other chemotherapy drugs. However, the therapeutic efficacy of matrine for prostate cancer remains poorly understood. In the present study, we showed that matrine inhibited the proliferation, migration and invasion of both DU145 and PC-3 cells in a dose- and time-dependent manner. It also reduced the cell population at S phase and increased the cell population at sub-G1 phase. The increases in both the apoptotic cell population and cell population at S and sub-G1 phases consistently indicated a pro-apoptotic effect of matrine. Decreases in levels of P65, p-P65, IKKα/β, p-IKKα/β, IKBα and p-IKBα as detected by immunoblot analysis in the matrine-treated DU145 and PC-3 cells suggested an involvement of the NF-κB signaling pathway. Therefore, it is a novel promising addition to the current arsenal of chemotherapy drugs for the treatment of androgen-independent prostate cancer.

  7. The AhR Ligand, TCDD, Regulates Androgen Receptor Activity Differently in Androgen-Sensitive versus Castration-Resistant Human Prostate Cancer Cells

    Directory of Open Access Journals (Sweden)

    Maryam Ghotbaddini

    2015-07-01

    Full Text Available The reported biological effects of TCDD include induction of drug metabolizing enzymes, wasting syndrome and tumor promotion. TCDD elicits most of its effects through binding the aryl hydrocarbon receptor (AhR. TCDD induced degradation of AhR has been widely reported and requires ubiquitination of the protein. The rapid depletion of AhR following TCDD activation serves as a mechanism to modulate AhR mediated gene induction. In addition to inducing AhR degradation, TCDD has been reported to induce degradation of hormone receptors. The studies reported here, evaluate the effect of TCDD exposure on androgen receptor (AR expression and activity in androgen-sensitive LNCaP and castration-resistant C4-2 prostate cancer cells. Our results show that TCDD exposure does not induce AhR or AR degradation in C4-2 cells. However, both AhR and AR are degraded in LNCaP cells following TCDD exposure. In addition, TCDD enhances AR phosphorylation and induces expression of AR responsive genes in LNCaP cells. Our data reveals that TCDD effect on AR expression and activity differs in androgen-sensitive and castration-resistant prostate cancer cell models.

  8. Matrine inhibits the proliferation, invasion and migration of castration-resistant prostate cancer cells through regulation of the NF-κB signaling pathway.

    Science.gov (United States)

    Li, Qi; Lai, Yiming; Wang, Chengbin; Xu, Guibin; He, Zheng; Shang, Xiaohong; Sun, Yi; Zhang, Fan; Liu, Leyuan; Huang, Hai

    2016-01-01

    Matrine is a naturally occurring alkaloid extracted from the Chinese herb Sophora flavescens. It has been demonstrated to exhibit antiproliferative properties, promote apoptosis and inhibit cell invasion in a number of cancer cell lines. It has also been shown to improve the efficacy of chemotherapy when it is combined with other chemotherapy drugs. However, the therapeutic efficacy of matrine for prostate cancer remains poorly understood. In the present study, we showed that matrine inhibited the proliferation, migration and invasion of both DU145 and PC-3 cells in a dose- and time-dependent manner. It also reduced the cell population at S phase and increased the cell population at sub-G1 phase. The increases in both the apoptotic cell population and cell population at S and sub-G1 phases consistently indicated a pro-apoptotic effect of matrine. Decreases in levels of P65, p-P65, IKKα/β, p-IKKα/β, IKBα and p-IKBα as detected by immunoblot analysis in the matrine-treated DU145 and PC-3 cells suggested an involvement of the NF-κB signaling pathway. Therefore, it is a novel promising addition to the current arsenal of chemotherapy drugs for the treatment of androgen-independent prostate cancer. PMID:26497618

  9. Hormone therapy for prostate cancer

    Science.gov (United States)

    ... this page: //medlineplus.gov/ency/patientinstructions/000908.htm Hormone therapy for prostate cancer To use the sharing ... helps slow the growth of prostate cancer. Male Hormones and Prostate Cancer Androgens are male sex hormones. ...

  10. miR-18a promotes cell proliferation of esophageal squamous cell carcinoma cells by increasing cylin D1 via regulating PTEN-PI3K-AKT-mTOR signaling axis.

    Science.gov (United States)

    Zhang, Weiguo; Lei, Caipeng; Fan, Junli; Wang, Jing

    2016-08-12

    Esophageal squamous cell carcinoma (ESCC) is one of the lethal cancers with a high incidence rate in Asia. Cyclin D1 is overexpressed and plays an important role in the carcinogenesis of ESCC; however the mechanism of the deregulation of Cyclin D1 in ESCC remains to be determined. In the study, we found that miR-18a promotes the expression Cyclin D1 by targeting PTEN in eophageal squamous cell carcinoma TE13 and Eca109 cells. Transfection of miR-18a mimetics increased cyclin D1, while transfection of miR-18a antagomir decreased D1. Moreover, miR-18a-mediated upregulation of cyclin D1 was accompanied with downregulation of PTEN, which is a direct target of miR-18a, and increase of the phosphorylation of AKT and S6K1. In addition, pharmacologic inhibition of AKT or mTOR kinases abolished the increase of cyclinD1 by miR-18a, which was accompanied with decreased phosphorylation of RbS780 and inhibition of cell proliferation. Our results demonstrated the upregulation of miR-18a promoted cell proliferation by increasing cylin D1 via regulating PTEN-PI3K-AKT-mTOR signaling axis, suggesting that small molecule inhibitors of AKT-mTOR signaling are potential agents for the treatment of ESCC patients with upregulation of miR-17-92 cluster. PMID:27291152

  11. An APC:WNT counter-current-like mechanism regulates cell division along the colonic crypt axis: a mechanism that explains how APC mutations induce proliferative abnormalities that drive colon cancer development.

    Directory of Open Access Journals (Sweden)

    Bruce M Boman

    2013-11-01

    Full Text Available APC normally down-regulates WNT signaling in human colon, and APC mutations cause proliferative abnormalities in premalignant crypts leading to colon cancer, but the mechanisms are unclear at the level of spatial and functional organization of the crypt. Accordingly, we postulated a counter-current-like mechanism based on gradients of factors (APC;WNT that regulate colonocyte proliferation along the crypt axis. During crypt renewal, stem cells (SCs at the crypt bottom generate non-SC daughter cells that proliferate and differentiate while migrating upwards. The APC concentration is low at the crypt bottom and high at the top (where differentiated cells reside. WNT signaling, in contrast, is high at the bottom (where SCs reside and low at the top. Given that WNT and APC gradients are counter to one another, we hypothesized that a counter-current-like mechanism exists. Since both APC and WNT signaling components (e.g. survivin are required for mitosis, this mechanism establishes a zone in the lower crypt where conditions are optimal for maximal cell division and mitosis orientation (symmetric versus asymmetric. APC haploinsufficiency diminishes the APC gradient, shifts the proliferative zone upwards, and increases symmetric division, which causes SC overpopulation. In homozygote mutant crypts, these changes are exacerbated. Thus, APC-mutation-induced changes in the counter-current-like mechanism cause expansion of proliferative populations (SCs, rapidly-proliferating cells during tumorigenesis. We propose this mechanism also drives crypt fission, functions in the crypt cycle, and underlies adenoma development. Novel chemoprevention approaches designed to normalize the two gradients and readjust the proliferative zone downwards, might thwart progression of these premalignant changes.

  12. CSR1 Suppresses Tumor Growth and Metastasis of Prostate Cancer

    OpenAIRE

    Yu, Guoying; Tseng, George C.; Yu, Yan Ping; Gavel, Tim; Nelson, Joel; Wells, Alan; Michalopoulos, George; Kokkinakis, Demetrius; Luo, Jian-Hua

    2006-01-01

    Prostate cancer is frequent among men over 45 years of age, but it generally only becomes lethal with metastasis. In this study, we identified a gene called cellular stress response 1 (CSR1) that was frequently down-regulated and methylated in prostate cancer samples. Survival analysis indicated that methylation of the CSR1 promoter, and to a lesser extent down-regulation of CSR1 protein expression, was associated with a high rate of prostate cancer metastasis. Forced expression of CSR1 in pr...

  13. Study on NDRG3 in Mesenchyma of Prostate

    Institute of Scientific and Technical Information of China (English)

    Wei-qun WANG; Yu-hua LI; Ai-zhen HONG; Biao-yang LIN; Xiao-feng JIA; Yang LI; Run-sheng LI

    2008-01-01

    Objective To study expression of NDRG3 in prostatic mesenchyma and effect of exogenous NDRG3 on prostatic stromal cells. Methods Immunohistochemical analysis was used to check expression of NDRG3 in prostate mesnenchyma.The WPMY-1 prostate immortalized mesenchyma cell line was stably-transfected with a NDRG3 gene expression vector.The NDRG3-stable transfected WPMY-1 sublines were studied along with parental and empty vector transfected WPMY-1 cells as controls.RT-PCR technology was applied to identity downstream gene expression under regulation of NDRG3 expression. Results Expression of DNRG3 was observed in prostate cancer mesenchyma,over-expression of NDRG3 in WPMY-1 cell up-regulated expression of chemotatic factors—CXCL3 and CXCL5. Conclusion Expression of stromal NDRG3 in prostate cancer specimens is significantly higher than that in benign prostatic hypertrophy(BPH)sample.There is a remarkable difference between the two groups of samples,NDRG3 may be related to angiogenesis in prostatic mesenchyma.

  14. The level of BMP4 signaling is critical for the regulation of distinct T-box gene expression domains and growth along the dorso-ventral axis of the optic cup

    Directory of Open Access Journals (Sweden)

    Sowden Jane C

    2006-12-01

    Full Text Available Abstract Background Polarised gene expression is thought to lead to the graded distribution of signaling molecules providing a patterning mechanism across the embryonic eye. Bone morphogenetic protein 4 (Bmp4 is expressed in the dorsal optic vesicle as it transforms into the optic cup. Bmp4 deletions in human and mouse result in failure of eye development, but little attempt has been made to investigate mammalian targets of BMP4 signaling. In chick, retroviral gene overexpression studies indicate that Bmp4 activates the dorsally expressed Tbx5 gene, which represses ventrally expressed cVax. It is not known whether the Tbx5 related genes, Tbx2 and Tbx3, are BMP4 targets in the mammalian retina and whether BMP4 acts at a distance from its site of expression. Although it is established that Drosophila Dpp (homologue of vertebrate Bmp4 acts as a morphogen, there is little evidence that BMP4 gradients are interpreted to create domains of BMP4 target gene expression in the mouse. Results Our data show that the level of BMP4 signaling is critical for the regulation of distinct Tbx2, Tbx3, Tbx5 and Vax2 gene expression domains along the dorso-ventral axis of the mouse optic cup. BMP4 signaling gradients were manipulated in whole mouse embryo cultures during optic cup development, by implantation of beads soaked in BMP4, or the BMP antagonist Noggin, to provide a local signaling source. Tbx2, Tbx3 and Tbx5, showed a differential response to alterations in the level of BMP4 along the entire dorso-ventral axis of the optic cup, suggesting that BMP4 acts across a distance. Increased levels of BMP4 caused expansion of Tbx2 and Tbx3, but not Tbx5, into the ventral retina and repression of the ventral marker Vax2. Conversely, Noggin abolished Tbx5 expression but only shifted Tbx2 expression dorsally. Increased levels of BMP4 signaling caused decreased proliferation, reduced retinal volume and altered the shape of the optic cup. Conclusion Our findings suggest

  15. Prostate carcinomas; Cancer de la prostate

    Energy Technology Data Exchange (ETDEWEB)

    Toledano, A.; Chauveinc, L.; Flam, T.; Thiounn, N.; Solignac, S.; Timbert, M.; Rosenwald, J.C.; Cosset, J.M.; Ammor, A.; Bonnetain, F.; Brenier, J.P.; Maingon, P.; Peignaux, K.; Truc, G.; Bosset, M.; Crevoisier, R. de; Tucker, S.; Dong, L.; Cheung, R.; Kuban, D.; Azria, D.; Llacer Moscardo, C.; Ailleres, N.; Allaw, A.; Serre, A.; Fenoglietto, P.; Hay, M.H.; Thezenas, S.; Dubois, J.B.; Pommier, P.; Perol, D.; Lagrange, J.L.; Richaud, P.; Brune, D.; Le Prise, E.; Azria, D.; Beckendorf, V.; Chabaud, S.; Carrie, C.; Bosset, M.; Bosset, J.F.; Maingon, P.; Ammor, A.; Crehangen, G.; Truc, G.; Peignaux, K.; Bonnetain, F.; Keros, L.; Bernier, V.; Aletti, P.; Wolf, D.; Marchesia, V.; Noel, A.; Artignan, X.; Fourneret, P.; Bacconier, M.; Shestaeva, O.; Pasquier, D.; Descotes, J.L.; Balosso, J.; Bolla, M.; Burette, R.; Corbusier, A.; Germeau, F.; Crevoisier, R. de; Dong, L.; Bonnen, M.; Cheung, R.; Tucker, S.; Kuban, D.; Crevoisier, R. de; Melancon, A.; Kuban, D.; Cheung, R.; Dong, L.; Peignaux, K.; Brenier, J.P.; Truc, G.; Bosset, M.; Ammor, A.; Barillot, I.; Maingon, P.; Molines, J.C.; Berland, E.; Cornulier, J. de; Coulet-Parpillon, A.; Cohard, C.; Picone, M.; Fourneret, P.; Artignan, X.; Daanen, V.; Gastaldo, J.; Bolla, M.; Collomb, D.; Dusserre, A.; Descotes, J.L.; Troccaz, J.; Giraud, J.Y.; Quero, L.; Hennequin, C.; Ravery, V.; Desgrandschamps, F.; Maylin, C.; Boccon-Gibod, L.; Salem, N.; Bladou, F.; Gravis, G.; Tallet, A.; Simonian, M.; Serment, G.; Salem, N.; Bladou, F.; Gravis, G.; Simonian, M.; Rosello, R.; Serment, G

    2005-11-15

    Some short communications on the prostate carcinoma are given here. The impact of pelvic irradiation, conformation with intensity modulation, association of radiotherapy and chemotherapy reduction of side effects, imaging, doses escalation are such subjects studied and reported. (N.C.)

  16. Anti-inflammatory effect and prostate gene expression profiling of steryl ferulate on experimental rats with non-bacterial prostatitis.

    Science.gov (United States)

    Hu, Yinzhou; Xiong, Lina; Huang, Weisu; Cai, Huafang; Luo, Yanxi; Zhang, Ying; Lu, Baiyi

    2014-06-01

    Steryl ferulate (SF) is a bioactive mixture extracted from rice bran and shows higher inhibitory activity against inflammation than the corresponding free sterols. In this study, the aim was to investigate the anti-inflammatory effect and prostate gene expression profiling of SF using a Xiaozhiling-induced non-bacterial prostatitis (NBP) rat model. The anti-inflammatory effect was evaluated by prostate weight, prostate index, acid phosphatase, density of lecithin corpuscles (DLC), white blood cell count (WBC), and prostatic histologic section. Prostate gene expression profiling was assessed by a cDNA microarray and validated by quantitative real-time PCR of five selected genes. Pathway analysis and Gene ontology (GO) analysis were applied to determine the roles of these differentially expressed genes involved in these biological pathways or GO terms. SF treatment could significantly inhibit prostate weight, prostate index, total acid phosphatase, prostatic acid phosphatase and WBC, suppress the severity of histological lesion and increase the DLC. Compared with the control group, the SF treatment group contained 238 up-regulated genes and 111 down-regulated genes. GO analysis demonstrated that the most significant expression genes were closely related to the terms of fibrinolysis, inflammatory response, high-density lipoprotein particle, protein-lipid complex, enzyme inhibitor activity, peptidase inhibitor activity and others. Canonical pathway analysis indicated five pathways were significantly regulated, which were associated with inflammation and tumorgenesis. In conclusion, SF may be used as a health supplement to prevent NBP, in that it could inhibit prostate inflammation in NBP patients by affecting the expression of genes in the related GO terms and pathways. PMID:24686498

  17. Differences in gene expression in prostate cancer, normal appearing prostate tissue adjacent to cancer and prostate tissue from cancer free organ donors

    International Nuclear Information System (INIS)

    Typical high throughput microarrays experiments compare gene expression across two specimen classes – an experimental class and baseline (or comparison) class. The choice of specimen classes is a major factor in the differential gene expression patterns revealed by these experiments. In most studies of prostate cancer, histologically malignant tissue is chosen as the experimental class while normal appearing prostate tissue adjacent to the tumor (adjacent normal) is chosen as the baseline against which comparison is made. However, normal appearing prostate tissue from tumor free organ donors represents an alterative source of baseline tissue for differential expression studies. To examine the effect of using donor normal tissue as opposed to adjacent normal tissue as a baseline for prostate cancer expression studies, we compared, using oligonucleotide microarrays, the expression profiles of primary prostate cancer (tumor), adjacent normal tissue and normal tissue from tumor free donors. Statistical analysis using Significance Analysis of Microarrays (SAM) demonstrates the presence of unique gene expression profiles for each of these specimen classes. The tumor v donor expression profile was more extensive that the tumor v adjacent normal profile. The differentially expressed gene lists from tumor v donor, tumor v adjacent normal and adjacent normal v donor comparisons were examined to identify regulated genes. When donors were used as the baseline, similar genes are highly regulated in both tumor and adjacent normal tissue. Significantly, both tumor and adjacent normal tissue exhibit significant up regulation of proliferation related genes including transcription factors, signal transducers and growth regulators compared to donor tissue. These genes were not picked up in a direct comparison of tumor and adjacent normal tissues. The up-regulation of these gene types in both tissue types is an unexpected finding and suggests that normal appearing prostate tissue

  18. Hibiscus sabdariffa Leaf Extract Inhibits Human Prostate Cancer Cell Invasion via Down-Regulation of Akt/NF-kB/MMP-9 Pathway.

    Science.gov (United States)

    Chiu, Chun-Tang; Chen, Jing-Hsien; Chou, Fen-Pi; Lin, Hui-Hsuan

    2015-07-01

    Hibiscus sabdariffa leaf has been previously shown to possess hypoglycemic, hypolipidemic, and antioxidant effects, and induce tumor cell apoptosis. However, the molecular mechanisms involved in the anticancer activity of H. sabdariffa leaf extract (HLE) are poorly understood. The object of the study was to examine the anti-invasive potential of HLE. First, HLE was demonstrated to be rich in polyphenols. The results of wound-healing assay and in vitro transwell assay revealed that HLE dose-dependently inhibited the migration and invasion of human prostate cancer LNCaP (lymph node carcinoma of the prostate) cells under non-cytotoxic concentrations. Our results further showed that HLE exerted an inhibitory effect on the activity and expressions of matrix metalloproteinase-9 (MMP-9). The HLE-inhibited MMP-9 expression appeared to be a consequence of nuclear factor-kappaB (NF-κB) inactivation because its DNA-binding activity was suppressed by HLE. Molecular data showed all these influences of HLE might be mediated via inhibition of protein kinase B (PKB, also known as Akt)/NF-kB/MMP-9 cascade pathway, as demonstrated by the transfection of Akt1 overexpression vector. Finally, the inhibitory effect of HLE was proven by its inhibition on the growth of LNCaP cells and the expressions of metastasis-related molecular proteins in vivo. These findings suggested that the inhibition of MMP-9 expression by HLE may act through the suppression of the Akt/NF-kB signaling pathway, which in turn led to the reduced invasiveness of the cancer cells. PMID:26115086

  19. Stromal microcalcification in prostate.

    Science.gov (United States)

    Muezzinoglu, B; Gurbuz, Y

    2001-06-01

    Prostatic calcification is most commonly encountered as calculus or intraluminal calcifications within atypical small glandular proliferations. This study was undertaken to detect stromal microcalcifications in prostate tissue. All slides from 194 needle biopsies were retrospectively reviewed. Six cases (3.1%) had stromal microcalcifications constantly associated with mononuclear inflammatory infiltrate around the each focus. Association with prostatic glands was not seen in any of the microcalcification foci. Three cases had simultaneous adenocarcinoma and one had high-grade prostatic intraepithelial neoplasia, all of which were apart from the microcalcification foci. In conclusion, stromal microcalcification is a dystrophic, inflammation-mediated, benign process.

  20. Diallyl trisulfide-induced apoptosis in human prostate cancer cells involves c-Jun N-terminal kinase and extracellular-signal regulated kinase-mediated phosphorylation of Bcl-2.

    Science.gov (United States)

    Xiao, Dong; Choi, Sunga; Johnson, Daniel E; Vogel, Victor G; Johnson, Candace S; Trump, Donald L; Lee, Yong J; Singh, Shivendra V

    2004-07-22

    Garlic-derived organosulfides (OSCs) including diallyl trisulfide (DATS) are highly effective in affording protection against chemically induced cancer in animals. Evidence is also mounting to indicate that some naturally occurring OSCs can suppress proliferation of cancer cells by causing apoptosis, but the sequence of events leading to proapoptotic effect of OSCs is poorly defined. Using PC-3 and DU145 human prostate cancer cells as a model, we now demonstrate that DATS is a significantly more potent apoptosis inducer than diallyl sulfide (DAS) or diallyl disulfide (DADS). DATS-induced apoptosis in PC-3 cells was associated with phosphorylation of Bcl-2, reduced Bcl-2 : Bax interaction, and cleavage of procaspase-9 and -3. Bcl-2 overexpressing PC-3 cells were significantly more resistant to apoptosis induction by DATS compared with vector-transfected control cells. DATS treatment resulted in activation of extracellular-signal regulated kinase 1/2 (ERK1/2) and c-jun N-terminal kinase 1 (JNK1) and/or JNK2, but not p38 mitogen-activated protein kinase. Phosphorylation of Bcl-2 in DATS-treated PC-3 cells was fully blocked in the presence of JNK-specific inhibitor SP600125. Moreover, JNK inhibitor afforded significant protection against DATS-induced apoptosis in both cells. DATS-induced Bcl-2 phosphorylation and apoptosis were partially attenuated by pharmacological inhibition of ERK1/2 using PD98059 or U0126. Overexpression of catalase inhibited DATS-mediated activation of JNK1/2, but not ERK1/2, and apoptosis induction in DU145 cells suggesting involvement of hydrogen peroxide as a second messenger in DATS-induced apoptosis. In conclusion, our data point towards important roles for Bcl-2, JNK and ERK in DATS-induced apoptosis in human prostate cancer cells.

  1. Differentially Expressed Genes and Signature Pathways of Human Prostate Cancer.

    Directory of Open Access Journals (Sweden)

    Jennifer S Myers

    Full Text Available Genomic technologies including microarrays and next-generation sequencing have enabled the generation of molecular signatures of prostate cancer. Lists of differentially expressed genes between malignant and non-malignant states are thought to be fertile sources of putative prostate cancer biomarkers. However such lists of differentially expressed genes can be highly variable for multiple reasons. As such, looking at differential expression in the context of gene sets and pathways has been more robust. Using next-generation genome sequencing data from The Cancer Genome Atlas, differential gene expression between age- and stage- matched human prostate tumors and non-malignant samples was assessed and used to craft a pathway signature of prostate cancer. Up- and down-regulated genes were assigned to pathways composed of curated groups of related genes from multiple databases. The significance of these pathways was then evaluated according to the number of differentially expressed genes found in the pathway and their position within the pathway using Gene Set Enrichment Analysis and Signaling Pathway Impact Analysis. The "transforming growth factor-beta signaling" and "Ran regulation of mitotic spindle formation" pathways were strongly associated with prostate cancer. Several other significant pathways confirm reported findings from microarray data that suggest actin cytoskeleton regulation, cell cycle, mitogen-activated protein kinase signaling, and calcium signaling are also altered in prostate cancer. Thus we have demonstrated feasibility of pathway analysis and identified an underexplored area (Ran for investigation in prostate cancer pathogenesis.

  2. The experience of using sonoelastography of prostate in prostatic diseases

    Directory of Open Access Journals (Sweden)

    P. S. Zubeev

    2014-11-01

    Full Text Available Objective. To assess sonoelastography opportunities in differential diagnosis of prostatic diseases; to place sonoelastography in general algorithm of prostatic diseases diagnostics.Materials and methods. 91 patients under examination were divided into three groups. The first group included 21 patients (23.1 % with suspected prostate carcinoma, later they underwent puncture multifocal biopsy of prostate with morphological verification of prostate carcinoma. The second group consisted of 51 patients (56.0 % with benign prostatic hyperplasia, and in the third group there were 19 patients (20.9 % with acute and chronic prostatitis.Results. 91 patients with different prostatic diseases were examined. There were defined PSA (prostate specific antigen level, and performed TRUS (transrectal ultrasound, biopsy and sonoelastography of prostate. In 72 patients SEG (sonoelastography-picture of prostate was compared to morphological diagnosis. According to SEG findings, 43 (81.1 % patients were revealed to have the areas of reduced compliance due to what malignancy in prostate gland (PG was excluded. Morphological diagnosis of prostate carcinoma was confirmed in 21 patients. In 51 patients SEG-picture corresponded to benign process confirmed by histology.Conclusion. Sonoelastography is a modern diagnostic technique of prostatic diseases, seminal vesicles, paraprostatic space. The distinguished mapping types enable to make differential diagnosis of different prostatic pathological processes. Sonoelastography improves prostate carcinoma diagnostics and staging, and also has economic significance value when compared to MRP (magnetic resonance tomography with bolus contrast.

  3. Activation of the hedgehog pathway in advanced prostate cancer

    Directory of Open Access Journals (Sweden)

    McCormick Frank

    2004-10-01

    Full Text Available Abstract Background The hedgehog pathway plays a critical role in the development of prostate. However, the role of the hedgehog pathway in prostate cancer is not clear. Prostate cancer is the second most prevalent cause of cancer death in American men. Therefore, identification of novel therapeutic targets for prostate cancer has significant clinical implications. Results Here we report that activation of the hedgehog pathway occurs frequently in advanced human prostate cancer. We find that high levels of hedgehog target genes, PTCH1 and hedgehog-interacting protein (HIP, are detected in over 70% of prostate tumors with Gleason scores 8–10, but in only 22% of tumors with Gleason scores 3–6. Furthermore, four available metastatic tumors all have high expression of PTCH1 and HIP. To identify the mechanism of the hedgehog signaling activation, we examine expression of Su(Fu protein, a negative regulator of the hedgehog pathway. We find that Su(Fu protein is undetectable in 11 of 27 PTCH1 positive tumors, two of them contain somatic loss-of-function mutations of Su(Fu. Furthermore, expression of sonic hedgehog protein is detected in majority of PTCH1 positive tumors (24 out of 27. High levels of hedgehog target genes are also detected in four prostate cancer cell lines (TSU, DU145, LN-Cap and PC3. We demonstrate that inhibition of hedgehog signaling by smoothened antagonist, cyclopamine, suppresses hedgehog signaling, down-regulates cell invasiveness and induces apoptosis. In addition, cancer cells expressing Gli1 under the CMV promoter are resistant to cyclopamine-mediated apoptosis. All these data suggest a significant role of the hedgehog pathway for cellular functions of prostate cancer cells. Conclusion Our data indicate that activation of the hedgehog pathway, through loss of Su(Fu or overexpression of sonic hedgehog, may involve tumor progression and metastases of prostate cancer. Thus, targeted inhibition of hedgehog signaling may have

  4. Prostate-Specific Antigen (PSA) Test

    Science.gov (United States)

    ... Understanding Laboratory Tests Prostate Cancer—Patient Version Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial Tumor Markers Understanding Prostate Changes: A Health Guide for Men ...

  5. Stromal mesenchyme cell genes of the human prostate and bladder

    Directory of Open Access Journals (Sweden)

    Pascal Laura E

    2005-12-01

    Full Text Available Abstract Background Stromal mesenchyme cells play an important role in epithelial differentiation and likely in cancer as well. Induction of epithelial differentiation is organ-specific, and the genes responsible could be identified through a comparative genomic analysis of the stromal cells from two different organs. These genes might be aberrantly expressed in cancer since cancer could be viewed as due to a defect in stromal signaling. We propose to identify the prostate stromal genes by analysis of differentially expressed genes between prostate and bladder stromal cells, and to examine their expression in prostate cancer. Methods Immunohistochemistry using antibodies to cluster designation (CD cell surface antigens was first used to characterize the stromas of the prostate and bladder. Stromal cells were prepared from either prostate or bladder tissue for cell culture. RNA was isolated from the cultured cells and analyzed by DNA microarrays. Expression of candidate genes in normal prostate and prostate cancer was examined by RT-PCR. Results The bladder stroma was phenotypically different from that of the prostate. Most notable was the presence of a layer of CD13+ cells adjacent to the urothelium. This structural feature was also seen in the mouse bladder. The prostate stroma was uniformly CD13-. A number of differentially expressed genes between prostate and bladder stromal cells were identified. One prostate gene, proenkephalin (PENK, was of interest because it encodes a hormone. Secreted proteins such as hormones and bioactive peptides are known to mediate cell-cell signaling. Prostate stromal expression of PENK was verified by an antibody raised against a PENK peptide, by RT-PCR analysis of laser-capture microdissected stromal cells, and by database analysis. Gene expression analysis showed that PENK expression was down-regulated in prostate cancer. Conclusion Our findings show that the histologically similar stromas of the prostate and

  6. Detecting Prostate Cancer

    Medline Plus

    Full Text Available ... rectal examination does not mean that they have prostate cancer. It means that we're concerned about it and they should go on to have other tests, such as a trans-rectal ultrasound ... made of the prostate gland. Usually these are accompanied by a biopsy -- ...

  7. Detecting Prostate Cancer

    Science.gov (United States)

    ... rectal examination does not mean that they have prostate cancer. It means that we're concerned about it and they should go on to have other tests, such as a trans-rectal ultrasound ... made of the prostate gland. Usually these are accompanied by a biopsy -- ...

  8. Clinical Studies on Treatment of Chronic Prostatitis with Acupuncture and Mild Moxibustion

    Institute of Scientific and Technical Information of China (English)

    Yu Yang; Kang Jingli; Duan Shumin

    2005-01-01

    To observe the therapeutic effect of acupuncture and mild moxibustion on chronic prostatitis and to probe into the mechanism of the therapy. Two hundred patients with chronic prostatitis were randomly divided into two groups so as to observe respectively the changes in clinical symptoms, count of WBC and lecithin corpuscles in succus prostaticus, prostatic capcules and internal echo, tenderness and elasticity of prostate by palpation before and after treatment. After treatment, a remarkable improvement was found in clinical symptoms, succus prostaticus test and ultrasonic examination in the treatment group with a statistically significant difference (P<0.05) as compared to the control group. The treatment of chronic prostatitis with acupuncture and mild moxibustion can remove the stagnation of succus prostaticus, improve the blood circulation in prostate, inhibit or kill the pathogenic micro-organisms, strengthen or regulate the immune function of the patients, improve local blood circulation, eliminate the accumulation of secretion and relieve the obstruction of the prostatic ducts.

  9. Optimizing prostate biopsy for repeat transrectal prostate biopsies patients

    Institute of Scientific and Technical Information of China (English)

    Xiaojun Deng; Jianwei Cao; Feng Liu; Weifeng Wang; Jidong Hao; Jiansheng Wan; Hui Liu

    2014-01-01

    Objective:Diagnosis of patients with negative prostate biopsy and persistent suspicion of prostate cancer re-mains a serious problem. In this study, we investigated the application of optimizing prostate biopsy for patients who need repeat prostate biopsy. Methods:In this prospective, non-randomized phase-I clinical trial, the prostate cancer detection rate of initial detection scheme was compared with optimizing prostate biopsy scheme. The number of punctures of initial detection scheme was the same as that of optimizing prostate biopsy scheme. The puncture direction of optimizing prostate biopsy was a 45° angle to the sagittal plane from front, middle, and back. The two cores from each lateral lobe were horizontal y inwardly inclined 45°. Results:A total of 45 patients with initial negative biopsy for cancer were received the optimizing prostate biopsy scheme. The cancer detection rate was 17.8%(8/45), and prostate intraepithelial neoplasm (PIN) was 6.7%(3/45). The pa-tients receiving repeat transrectal prostate biopsies were pathological y diagnosed as lower Gleason grade prostate cancers. Conclusion:The cancer detection rate of repeat biopsy prostate cancer is lower than that of initial biopsy. Our study showed that the optimizing prostate biopsy is important to improve the detection rate of repeat transrectal prostate biopsies patients.

  10. ODM-201: a new-generation androgen receptor inhibitor in castration-resistant prostate cancer

    OpenAIRE

    Fizazi, Karim; Albiges, Laurence; Loriot, Yohann; Massard, Christophe

    2015-01-01

    Androgen deprivation therapy is the standard of care for patients with advanced hormone-sensitive prostate cancer. Despite an initial response, most patients progress to castration-resistant prostate cancer (CRPC). The realization that CRPC remains driven by androgen receptor (AR) signaling has formed the basis for a new generation of agents targeting the AR axis. Two of these agents, abiraterone acetate and enzalutamide, have been shown to prolong overall survival in patients with CRPC. Seve...

  11. MicroRNAs associated with metastatic prostate cancer.

    Directory of Open Access Journals (Sweden)

    Akira Watahiki

    Full Text Available OBJECTIVE: Metastasis is the most common cause of death of prostate cancer patients. Identification of specific metastasis biomarkers and novel therapeutic targets is considered essential for improved prognosis and management of the disease. MicroRNAs (miRNAs form a class of non-coding small RNA molecules considered to be key regulators of gene expression. Their dysregulation has been shown to play a role in cancer onset, progression and metastasis, and miRNAs represent a promising new class of cancer biomarkers. The objective of this study was to identify down- and up-regulated miRNAs in prostate cancer that could provide potential biomarkers and/or therapeutic targets for prostate cancer metastasis. METHODS: Next generation sequencing technology was applied to identify differentially expressed miRNAs in a transplantable metastatic versus a non-metastatic prostate cancer xenograft line, both derived from one patient's primary cancer. The xenografts were developed via subrenal capsule grafting of cancer tissue into NOD/SCID mice, a methodology that tends to preserve properties of the original cancers (e.g., tumor heterogeneity, genetic profiles. RESULTS: Differentially expressed known miRNAs, isomiRs and 36 novel miRNAs were identified. A number of these miRNAs (21/104 have previously been reported to show similar down- or up-regulation in prostate cancers relative to normal prostate tissue, and some of them (e.g., miR-16, miR-34a, miR-126*, miR-145, miR-205 have been linked to prostate cancer metastasis, supporting the validity of the analytical approach. CONCLUSIONS: The use of metastatic and non-metastatic prostate cancer subrenal capsule xenografts derived from one patient's cancer makes it likely that the differentially expressed miRNAs identified in this study include potential biomarkers and/or therapeutic targets for human prostate cancer metastasis.

  12. Down-regulation of protein kinase Ceta potentiates the cytotoxic effects of exogenous tumor necrosis factor-related apoptosis-inducing ligand in PC-3 prostate cancer cells.

    Science.gov (United States)

    Sonnemann, Jürgen; Gekeler, Volker; Sagrauske, Antje; Müller, Cornelia; Hofmann, Hans-Peter; Beck, James F

    2004-07-01

    Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a highly promising candidate for the treatment of cancer because it elicits cell death in the majority of tumor cells while sparing most normal cells. Some cancers, however, display resistance to TRAIL, suggesting that treatment with TRAIL alone may be insufficient for cancer therapy. In the present study, we explored whether the apoptotic responsiveness of PC-3 prostate cancer cells to TRAIL could be enhanced by targeting the novel protein kinase C (PKC) isoform eta. Transfection of PC-3 cells with second-generation chimeric antisense oligonucleotides against PKCeta caused a time- and dose-dependent knockdown of PKCeta, as revealed by real-time RT-PCR and Western blot analyses. Knockdown of PKCeta resulted in a marked amplification of TRAIL's cytotoxic activity. Cell killing could be substantially prevented by the pan-caspase inhibitor z-VAD-fmk. In addition, PKCeta knockdown and administration of TRAIL significantly synergized in activation of caspase-3 and internucleosomal DNA fragmentation. Knockdown of PKCeta augmented TRAIL-induced dissipation of the mitochondrial transmembrane potential and release of cytochrome c from mitochondria into the cytosol, indicating that PKCeta acts upstream of mitochondria. We conclude that PKCeta represents a considerable resistance factor with respect to TRAIL and a promising target to exploit the therapeutic potential of TRAIL. PMID:15252138

  13. Indole-3-carbinol and 3’, 3’-diindolylmethane modulate androgen effect up-regulation on C-C chemokine ligand 2 and monocyte attraction to prostate cancer cells

    Science.gov (United States)

    Inflammation has a role in prostate tumorigenesis. Recruitment of inflammatory monocytes to the tumor site is mediated by C-C chemokine ligand 2 (CCL2) through binding to its receptor CCR2. We hypothesized that androgen could modulate CCL2 expression in hormone-responsive prostate cancer cells, and ...

  14. Prostate Cancer and Sexual Function

    OpenAIRE

    Hyun, Jae Saog

    2012-01-01

    Prostate cancer is now ranked fifth in incidence among cancers in Korean adult males. This is attributable to the more Westernized dietary style which increases the morbidity of prostate cancer and the development of cancer diagnostic technologies, such as prostate-specific antigen and advanced medical systems, increasing the rate of prostate cancer diagnosis. Prostate cancer effects include not only erectile dysfunction caused by the disease itself, but also by psychiatric disorders caused b...

  15. Prostate cancer; Cancer de la prostate

    Energy Technology Data Exchange (ETDEWEB)

    Vieillot, S.; Fenoglietto, P.; Ailleres, N.; Hay, M.H.; Dubois, J.B.; Azria, D. [Departement de cancerologie radiotherapie, Universite Montpellier I, CRLC Val d' Aurelle, 34 - Montpellier (France)

    2010-07-01

    Radiation therapy is now widely accepted as an efficacious treatment of localized prostate cancer. The technical developments of recent years have enabled the evolution of a three-dimensional conformal radiotherapy, offering a better adaptation of the dose distribution, and leading therefore to preserve organs at risk. In addition, the required dose delivered to the target volume permit physician to increase the total dose if necessary. This requires a thorough knowledge of the radio-anatomy of the prostate, the natural history of the disease but also the ballistics and dosimetry. The objectives of this work were to detail epidemiology and radio-anatomy of the prostate cancer. In addition, conformal radiation modalities are illustrated by a case report. (authors)

  16. Preferred axis in cosmology

    CERN Document Server

    Zhao, Wen

    2016-01-01

    The foundation of modern cosmology relies on the so-called cosmological principle which states an homogeneous and isotropic distribution of matter in the universe on large scales. However, recent observations, such as the temperature anisotropy of the cosmic microwave background (CMB) radiation, the motion of galaxies in the universe, the polarization of quasars and the acceleration of the cosmic expansion, indicate preferred directions in the sky. If these directions have a cosmological origin, the cosmological principle would be violated, and modern cosmology should be reconsidered. In this paper, by considering the preferred axis in the CMB parity violation, we find that it coincides with the preferred axes in CMB quadrupole and CMB octopole, and they all align with the direction of the CMB kinematic dipole. In addition, the preferred directions in the velocity flows, quasar alignment, anisotropy of the cosmic acceleration, the handedness of spiral galaxies, and the angular distribution of the fine-structu...

  17. What Tests Can Detect Prostate Cancer?

    Science.gov (United States)

    ... saved articles window. My Saved Articles » My ACS » Prostate Cancer Prevention and Early Detection + - Text Size Download Printable Version [ ... coverage for prostate cancer screening Additional resources for prostate cancer prevention and early detection References: Prostate cancer prevention and ...

  18. Prostate-specific antigen (PSA) blood test

    Science.gov (United States)

    Prostate-specific antigen; Prostate cancer screening test; PSA ... PSA testing is an important tool for detecting prostate cancer, but it is not foolproof. Other conditions can cause a rise in PSA, including: A larger prostate ...

  19. Ultrasound- and MRI-Guided Prostate Biopsy

    Science.gov (United States)

    ... Index A-Z Ultrasound- and MRI-Guided Prostate Biopsy Ultrasound- and MRI-guided prostate biopsy uses imaging ... Biopsy? What is Ultrasound- and MRI-guided Prostate Biopsy? Ultrasound- and MRI-guided prostate biopsies are performed ...

  20. Prostate Cancer Screening (Beyond the Basics)

    Science.gov (United States)

    ... best in your individual situation. WHAT IS PROSTATE CANCER? — Prostate cancer is a cancer of the prostate, a ... most of them do not die from their cancer. Prostate cancer often grows so slowly that many men ...

  1. The hedgehog/Gli signaling paradigm in prostate cancer

    OpenAIRE

    Chen, Mengqian; Carkner, Richard; Buttyan, Ralph

    2011-01-01

    Hedgehog is a ligand-activated signaling pathway that regulates Gli-mediated transcription. Although most noted for its role as an embryonic morphogen, hyperactive hedgehog also causes human skin and brain malignancies. The hedgehog-related gene anomalies found in these tumors are rarely found in prostate cancer. Yet surveys of human prostate tumors show concordance of high expression of hedgehog ligands and Gli2 that correlate with the potential for metastasis and therapy-resistant behavior....

  2. A host defense mechanism involving CFTR-mediated bicarbonate secretion in bacterial prostatitis.

    Directory of Open Access Journals (Sweden)

    Chen Xie

    Full Text Available BACKGROUND: Prostatitis is associated with a characteristic increase in prostatic fluid pH; however, the underlying mechanism and its physiological significance have not been elucidated. METHODOLOGY/PRINCIPAL FINDINGS: In this study a primary culture of rat prostatic epithelial cells and a rat prostatitis model were used. Here we reported the involvement of CFTR, a cAMP-activated anion channel conducting both Cl(- and HCO(3(-, in mediating prostate HCO(3(- secretion and its possible role in bacterial killing. Upon Escherichia coli (E. coli-LPS challenge, the expression of CFTR and carbonic anhydrase II (CA II, along with several pro-inflammatory cytokines was up-regulated in the primary culture of rat prostate epithelial cells. Inhibiting CFTR function in vitro or in vivo resulted in reduced bacterial killing by prostate epithelial cells or the prostate. High HCO(3(- content (>50 mM, rather than alkaline pH, was found to be responsible for bacterial killing. The direct action of HCO(3(- on bacterial killing was confirmed by its ability to increase cAMP production and suppress bacterial initiation factors in E. coli. The relevance of the CFTR-mediated HCO(3(- secretion in humans was demonstrated by the upregulated expression of CFTR and CAII in human prostatitis tissues. CONCLUSIONS/SIGNIFICANCE: The CFTR and its mediated HCO(3(- secretion may be up-regulated in prostatitis as a host defense mechanism.

  3. Methods for Prostate Biopsy

    OpenAIRE

    M. Ghafoori

    2008-01-01

    Prostate cancer is currently the most prevalent form of cancer in men and the second leading cause of can-cer death in the United States, and the third most common cancer in men worldwide. Increasing mor-tality rates due to prostate carcinoma have been ob-served worldwide. This disease usually progresses im-perceptibly; thus, patients are unlikely to seek medi-cal help during the early stages. For these reasons, screening programs aimed at early detection have been developed. The prostate-spe...

  4. Cholesterol Metabolism and Prostate Cancer Lethality.

    Science.gov (United States)

    Stopsack, Konrad H; Gerke, Travis A; Sinnott, Jennifer A; Penney, Kathryn L; Tyekucheva, Svitlana; Sesso, Howard D; Andersson, Swen-Olof; Andrén, Ove; Cerhan, James R; Giovannucci, Edward L; Mucci, Lorelei A; Rider, Jennifer R

    2016-08-15

    Cholesterol metabolism has been implicated in prostate cancer pathogenesis. Here, we assessed the association of intratumoral mRNA expression of cholesterol synthesis enzymes, transporters, and regulators in tumor specimen at diagnosis and lethal prostate cancer, defined as mortality or metastases from prostate cancer in contrast to nonlethal disease without evidence of metastases after at least 8 years of follow-up. We analyzed the prospective prostate cancer cohorts within the Health Professionals Follow-up Study (n = 249) and the Physicians' Health Study (n = 153) as well as expectantly managed patients in the Swedish Watchful Waiting Study (n = 338). The expression of squalene monooxygenase (SQLE) was associated with lethal cancer in all three cohorts. Men with high SQLE expression (>1 standard deviation above the mean) were 8.3 times (95% confidence interval, 3.5 to 19.7) more likely to have lethal cancer despite therapy compared with men with the mean level of SQLE expression. Absolute SQLE expression was associated with lethal cancer independently from Gleason grade and stage, as was a SQLE expression ratio in tumor versus surrounding benign prostate tissue. Higher SQLE expression was tightly associated with increased histologic markers of angiogenesis. Collectively, this study establishes the prognostic value of intratumoral cholesterol synthesis as measured via SQLE, its second rate-limiting enzyme. SQLE expression at cancer diagnosis is prognostic for lethal prostate cancer both after curative-intent prostatectomy and in a watchful waiting setting, possibly by facilitating micrometastatic disease. Cancer Res; 76(16); 4785-90. ©2016 AACR.

  5. Gastric adenocarcinoma with prostatic metastasis.

    Science.gov (United States)

    Roshni, S; Anoop, Tm; Preethi, Tr; Shubanshu, G; Lijeesh, Al

    2014-06-01

    Metastasis of gastric adenocarcinoma to the prostate gland is extremely rare. Herein, we report a case of gastric adenocarcinoma in a 56-year-old man with prostatic metastasis diagnosed through the analysis of biopsy specimens from representative lesions in the stomach and prostate gland. Immunohistochemistry of the prostatic tissue showed positive staining for cytokeratin 7 and negative staining for prostate-specific antigen (PSA), whereas the serum PSA level was normal, confirming the diagnosis of prostatic metastasis from carcinoma of the stomach. PMID:25061542

  6. Gastric Adenocarcinoma with Prostatic Metastasis

    Science.gov (United States)

    Roshni, S; Preethi, TR; Shubanshu, G; Lijeesh, AL

    2014-01-01

    Metastasis of gastric adenocarcinoma to the prostate gland is extremely rare. Herein, we report a case of gastric adenocarcinoma in a 56-year-old man with prostatic metastasis diagnosed through the analysis of biopsy specimens from representative lesions in the stomach and prostate gland. Immunohistochemistry of the prostatic tissue showed positive staining for cytokeratin 7 and negative staining for prostate-specific antigen (PSA), whereas the serum PSA level was normal, confirming the diagnosis of prostatic metastasis from carcinoma of the stomach. PMID:25061542

  7. Detecting Prostate Cancer

    Medline Plus

    Full Text Available ... have other tests, such as a trans-rectal ultrasound and a biopsy. Physician: Now, just relax -- the ... exam or PSA test indicates an abnormality, an ultrasound image is made of the prostate gland. Usually ...

  8. Prostate radiation - discharge

    Science.gov (United States)

    ... day. Avoid orange juice, grapefruit juice, and other citrus juices if they make the bowel or bladder ... A.D.A.M. Editorial team. Related MedlinePlus Health Topics Prostate Cancer Browse the Encyclopedia A.D. ...

  9. Epigenetics in Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Costantine Albany

    2011-01-01

    Full Text Available Prostate cancer (PC is the most commonly diagnosed nonskin malignancy and the second most common cause of cancer death among men in the United States. Epigenetics is the study of heritable changes in gene expression caused by mechanisms other than changes in the underlying DNA sequences. Two common epigenetic mechanisms, DNA methylation and histone modification, have demonstrated critical roles in prostate cancer growth and metastasis. DNA hypermethylation of cytosine-guanine (CpG rich sequence islands within gene promoter regions is widespread during neoplastic transformation of prostate cells, suggesting that treatment-induced restoration of a “normal” epigenome could be clinically beneficial. Histone modification leads to altered tumor gene function by changing chromosome structure and the level of gene transcription. The reversibility of epigenetic aberrations and restoration of tumor suppression gene function have made them attractive targets for prostate cancer treatment with modulators that demethylate DNA and inhibit histone deacetylases.

  10. What Is Prostate Cancer?

    Medline Plus

    Full Text Available ... the more likely he is to develop the disease. Physician: Come on back, first room. Narrator: Most ... cancer. Prostate cancer is really a spectrum of diseases where on one end of the spectrum there ...

  11. Screening for Prostate Cancer

    Science.gov (United States)

    ... absolute reduction in mortal- ity. Preliminary results from PIVOT (Prostate Cancer In- tervention Versus Observation Trial), in ... early PSA screening era, prelim- inary findings from PIVOT show that, after 12 years, in- tention to ...

  12. Prostate brachytherapy - discharge

    Science.gov (United States)

    ... into your prostate. They were inserted through your perineum (the area between the scrotum and the anus). ... feel the urge to urinate more often. Your perineum may be tender and bruised. You can use ...

  13. Detecting Prostate Cancer

    Medline Plus

    Full Text Available ... have by having their blood sampled and what we look for is a particular glyco-protein that's ... that they have prostate cancer. It means that we're concerned about it and they should go ...

  14. Detecting Prostate Cancer

    Medline Plus

    Full Text Available ... abnormal and raises the index of suspicion that cancer may be present. Narrator: While the use of ... examination does not mean that they have prostate cancer. It means that we're concerned about it ...

  15. Detecting Prostate Cancer

    Medline Plus

    Full Text Available ... stands for Prostate Specific Antigen. It is a test that men have by having their blood sampled ... be present. Narrator: While the use of the test remains controversial, a normal PSA level is considered ...

  16. Detecting Prostate Cancer

    Medline Plus

    Full Text Available ... M.D.: PSA stands for Prostate Specific Antigen. It is a test that men have by having ... detection is the digital rectal exam. Barry Trevithick: It doesn't make sense to be afraid of ...

  17. What Is Prostate Cancer?

    Medline Plus

    Full Text Available ... visit to their urologist. John Bertini, M.D.: It's a wide variety of reasons why they might ... have a prostate. Most men don't pronounce it correctly and wouldn't know where it's located ...

  18. Prostate Cancer Foundation

    Science.gov (United States)

    ... Financials Our Leadership Leadership Team A Legacy of Leadership Featured ... Medicine Revolution Welcome to the world of precision medicine—where doctors can target each prostate cancer with new, more effective drugs. And this is just the beginning. Learn ...

  19. Prostate Cancer Screening

    Science.gov (United States)

    ... man's bladder that produces fluid for semen. Cancer screening is looking for cancer before you have any ... be easier to treat. There is no standard screening test for prostate cancer. Researchers are studying different ...

  20. Effect of β Radiation on Bcl-2 and Bax Expressions in Benign Prostate Hyperplasia Tissues

    Institute of Scientific and Technical Information of China (English)

    MA Qing-jie; GAO Shi; ZHAO Jie; GU Xin-quan; CAI Shan-yu; ZHAO Guo-qing

    2008-01-01

    The authors chose specimens from nine normal prostate tissues(NP group),15 benign prostate hyperplasia(BPH) prostates(BPH group),and 35 BPH prostates that had been treated with 90Sr/90Y Prostatic Hyperplasia Applicator(exposure group),The expressions of bcl-2 and bax in stroma and epithelia of prostate tissues were demonstrated by means of immunohistochemical staining,and the staining positive rate was semiquantatively determined,so as to observe the expression of bcl-2 and bax genes in the prostate tissues of normal individuals and BPH patients,before and after β radiation,and to evaluate the influence of β radiation on bcl-2 and bax expressions,The expressions of gene bcl-2 in the prostate epithelia of NP and BPH are significantly higher than those in the prostate stroma(P<0.01),However,the expressions of bcl-2 in the prostate epithelia and stroma of the BPH group are obviously higher than those in the NP group(P<0.01),The expression of gene bax in the prostate epithelia of the NP group is higher than that in the BPH group(P<0.05),However,bcl-2 expressions in the prostate epithelia and stroma of the BPH group are significantly higher than the bax expressions(P<0.01),Compared with those of the NP group,the expressions of bcl-2 in the prostate epithelia and stroma of the exposure group decrease remarkably,even as the expressions of the bax notably increase(P<0.01),Thus,the administration of β radiation can remarkably affect bcl-2 and bax gene expressions,to regulate cell apoptosis,in the prostate tissues of BPH.

  1. Prostate Epithelial Pten/TP53 Loss Leads to Transformation of Multipotential Progenitors and Epithelial to Mesenchymal Transition

    OpenAIRE

    Martin, Philip; Liu, Yen-Nien; Pierce, Rachel; Abou-Kheir, Wassim; Casey, Orla; Seng, Victoria; Camacho, Daniel; Simpson, R. Mark; Kelly, Kathleen

    2011-01-01

    Loss of PTEN and loss of TP53 are common genetic aberrations occurring in prostate cancer. PTEN and TP53 contribute to the regulation of self-renewal and differentiation in prostate progenitors, presumptive tumor initiating cells for prostate cancer. Here we characterize the transformed phenotypes resulting from deletion of the Pten and TP53 tumor suppressors in prostate epithelium. Using the PB-Cre4+Ptenfl/flTP53fl/fl model of prostate cancer, we describe the histological and metastatic prop...

  2. Marked heterogeneity of ERG expression in large primary prostate cancers.

    Science.gov (United States)

    Minner, Sarah; Gärtner, Michael; Freudenthaler, Fabian; Bauer, Melanie; Kluth, Martina; Salomon, Georg; Heinzer, Hans; Graefen, Markus; Bokemeyer, Carsten; Simon, Ronald; Sauter, Guido; Schlomm, Thorsten; Wilczak, Waldemar

    2013-01-01

    Approximately 50% of prostate cancers are characterized by TMPRSS2 (transmembrane protease serine 2)-ERG (avian v-ets erythroblastosis virus E26 oncogene homolog) gene fusions resulting in an androgen-regulated overexpression of the transcription factor ERG. Some studies have suggested prognostic or predictive relevance of ERG status in prostate cancer. Such concepts could be impaired by extensive ERG heterogeneity in analyzed tumors. The aim of this study was to analyze the extent of heterogeneity for TMPRSS2-ERG fusion in prostate cancer. To enable large-scale studies on the extent of heterogeneity of biomarkers in prostate cancer, a heterogeneity tissue microarray containing samples from 10 different tumor blocks of 190 large prostate cancers selected from a consecutive series of 480 radical prostatectomies was developed. ERG expression was analyzed by immunohistochemistry. Positive ERG immunostaining was found in arrayed cancer-containing samples from 103 of the 178 analyzable patients (58%). ERG immunostaining was homogeneously positive in 29 prostate cancers (16%), whereas heterogeneous ERG positivity was seen in 74 cancers (42%). ERG heterogeneity was within one tumor focus (intrafocal heterogeneity) in 69 cases (93% of heterogeneous cases) and between different tumor foci (interfocal heterogeneity) in 5 cases (7%). Marked intrafocal heterogeneity challenges the concept of TMPRSS2-ERG fusion always representing an early step in prostate cancer development. Marked heterogeneity also compromises the concept of analyzing ERG status for treatment decisions in diagnostic needle core biopsies. PMID:22899295

  3. Prostatitis - eine endlose Geschichte?

    Directory of Open Access Journals (Sweden)

    Riedl CR

    2001-01-01

    Full Text Available Aktuelle epidemiologische Daten aus den USA zeigen, daß der urogenitale Symptomenkomplex, der langläufig als "Prostatitis" bezeichnet wird, ein nicht unbeträchtliches volksgesundheitliches und volkswirtschaftliches Problem darstellt: dieses Krankheitsbild ist jährlich für 2 Millionen Arztbesuche und für 8% aller urologischen Konsulationen in den USA verantwortlich. Umgekehrt sieht jeder Urologe im Jahr zwischen 150 und 250 Patienten mit "Prostatitis".

  4. ICAM-1 and AMPK regulate cell detachment and apoptosis by N-methyl-N Prime -nitro-N-nitrosoguanidine, a widely spread environmental chemical, in human hormone-refractory prostate cancers

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Yi-Cheng; Lu, Pin-Hsuan; Hsu, Jui-Ling; Yu, Chia-Chun; Guh, Jih-Hwa, E-mail: jhguh@ntu.edu.tw

    2011-12-15

    Poly(ADP-ribose) polymerase-1 (PARP-1), a sensor of DNA damage, plays a crucial role in the regulation of DNA repair. PARP-1 hyperactivation causes DNA damage and cell death. The underlying mechanism is complicated and is through diverse pathways. The understanding of responsible signaling pathways may offer implications for effective therapies. After concentration-response determination of N-Methyl-N Prime -Nitro-N-Nitrosoguanidine (MNNG, a PARP-1 activating agent and an environmental mutagen) in human hormone-refractory prostate cancers, the data showed that concentrations below 5 {mu}M did not change cell survival but cause a time-dependent up-regulation of intracellular adhesion molecule-1 (ICAM-1) in mRNA, total protein and cell surface levels. Detection of phosphorylation and degradation of I{kappa}B-{alpha} and nuclear translocation of NF-{kappa}B showed that MNNG induced the activation of NF-{kappa}B that was responsible for the ICAM-1 up-regulation since PDTC (a NF-{kappa}B inhibitor) significantly abolished this effect. However, higher concentrations (e.g., 10 {mu}M) of MNNG induced a 61% detachment of the cells which were apoptosis associated with the activation of AMP-activated protein kinase (AMPK), c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK). Further identification showed that both AMPK and JNK other than p38 MAPK functionally contributed to cell death. The remaining 39% attached cells were survival associated with high ICAM-1 expression. In conclusion, the data suggest that NF-{kappa}B-dependent up-regulation of ICAM-1 plays a key role on cell attachment and survival; whereas, activation of AMPK and JNK participates in cytotoxic signaling pathways in detached cells caused by PARP-1 activation. Highlights: Black-Right-Pointing-Pointer Low level of DNA damage helps cell attachment and survival via ICAM-1 upregulation. Black-Right-Pointing-Pointer High level of DNA damage causes AMPK- and JNK-involved cell detachment

  5. Obesity and prostate cancer: gene expression signature of human periprostatic adipose tissue

    Directory of Open Access Journals (Sweden)

    Ribeiro Ricardo

    2012-09-01

    Full Text Available Abstract Background Periprostatic (PP adipose tissue surrounds the prostate, an organ with a high predisposition to become malignant. Frequently, growing prostatic tumor cells extend beyond the prostatic organ towards this fat depot. This study aimed to determine the genome-wide expression of genes in PP adipose tissue in obesity/overweight (OB/OW and prostate cancer patients. Methods Differentially expressed genes in human PP adipose tissue were identified using microarrays. Analyses were conducted according to the donors' body mass index characteristics (OB/OW versus lean and prostate disease (extra prostatic cancer versus organ confined prostate cancer versus benign prostatic hyperplasia. Selected genes with altered expression were validated by real-time PCR. Ingenuity Pathway Analysis (IPA was used to investigate gene ontology, canonical pathways and functional networks. Results In the PP adipose tissue of OB/OW subjects, we found altered expression of genes encoding molecules involved in adipogenic/anti-lipolytic, proliferative/anti-apoptotic, and mild immunoinflammatory processes (for example, FADS1, down-regulated, and LEP and ANGPT1, both up-regulated. Conversely, in the PP adipose tissue of subjects with prostate cancer, altered genes were related to adipose tissue cellular activity (increased cell proliferation/differentiation, cell cycle activation and anti-apoptosis, whereas a downward impact on immunity and inflammation was also observed, mostly related to the complement (down-regulation of CFH. Interestingly, we found that the microRNA MIRLET7A2 was overexpressed in the PP adipose tissue of prostate cancer patients. Conclusions Obesity and excess adiposity modified the expression of PP adipose tissue genes to ultimately foster fat mass growth. In patients with prostate cancer the expression profile of PP adipose tissue accounted for hypercellularity and reduced immunosurveillance. Both findings may be liable to promote a favorable

  6. Prostate specific antigen gene expression in androgen insensitive prostate carcinoma subculture cell line.

    Science.gov (United States)

    Tsui, Ke-Hung; Feng, Tsui-Hsia; Chung, Li-Chuan; Chao, Chun-Hsiang; Chang, Phei-Lang; Juang, Horng-Heng

    2008-01-01

    A novel prostate cancer cell line (PC-J) was isolated from an androgen independent non-prostate specific antigen (non-PSA) producing carcinoma cell line. The homologous correlation between PC-J and PC-3 was determined by short tandem repeat analysis. The PSA promoter activity was detected by transient expression assay in the PC-J and LNCaP cells but not in androgen insensitive PC-3 cells. When the PC-J cells were cotransfected with androgen receptor, androgen receptor coactivators and PSA reporter vector cells, the reporter assays indicated that nuclear receptor coactivator 4 (NCOA4) but not androgen receptor activator 24 (ARA24) increased the sensitivity and maximum stimulation of dihydrotestosterone (DHT)-inducing PSA promoter activity. The RT-PCR assays revealed that the expression of several tumor markers, including interleukin-6, prostate stem cell antigen (PSCA), prostate epithelium-specific Ets transcription factor (PDEF) and matriptase, was lower in the PC-J cells than in the PC-3 cells. This cell model elucidated the regulation of PSA expression and enabled comparison of the gene profile at different stages of metastasis in prostatic carcinoma.

  7. Bmi-1, stem cells and prostate carcinogenesis

    Institute of Scientific and Technical Information of China (English)

    David Moscatelli; E Lynette Wilson

    2011-01-01

    @@ Malignant transformation is likely to arise in a subset of organ-specific primitive cells that are subverted to acquire the properties of uncontrolled self-renewal.1,2 It is therefore likely that stem cells and tumor-initiating cells share many properties and that an understanding of the biology of normal stem cells and the identification of the pathways and molecules that regulate their self-renewal may result in our ability to design inhibitors that control the growth of tumor cells.In an interesting recent paper, Lukacs et al.3 show that the polycomb group transcriptional repressor, Bmi-1, regulates the self-renewal of normal prostate stem cells and also contributes to the initiation of prostate cancer.

  8. Androgen receptor is the key transcriptional mediator of the tumor suppressor SPOP in prostate cancer.

    Science.gov (United States)

    Geng, Chuandong; Rajapakshe, Kimal; Shah, Shrijal S; Shou, John; Eedunuri, Vijay Kumar; Foley, Christopher; Fiskus, Warren; Rajendran, Mahitha; Chew, Sue Anne; Zimmermann, Martin; Bond, Richard; He, Bin; Coarfa, Cristian; Mitsiades, Nicholas

    2014-10-01

    Somatic missense mutations in the substrate-binding pocket of the E3 ubiquitin ligase adaptor SPOP are present in up to 15% of human prostate adenocarcinomas, but are rare in other malignancies, suggesting a prostate-specific mechanism of action. SPOP promotes ubiquitination and degradation of several protein substrates, including the androgen receptor (AR) coactivator SRC-3. However, the relative contributions that SPOP substrates may make to the pathophysiology of SPOP-mutant (mt) prostate adenocarcinomas are unknown. Using an unbiased bioinformatics approach, we determined that the gene expression profile of prostate adenocarcinoma cells engineered to express mt-SPOP overlaps greatly with the gene signature of both SRC-3 and AR transcriptional output, with a stronger similarity to AR than SRC-3. This finding suggests that in addition to its SRC-3-mediated effects, SPOP also exerts SRC-3-independent effects that are AR-mediated. Indeed, we found that wild-type (wt) but not prostate adenocarcinoma-associated mutants of SPOP promoted AR ubiquitination and degradation, acting directly through a SPOP-binding motif in the hinge region of AR. In support of these results, tumor xenografts composed of prostate adenocarcinoma cells expressing mt-SPOP exhibited higher AR protein levels and grew faster than tumors composed of prostate adenocarcinoma cells expressing wt-SPOP. Furthermore, genetic ablation of SPOP was sufficient to increase AR protein levels in mouse prostate. Examination of public human prostate adenocarcinoma datasets confirmed a strong link between transcriptomic profiles of mt-SPOP and AR. Overall, our studies highlight the AR axis as the key transcriptional output of SPOP in prostate adenocarcinoma and provide an explanation for the prostate-specific tumor suppressor role of wt-SPOP.

  9. Estrogen receptors in the human male prostatic urethra and prostate in prostatic cancer and benign prostatic hyperplasia

    DEFF Research Database (Denmark)

    Bødker, A; Bruun, J; Balslev, E;

    1999-01-01

    stroma in eight cases and in the glandular epithelium in one. In four cases ERs were seen in the prostatic stroma and in the glandular epithelium. In the prostatic urethra, ERs were found in 19 cases located in the urothelium, lamina propria and/or periurethral glands. In the PC group, ERs were...... demonstrated in the prostatic stroma and/or prostatic urethra in 6 out of 11 cases. In both BPH and PC patients, immunoreactivity was weak and confined to few cells, indicating low ER content in the prostate as well as in the prostatic urethra. Dextran-coated charcoal (DCC) analysis was used for detection...... in the stroma, but in BPH specimens they can also be found in the glandular epithelium. Biochemically, the use of the DCC analysis is of limited value, since ER content in the human prostate and prostatic urethra is at the limit of detection with this method....

  10. New Prostate Cancer Treatment Target

    Science.gov (United States)

    Researchers have identified a potential alternative approach to blocking a key molecular driver of an advanced form of prostate cancer, called androgen-independent or castration-resistant prostate cancer.

  11. Human RecQL4 helicase plays critical roles in prostate carcinogenesis

    DEFF Research Database (Denmark)

    Su, Yanrong; Meador, Jarah A; Calaf, Gloria M;

    2010-01-01

    Prostate cancer is the second leading cause of cancer-associated deaths among men in the western countries. Here, we report that human RecQL4 helicase, which is implicated in the pathogenesis of a subset of cancer-prone Rothmund-Thomson syndrome, is highly elevated in metastatic prostate cancer c...... for prostate cancer promotion. Observation of a direct interaction of retinoblastoma (Rb) and E2F1 proteins with RecQL4 promoter suggests that Rb-E2F1 pathway may regulate RecQL4 expression. Collectively, our study shows that RecQL4 is an essential factor for prostate carcinogenesis....

  12. Ezrin mediates c-Myc actions in prostate cancer cell invasion

    DEFF Research Database (Denmark)

    Chuan, Yin Choy; Iglesias Gato, Diego; Fernandez-Perez, L;

    2010-01-01

    The forced overexpression of c-Myc in mouse prostate and in normal human prostate epithelial cells results in tumor transformation with an invasive phenotype. How c-Myc regulates cell invasion is poorly understood. In this study, we have investigated the interplay of c-Myc and androgens in the re...

  13. Prostate cancer epigenetics and its clinical implications

    Directory of Open Access Journals (Sweden)

    Srinivasan Yegnasubramanian

    2016-01-01

    Full Text Available Normal cells have a level of epigenetic programming that is superimposed on the genetic code to establish and maintain their cell identity and phenotypes. This epigenetic programming can be thought as the architecture, a sort of cityscape, that is built upon the underlying genetic landscape. The epigenetic programming is encoded by a complex set of chemical marks on DNA, on histone proteins in nucleosomes, and by numerous context-specific DNA, RNA, protein interactions that all regulate the structure, organization, and function of the genome in a given cell. It is becoming increasingly evident that abnormalities in both the genetic landscape and epigenetic cityscape can cooperate to drive carcinogenesis and disease progression. Large-scale cancer genome sequencing studies have revealed that mutations in genes encoding the enzymatic machinery for shaping the epigenetic cityscape are among the most common mutations observed in human cancers, including prostate cancer. Interestingly, although the constellation of genetic mutations in a given cancer can be quite heterogeneous from person to person, there are numerous epigenetic alterations that appear to be highly recurrent, and nearly universal in a given cancer type, including in prostate cancer. The highly recurrent nature of these alterations can be exploited for development of biomarkers for cancer detection and risk stratification and as targets for therapeutic intervention. Here, we explore the basic principles of epigenetic processes in normal cells and prostate cancer cells and discuss the potential clinical implications with regards to prostate cancer biomarker development and therapy.

  14. Prostate cancer epigenetics and its clinical implications.

    Science.gov (United States)

    Yegnasubramanian, Srinivasan

    2016-01-01

    Normal cells have a level of epigenetic programming that is superimposed on the genetic code to establish and maintain their cell identity and phenotypes. This epigenetic programming can be thought as the architecture, a sort of cityscape, that is built upon the underlying genetic landscape. The epigenetic programming is encoded by a complex set of chemical marks on DNA, on histone proteins in nucleosomes, and by numerous context-specific DNA, RNA, protein interactions that all regulate the structure, organization, and function of the genome in a given cell. It is becoming increasingly evident that abnormalities in both the genetic landscape and epigenetic cityscape can cooperate to drive carcinogenesis and disease progression. Large-scale cancer genome sequencing studies have revealed that mutations in genes encoding the enzymatic machinery for shaping the epigenetic cityscape are among the most common mutations observed in human cancers, including prostate cancer. Interestingly, although the constellation of genetic mutations in a given cancer can be quite heterogeneous from person to person, there are numerous epigenetic alterations that appear to be highly recurrent, and nearly universal in a given cancer type, including in prostate cancer. The highly recurrent nature of these alterations can be exploited for development of biomarkers for cancer detection and risk stratification and as targets for therapeutic intervention. Here, we explore the basic principles of epigenetic processes in normal cells and prostate cancer cells and discuss the potential clinical implications with regards to prostate cancer biomarker development and therapy. PMID:27212125

  15. Molecular genetic, diagnosis, prevention and gene therapy in prostatic cancer: review article

    Directory of Open Access Journals (Sweden)

    Noori Daloii MR

    2009-04-01

    Full Text Available "nThe prostate is a small gland located below the bladder and upper part of the urethra. In developed countries prostate cancer is the second common cancer (after skin cancer, and also the second leading cause of cancer death (after lung cancer among men. The several studies have been shown prostate cancer familial aggregation. The main reason for this aggregation is inheritance included genes. The family history is an important risk factor for developing the disease. The genes AR, CYP17, SRD5A2, HSD3B1 and HSD3B2 are all intimately involved in androgen metabolism and cell proliferation in the prostate. Each shows intraspecific polymorphism and variation among racial-ethnic groups that is associated with the risk of prostate cancer. Some of genes expressed in the prostate are in association with the production of seminal fluid and also with prostate cancer. Epigenetic modifications, specifically DNA hypermethylation, are believed to play an important role in the down-regulation of genes important for protection against prostate cancer. In prostate cancer numerous molecular and genetic aberrations have been described. It is now well established that cancer cells exhibit a number of genetic defects in apoptotic pathways. In this review article, the most recent data in molecular genetic, prevention and especially gene therapy in prostate cancer are introduced.

  16. Effect of magnesium oxide on interfraction prostate motion and rectal filling in prostate cancer radiotherapy. Analysis of a randomized clinical trial

    International Nuclear Information System (INIS)

    To investigate whether magnesium oxide reduces the interfraction motion of the prostate and the amount of rectal filling and rectal gas, which influences prostate position during radiotherapy for prostate cancer. From December 2008 to February 2010, 92 prostate cancer patients scheduled for intensity-modulated radiotherapy (77 Gy in 35 fractions) using fiducial marker-based position verification were randomly assigned to receive magnesium oxide (500 mg twice a day) or placebo during radiotherapy. In a previous study, we investigated the effect on intrafraction motion and did not find a difference between the treatment arms. Here, we compared the interfraction prostate motion between the two treatment arms as well as the amount of rectal filling and rectal air pockets using pretreatment planning computed tomography and magnetic resonance imaging scans. There was no statistically significant difference between the treatment arms in translation and rotation of the prostate between treatment fractions, except for the rotation around the cranial caudal axis. However, the difference was less than 1 and therefore considered not clinically relevant. There was no significant difference in the amount of rectal filling and rectal air pockets between the treatment arms. Magnesium oxide is not effective in reducing the interfraction prostate motion or the amount of rectal filling and rectal gas during external-beam radiotherapy. Therefore, magnesium oxide is not recommended in clinical practice for these purposes. (orig.)

  17. Methods for Prostate Biopsy

    Directory of Open Access Journals (Sweden)

    M. Ghafoori

    2008-01-01

    Full Text Available Prostate cancer is currently the most prevalent form of cancer in men and the second leading cause of can-cer death in the United States, and the third most common cancer in men worldwide. Increasing mor-tality rates due to prostate carcinoma have been ob-served worldwide. This disease usually progresses im-perceptibly; thus, patients are unlikely to seek medi-cal help during the early stages. For these reasons, screening programs aimed at early detection have been developed. The prostate-specific antigen (PSA test is among the best screening tools available in medicine today and is recognized as the best marker for its early detection. Prostate cancers detected by DRE method alone are clinically localized only 50% to 60% of the time, whereas PSA-detected tumors are clinically localized 90% of the time and pathologi-cally confined to the prostate as determined at prostatectomy about two thirds of the time. Recently, the detection of localized prostate cancers has improved, owing to the development of various new biopsy methods. However, a standard biopsy method, including number of cores, has not yet been established at present. When screening results indi-cate the possibility of prostate cancer, a pathologic diagnosis may be pursued by ultrasound guided trans-rectal needle biopsy. Prostate biopsy is usually ad-vised if serum PSA is >4 ng/mL, and this procedure remains the gold standard for prostate cancer diagno-sis. Fine needle biopsy is less painful than core bi-opsy, but also less diagnostically accurate. Systematic biopsy protocols: In 1989, Hodge et al. coined the sextant biopsy method that is still the standard of reference in prostate cancer detection. The prostate is bilaterally divided into three regions (apex, midgland, and base, all of which are system-atically biopsied once. Although Hodge et al. first proposed sextant biopsy under transrectal ultrasound guidance, some recent reports have indicated that systematic sextant biopsy

  18. Genetic epidemiology of prostate cancer

    OpenAIRE

    Wiklund, Fredrik

    2004-01-01

    Prostate cancer is a major health burden throughout the world, yet the etiology of prostate cancer is poorly understood. Evidence has accumulated supporting the existence of a hereditary form of this disease. Improved understanding of the genetic mechanisms underlying the development and progression of prostate cancer would be a major advance for improved prevention, detection and treatment strategies. This thesis evaluates different aspects of the genetic epidemiology of prostate cancer. In ...

  19. Prostate cancer: emerging pharmacotherapeutic modalities

    OpenAIRE

    Pratap Shankar; Anoop Kumar Verma; Rakesh Kumar Dixit; Amod Kumar Sachan

    2013-01-01

    Prostate cancer is the most common cancer in the world due to factors like old age, family history, ethnicity, diet and some elements exposure, with lot of controversies regarding prevention of prostate cancer. Though the exact pathogenesis is not clear, epidemiological evidence supports a relationship between prostate cancer and hormone levels. In this review article we are focusing on the advances in different pharmacotherapeutic modalities i.e. Chemoprevention, Prostate-Specific Antigen, H...

  20. Computed tomography of the prostate.

    Science.gov (United States)

    Van Engelshoven, J M; Kreel, L

    1979-02-01

    The conventional anatomy of the prostate is reviewed and the computed tomography (CT) anatomy described and illustrated. The results of 55 "normal" cases were analyzed for size and relationship to the symphysis pubis, retropubic space, and bladder, as shown on CT sections correlating the features with age and possible urinary symptoms. Attention is also drawn to the differences between phleboliths and prostatic calcification. Computed tomography is an effective method of demonstrating the prostate and surrounding structures and of assessing prostatic enlargement.

  1. Molecular markers for prostate cancer.

    NARCIS (Netherlands)

    Reynolds, M.A.; Kastury, K.; Groskopf, J.; Schalken, J.A.; Rittenhouse, H.G.

    2007-01-01

    Serum PSA testing has been used for over 20 years as an aid in the diagnosis and management of prostate cancer. Although highly sensitive, it suffers from a lack of specificity, showing elevated serum levels in a variety of other conditions including prostatitis, benign prostate hyperplasia, and non

  2. Metastaze raka prostate u penis

    OpenAIRE

    Krpina, Kristian; Markić, Dean; Španjol, Josip; Valenčić, Maksim; Fučkar, Željko

    2011-01-01

    Metastaziranje adenokarcinoma prostate u penis je rijetko. Prikazuje se slučaj adenokarcinoma prostate s metastazama u glans penis. U ovom slučaju metastaze u penis razvile su se devet godina nakon dijagnosticiranja raka prostate s metastazama u regionalne limfne čvorove.

  3. Recurrent SKIL-activating rearrangements in ETS-negative prostate cancer.

    Science.gov (United States)

    Annala, Matti; Kivinummi, Kati; Tuominen, Joonas; Karakurt, Serdar; Granberg, Kirsi; Latonen, Leena; Ylipää, Antti; Sjöblom, Liisa; Ruusuvuori, Pekka; Saramäki, Outi; Kaukoniemi, Kirsi M; Yli-Harja, Olli; Vessella, Robert L; Tammela, Teuvo L J; Zhang, Wei; Visakorpi, Tapio; Nykter, Matti

    2015-03-20

    Prostate cancer is the third most common cause of male cancer death in developed countries, and one of the most comprehensively characterized human cancers. Roughly 60% of prostate cancers harbor gene fusions that juxtapose ETS-family transcription factors with androgen regulated promoters. A second subtype, characterized by SPINK1 overexpression, accounts for 15% of prostate cancers. Here we report the discovery of a new prostate cancer subtype characterized by rearrangements juxtaposing the SMAD inhibitor SKIL with androgen regulated promoters, leading to increased SKIL expression. SKIL fusions were found in 6 of 540 (1.1%) prostate cancers and 1 of 27 (3.7%) cell lines and xenografts. 6 of 7 SKIL-positive cancers were negative for ETS overexpression, suggesting mutual exclusivity with ETS fusions. SKIL knockdown led to growth arrest in PC-3 and LNCaP cell line models of prostate cancer, and its overexpression led to increased invasiveness in RWPE-1 cells. The role of SKIL as a prostate cancer oncogene lends support to recent studies on the role of TGF-β signaling as a rate-limiting step in prostate cancer progression. Our findings highlight SKIL as an oncogene and potential therapeutic target in 1-2% of prostate cancers, amounting to an estimated 10,000 cancer diagnoses per year worldwide.

  4. Does prostate cancer co-opt the developmental program?

    Science.gov (United States)

    Marker, Paul C

    2008-07-01

    The hypothesis that cancer is a caricature of normal development and tissue renewal was originally based on descriptive studies of normal tissues and cancers. The concepts that arose from these studies were that both normal tissues and tumors are sustained by a self-renewing population of stem cells that initially gives rise to undifferentiated and highly proliferative progeny. Eventually, derivatives of these proliferating cells become growth quiescent and express differentiation markers characteristic of the organs within which they reside. A major difference between normal tissues and tumors is the impairment of differentiation in tumors such that undifferentiated, mitotically active cells accumulate in tumors. An important feature of the model is the idea that the biology of the undifferentiated and proliferating cell populations in tumors is governed by the same pathways that regulate normal development and tissue renewal. At the time these ideas were formulated, we lacked sufficient understanding of the molecular and cellular basis of prostate development and cancer progression to evaluate the validity of these ideas for understanding prostate cancer. Research in recent years has validated the prediction that cells with stem cell-like properties are a critical source of new cells both during prostate development and during prostate cancer progression. It is also the case that many of the genes that regulate prostatic development re-appear during prostate cancer progression. A closer examination of the best understood of these developmental regulatory pathways, the androgen-signaling pathway, reveals important differences between normal development and tumors. This pathway is co-opted in prostate cancer by genetic and epigenetic changes that alter the molecular details of how signaling is initiated and alter the transcriptional outcome of signaling by silencing key targets of androgen signaling and fusing androgen-responsive promoters to new genes to create

  5. Biomarkers for the diagnosis of prostatic inflammation in benign prostatic hyperplasia

    NARCIS (Netherlands)

    Robert, G.Y.M.; Smit, F.; Hessels, D.; Jannink, S.A.; Karthaus, H.F.M.; Aalders, T.; Jansen, K.; Taille, A. De La; Mulders, P.F.A.; Schalken, J.A.

    2011-01-01

    BACKGROUND: Chronic prostatic inflammation could be a central mechanism in benign prostatic hyperplasia (BPH) progression. Currently, the histological examination of prostate biopsies remains the only way to diagnose prostatic inflammation. Our objective was to find new noninvasive biomarkers for th

  6. Steroid hormone receptors in prostatic hyperplasia and prostatic carcinoma.

    Science.gov (United States)

    Khalid, B A; Nurshireen, A; Rashidah, M; Zainal, B Y; Roslan, B A; Mahamooth, Z

    1990-06-01

    One hundred and six prostatic tissue samples obtained from transurethral resection were analysed for androgen and estrogen receptors. In 62 of these, progesterone and glucocorticoid receptors were also assayed. Steroid receptors were assayed using single saturation dose 3H-labelled ligand assays. Ninety percent of the 97 prostatic hyperplasia tissues and six of the nine prostatic carcinoma tissues were positive for androgen receptors. Estrogen receptors were only present in 19% and 33% respectively. Progesterone receptors were present in 70% of the tissues, but glucocorticoid receptors were present in only 16% of prostatic hyperplasia and none in prostatic carcinoma. PMID:1725553

  7. The link between benign prostatic hyperplasia and prostate cancer

    DEFF Research Database (Denmark)

    Ørsted, David Dynnes; Bojesen, Stig E

    2013-01-01

    therapy. Furthermore, risk factors such as prostate inflammation and metabolic disruption have key roles in the development of both diseases. Despite these commonalities, BPH and prostate cancer exhibit important differences in terms of histology and localization. Although large-scale epidemiological......Benign prostatic hyperplasia (BPH) and prostate cancer are among the most common diseases of the prostate gland and represent significant burdens for patients and health-care systems in many countries. The two diseases share traits such as hormone-dependent growth and response to antiandrogen...... studies have shown that men with BPH have an increased risk of prostate cancer and prostate-cancer-related mortality, it remains unclear whether this association reflects a causal link, shared risk factors or pathophysiological mechanisms, or detection bias upon statistical analysis. Establishing BPH...

  8. A single-center experience with abiraterone as treatment for metastatic castration-resistant prostate cancer

    DEFF Research Database (Denmark)

    Thortzen, Anita; Thim, Stine; Røder, Martin Andreas;

    2016-01-01

    BACKGROUND: Continuous stimulation of the androgen receptor (AR) axis is a prerequisite for growth in castration-resistant prostate cancer (CRPC). Abiraterone acetate (AA) is a potent inhibitor of extracellular and intracellular androgen synthesis by inhibition of the CYP-17 enzyme system, which...

  9. ETS rearrangements in prostate cancer

    Institute of Scientific and Technical Information of China (English)

    Mark A Rubin

    2012-01-01

    Prostate cancer is a clinically and molecularly heterogeneous disease.Understanding the biologic underpinning of prostate cancer is necessary to best determine how biology is associated with the risk of disease progression and how this understanding might provide insight into the development of novel therapeutic approaches.The focus of this review is on the recently identified common ETS and non-ETS gene rearrangements in prostate cancer.Although multiple molecular alterations have been detected in prostate cancer,a basic understanding of gene fusion prostate cancer should help explain the clinical and biologic diversity,providing a rationale for a molecular subclassification of the disease.

  10. Systems Pharmacology Modeling of Prostate‐Specific Antigen in Patients With Prostate Cancer Treated With an Androgen Receptor Antagonist and Down‐Regulator

    Science.gov (United States)

    Mistry, HB; Young, J; Clack, G; Dickinson, PA

    2016-01-01

    First‐in‐human (FIH) studies with AZD3514, a selective androgen receptor (AR) down‐regulator, showed decreases of >30% in the prostate‐specific antigen (PSA) in some patients. A modeling approach was adopted to understand these observations and define the optimum clinical use hypothesis for AZD3514 for clinical testing. Initial empirical modeling showed that only baseline PSA correlated significantly with this biological response, whereas drug concentration did not. To identify the mechanistic cause of this observation, a mechanism‐based model was first developed, which described the effects of AZD3514 on AR protein and PSA mRNA levels in LNCaP cells with and without dihydrotestosterone (DHT). Second, the mechanism‐based model was linked to a population pharmacokinetic (PK) model; PSA effects of clinical doses were subsequently simulated under different clinical conditions. This model was used to adjust the design of the ongoing clinical FIH study and direct the backup program. PMID:27299938

  11. XAF1 expression and regulatory effects of somatostatin on XAF1 in prostate cancer cells

    Directory of Open Access Journals (Sweden)

    Li Chunde

    2010-12-01

    Full Text Available Abstract Background Somatostatin prevents cell proliferation by inducing apoptosis. Downregulation of the XAF1 transcript may occur during the development of prostate cancer. It is interesting to evaluate the potential regulatory effects of somatostatin on XAF1 expression during the development of prostate cancer cells. Methods XAF1 mRNA and protein expression in human prostate epithelial cells RWPE-1, androgen dependent prostate cancer LNCaP, and androgen independent DU145 and PC3 cells were evaluated using RT-PCR and Western blot. The regulation of XAF1 mRNA and protein expression by somatostatin and its analogue Octreotide was evaluated. Results Substantial levels of XAF1 mRNA and proteins were detected in RWPE-1 cells, whereas prostate cancer cells LNCaP, DU145 and PC3 exhibited lower XAF1 expression. Somatostatin and Octreotide up-regulated XAF1 mRNA and protein expression in all prostate cancer cell lines. Conclusions XAF1 down-regulation may contribute to the prostate cancer development. The enhanced XAF1 expression by somatostatin indicates a promising strategy for prostate cancer therapy.

  12. Osteoporosis and prostate cancer

    DEFF Research Database (Denmark)

    Poulsen, Mads Hvid; Nielsen, Morten Frost Munk; Abrahamsen, Bo;

    2014-01-01

    Abstract Objective. The aim of this study was to analyse the prevalence of osteoporosis and risk factors of osteoporotic fractures before androgen deprivation in Danish men. Treatment and prognosis of prostate cancer necessitate management of long-term consequences of androgen deprivation therapy...... (ADT), including accelerated bone loss resulting in osteoporosis. Osteoporotic fractures are associated with excess morbidity and mortality. Material and methods. Patients with prostate cancer awaiting initiation of ADT were consecutively included. Half of the patients had localized disease and were...... level was 30.5 g/l (1-5714 g/l). The average Gleason score was 7.8 (range 5-10, SD 1.1). Fifty patients had localized prostate cancer and the other 55 patients had disseminated disease. The prevalence of osteoporosis was 10% and the prevalence of osteopenia was 58% before ADT. There was no significant...

  13. Conditional Expression of Human 15-Lipoxygenase-1 in Mouse Prostate Induces Prostatic Intraepithelial Neoplasia: The FLiMP Mouse Model

    Directory of Open Access Journals (Sweden)

    Uddhav P. Kelavkar

    2006-06-01

    Full Text Available The incidence and mortality of prostate cancer (PCa vary greatly in different geographic regions, for which lifestyle factors, such as dietary fat intake, have been implicated. Human 15-lipoxygenase-1 (h15-LO-1, which metabolizes polyunsaturated fatty acids, is a highly regulated, tissue-specific, lipid-peroxidating enzyme that functions in physiological membrane remodeling and in the pathogenesis of atherosclerosis, inflammation, and carcinogenesis. We have shown that aberrant overexpression of 15-LO-1 occurs in human PCa, particularly high-grade PCa, and in high-grade prostatic intraepithelial neoplasia (HGPIN, and that the murine orthologue is increased in SV40-based genetically engineered mouse (GEM models of PCa, such as LADY and TRansgenic Adenocarcinoma of Mouse Prostate. To further define the role of 15-LO-1 in prostate carcinogenesis, we established a novel GEM model with targeted overexpression of h15-LO-1 in the prostate [human fifteen lipoxygenase-1 in mouse prostate (FLiMP]. We used a Cre- mediated and a loxP-mediated recombination strategy to target h15-LO-1 specifically to the prostate of C57BL/6 mice. Wild-type (wt, FLiMP+/-, and FLiMP+/+ mice aged 7 to 21, 24 to 28, and 35 weeks were characterized by histopathology, immunohistochemistry (IHC, and DNA/RNA and enzyme analyses. Compared to wt mice, h15-LO-1 enzyme activity was increased similarly in both homozygous FLiMP+/+ and hemizygous FLiMP+/- prostates. Dorsolateral and ventral prostates of FLiMP mice showed focal and progressive epithelial hyperplasia with nuclear atypia, indicative of the definition of mouse prostatic intraepithelial neoplasia (mPIN according to the National Cancer Institute. These foci showed increased proliferation by Ki-67 IHC. No progression to invasive PCa was noted up to 35 weeks. By IHC, h15-LO-1 expression was limited to luminal epithelial cells, with increased expression in mPIN foci (similar to human HGPIN. In summary, targeted overexpression of h

  14. Staging of prostate cancer.

    Science.gov (United States)

    Cheng, Liang; Montironi, Rodolfo; Bostwick, David G; Lopez-Beltran, Antonio; Berney, Daniel M

    2012-01-01

    Prostatic carcinoma (PCa) is a significant cause of cancer morbidity and mortality worldwide. Accurate staging is critical for prognosis assessment and treatment planning for PCa. Despite the large volume of clinical activity and research, the challenge to define the most appropriate and clinically relevant staging system remains. The pathologically complex and uncertain clinical course of prostate cancer further complicates the design of staging classification and a substaging system suitable for individualized care. This review will focus on recent progress and controversial issues related to prostate cancer staging. The 2010 revision of the American Joint Committee on Cancer/Union Internationale Contre le Cancer (AJCC/UICC) tumour, node and metastasis (TNM) system is the most widely used staging system at this time. Despite general acceptance of the system as a whole, there is controversy and uncertainty about its application, particularly for T2 subclassification. The three-tiered T2 classification system for organ-confined prostate cancer is superfluous, considering the biology and anatomy of PCa. A tumour size-based substaging system may be considered in the future TNM subclassification of pT2 cancer. Lymph node status is one of the most important prognostic factors for prostate cancer. Nevertheless, clinical outcomes in patients with positive lymph nodes are variable. Identification of patients at the greatest risk of systemic progression helps in the selection of appropriate therapy. The data suggest that the inherent aggressiveness of metastatic prostate cancer is closely linked to the tumour volume of lymph node metastasis. We recommend that a future TNM staging system should consider subclassification of node-positive cancer on the basis of nodal cancer volume, using the diameter of the largest nodal metastasis and/or the number of positive nodes.

  15. Chemotherapy in Prostate Cancer.

    Science.gov (United States)

    Hurwitz, Michael

    2015-10-01

    For approximately a decade, chemotherapy has been shown to prolong life in patients with metastatic castration-resistant prostate cancer (mCRPC). Since that time, however, only two agents have proven to prolong life (docetaxel and cabazitaxel). However, in the last year, the addition of chemotherapy to primary hormonal therapy became a standard of care for high-volume castration-sensitive metastatic disease. Here I will review current prostate cancer chemotherapies, mechanisms of resistance to those therapies, and ongoing clinical studies of chemotherapy combinations and novel chemotherapeutics. PMID:26216506

  16. Prostate Cancer Research Trial Helps John Spencer Treat His Cancer

    Science.gov (United States)

    ... this page please turn Javascript on. Feature: Prostate Cancer Prostate Cancer Research Trial Helps John Spencer Treat His ... Read More "Prostate Cancer" Articles Progress Against Prostate Cancer / Prostate Cancer Research Trial Helps John Spencer Treat His ...

  17. Benign Prostatic Hyperstatic Hyperplasia (BPH) (Beyond the Basics)

    Science.gov (United States)

    ... names for benign prostatic hyperplasia include benign prostatic hypertrophy, an enlarged prostate, and BPH. BPH occurs only ... prostatic hyperplasia" .) Alpha blockers — These medications relax the muscle of the prostate and bladder neck, which allows ...

  18. Prostate specific antigen in boys with precocious puberty before and during gonadal suppression by GnRH agonist treatment

    DEFF Research Database (Denmark)

    Juul, A; Müller, J; Skakkebaek, N E

    1997-01-01

    In healthy boys, the pituitary-gonadal axis exhibits diurnal variation in early puberty. Serum testosterone levels are higher during the night and low or immeasurable during the day. These fluctuating levels of circulating androgens in early pubertal boys are difficult to monitor. Prostate specific...... antigen (PSA) is a marker of the androgen-dependent prostatic epithelial cell activity and it is used in the diagnosis and surveillance of adult patients with prostatic cancer. We have measured PSA concentrations in serum from boys with precocious puberty before and during gonadal suppression with Gn...

  19. Simultaneous inactivation of Par-4 and PTEN in vivo leads to synergistic NF-κB activation and invasive prostate carcinoma

    Science.gov (United States)

    Fernandez-Marcos, Pablo J.; Abu-Baker, Shadi; Joshi, Jayashree; Galvez, Anita; Castilla, Elias A.; Cañamero, Marta; Collado, Manuel; Saez, Carmen; Moreno-Bueno, Gema; Palacios, Jose; Leitges, Michael; Serrano, Manuel; Moscat, Jorge; Diaz-Meco, Maria T.

    2009-01-01

    Prostate cancer is one of the most common neoplasias in men. The tumor suppressor Par-4 is an important negative regulator of the canonical NF-κB pathway and is highly expressed in prostate. Here we show that Par-4 expression is lost in a high percentage of human prostate carcinomas, and this occurs in association with phosphatase and tensin homolog deleted from chromosome 10 (PTEN) loss. Par-4 null mice, similar to PTEN-heterozygous mice, only develop benign prostate lesions, but, importantly, concomitant Par-4 ablation and PTEN-heterozygosity lead to invasive prostate carcinoma in mice. This strong tumorigenic cooperation is anticipated in the preneoplastic prostate epithelium by an additive increase in Akt activation and a synergistic stimulation of NF-κB. These results establish the cooperation between Par-4 and PTEN as relevant for the development of prostate cancer and implicate the NF-κB pathway as a critical event in prostate tumorigenesis. PMID:19470463

  20. Nonprostatic sources of prostate-specific antigen.

    Science.gov (United States)

    Diamandis, E P; Yu, H

    1997-05-01

    The name prostate-specific antigen has been given to a protein that now is known not to be prostate-specific; however, prostatic tissue does produces extremely high levels of PSA and secrets it into the seminal plasma. Seminal plasma contains about 1 million micrograms/L of PSA and is the richest source of PSA reported. The biologic fluid with the second highest PSA concentration, however, is nipple aspirate fluid from the female breast (up to about 5000 micrograms/L), and the third is milk from lactating women (up to 300 micrograms/L). Male serum PSA is usually less than 4 micrograms/L. In nonprostatic tissues, PSA exists mainly in its free molecular form, but PSA-ACT complex is also present in most of the fluids that contain PSA, such as breast secretions and amniotic fluid. The gene expression and protein production of PSA in nonprostatic tissues are under the regulation of steroid hormones via their receptors. Androgens, glucocorticoids, and progestins up-regulate the PSA gene expression, resulting in an increase of protein production. Estrogen by itself seems to have no effect on PSA regulation, but it can impair PSA production induced by androgen. It remains unknown whether PSA is enzymatically active and what is the physiologic role of PSA in nonprostatic tissues. It is speculated that PSA may be involved in the regulation of growth factors. Measuring PSA in breast cancer cytosol, breast-nipple aspirate fluid, and female serum may have potential clinical utilities, including breast cancer prognosis, breast cancer risk assessment, and evaluation of androgen excess. Further studies are needed to identify the exact function and regulation of PSA in nonprostatic tissues and to explore the clinical application of this protein. PMID:9126224

  1. Prostate Cancer-Associated Kallikrein-Related Peptidase 4 Activates Matrix Metalloproteinase-1 and Thrombospondin-1.

    Science.gov (United States)

    Fuhrman-Luck, Ruth A; Stansfield, Scott H; Stephens, Carson R; Loessner, Daniela; Clements, Judith A

    2016-08-01

    Prostate cancer metastasis to bone is terminal; thus, novel therapies are required to prevent end-stage disease. Kallikrein-related peptidase 4 (KLK4) is a serine protease that is overproduced in localized prostate cancer and is abundant in prostate cancer bone metastases. In vitro, KLK4 induces tumor-promoting phenotypes; however, the underlying proteolytic mechanism is undefined. The protein topography and migration analysis platform (PROTOMAP) was used for high-depth identification of KLK4 substrates secreted by prostate cancer bone metastasis-derived PC-3 cells to delineate the mechanism of KLK4 action in advanced prostate cancer. Thirty-six putative novel substrates were determined from the PROTOMAP analysis. In addition, KLK4 cleaved the established substrate, urokinase-type plasminogen activator, thus validating the approach. KLK4 activated matrix metalloproteinase-1 (MMP1), a protease that promotes prostate tumor growth and metastasis. MMP1 was produced in the tumor compartment of prostate cancer bone metastases, highlighting its accessibility to KLK4 at this site. KLK4 further liberated an N-terminal product, with purported angiogenic activity, from thrombospondin-1 (TSP1) and cleaved TSP1 in an osteoblast-derived matrix. This is the most comprehensive analysis of the proteolytic action of KLK4 in an advanced prostate cancer model to date, highlighting KLK4 as a potential multifunctional regulator of prostate cancer progression. PMID:27378148

  2. Long term organ culture of human prostate tissue in a NASA-designed rotating wall bioreactor

    Science.gov (United States)

    Margolis, L.; Hatfill, S.; Chuaqui, R.; Vocke, C.; Emmert-Buck, M.; Linehan, W. M.; Duray, P. H.

    1999-01-01

    PURPOSE: To maintain ex vivo integral prostatic tissue including intact stromal and ductal elements using the NASA-designed Rotating Wall Vessel (RWV) which maintains colocalized cells in an environment that promotes both three-dimensional cellular interactions together with the uniform mass transfer of nutrients and metabolic wastes. MATERIALS AND METHODS: Samples of normal prostate were obtained as a byproduct of transurethral prostatectomy or needle biopsy. Prostatic tissue dissected into small 1 x 1 mm. blocks was cultured in the Rotating Wall Vessel (RWV) Bioreactor for various time periods and analyzed using histological, immunochemical, and total cell RNA assays. RESULTS: We report the long term maintenance of benign explanted human prostate tissue grown in simple culture medium, under the simulated microgravity conditions afforded by the RWV bioreactor. Mesenchymal stromal elements including blood vessels and architecturally preserved tubuloglandular acini were maintained for a minimum of 28 days. Cytokeratins, vimentin and TGF-beta2 receptor and ligand were preserved through the entire culture period as revealed by immunocytochemistry. Prostatic acid phosphatase (PAP) was continuously expressed during the culture period, although somewhat decreased. Prostatic specific antigen (PSA) and its transcript were down regulated over time of culture. Prostatic carcinoma cells from the TSU cell line were able to invade RWV-cultured benign prostate tissue explants. CONCLUSIONS: The RWV bioreactor represents an additional new technology for culturing prostate tissue for further investigations concerning the basic physiology and pathobiology of this clinically important tissue.

  3. Androgen receptor signaling is required for androgen-sensitive human prostate cancer cell proliferation and survival

    Directory of Open Access Journals (Sweden)

    Day Wanda V

    2005-04-01

    Full Text Available Abstract Background Androgens and androgen receptors (AR regulate normal prostate development and growth. They also are involved in pathological development of prostatic diseases, including benign prostatic hyperplasia (BPH and prostate cancer (PCa. Antiandrogen therapy for PCa, in conjunction with chemical or surgical castration, offers initial positive responses and leads to massive prostate cell death. However, cancer cells later appear as androgen-independent PCa. To investigate the role of AR in prostate cell proliferation and survival, we introduced a vector-based small interfering RNA (siRNA. This siRNA targeted 5'-untranslated region of AR mRNA for extended suppression of AR expression in androgen-sensitive human prostate LNCaP cells. Results The siRNA design successfully suppressed endogenous AR expression, as revealed by western blotting and immunofluorescence staining in LNCaP cells. LNCaP cells did not proliferate in the absence of AR and underwent apoptosis, based on elevated phospho-Histone H2B expression and higher number of apoptotic body as compared to control cells. Conclusion We demonstrated that AR is vital for prostate cell proliferation and survival in this androgen-sensitive prostate cell line. These results further strengthen the hypothesis that AR can be a therapeutic target for treating androgen-sensitive stages of PCa. Unlike antiandorgens, however, siRNA targeting AR provides a direct inactivation of AR function through the suppression of AR protein expression.

  4. Survival in prostate cancer prevention trial detailed

    Science.gov (United States)

    In the NCI-sponsored Prostate Cancer Prevention Trial, initial findings from a decade ago showed that the drug finasteride significantly reduced the risk of prostate cancer, but among those who did develop prostate cancer, paradoxically, the drug was asso

  5. Giant prostatic fossa with misleading radiographic features.

    Science.gov (United States)

    Stenzl, A; Fuchs, G J

    1989-01-01

    The long-term complication of a perforation of the prostatic capsule during transurethral resection of the prostate is described. Calcifications in a giant prostatic fossa led to initially misleading radiologic findings.

  6. [Chemotherapy for prostate cancer].

    Science.gov (United States)

    Rauchenwald, Michael; De Santis, Maria; Fink, Eleonore; Höltl, Wolfgang; Kramer, Gero; Marei, Isabella-Carolina; Neumann, Hans-Jörg; Reissigl, Andreas; Schmeller, Nikolaus; Stackl, Walter; Hobisch, Alfred; Krainer, Michael

    2008-01-01

    For many years the benefit of chemotherapy in patients with prostate cancer was thought to be limited to palliation of late-stage disease, and thus this treatment option only became involved in patient care towards the end of the disease process, if at all. However, two landmark phase-III trials with docetaxel-based therapy (TAX 327 and Southwest Oncology Group, SWOG, 9916) have shown a survival benefit for patients with hormone refractory prostate cancer (HRPC) thus prompting a change in patterns of care. With raising interest for chemotherapeutic options and clinical trials for new drugs and new indications (neoadjuvant therapy, adjuvant therapy, increasing PSA levels after local treatment, and hormone sensitive cancer) under way our goal was to review within the context of a multidisciplinary team the available evidence and explore the standard for the medical treatment of prostate cancer outside of clinical trials. We are carefully evaluating the current treatment recommendations based on the available evidence and highlight potential future treatment options but also discuss important clinical topics (treatment until progression versus the advantage of chemo holidays, definition of particular patient subgroups and potential second line options) for which there are no clear cut answers to date. The role and importance of radiotherapy, biphosphonate treatment and the medical management of pain and side effects is also discussed. The multitude of treatment options for patients with advanced prostate cancer clearly asks for a close collaboration between urologists, medical oncologists and radiation therapists. PMID:18726672

  7. Detecting Prostate Cancer

    Medline Plus

    Full Text Available Roger Babaian, M.D.: PSA stands for Prostate Specific Antigen. It is a test that men have by having their blood sampled and ... testing may be required. Physician: OK, what I'd like to do is just do a rectal ...

  8. Vertical axis wind turbine airfoil

    Science.gov (United States)

    Krivcov, Vladimir; Krivospitski, Vladimir; Maksimov, Vasili; Halstead, Richard; Grahov, Jurij Vasiljevich

    2012-12-18

    A vertical axis wind turbine airfoil is described. The wind turbine airfoil can include a leading edge, a trailing edge, an upper curved surface, a lower curved surface, and a centerline running between the upper surface and the lower surface and from the leading edge to the trailing edge. The airfoil can be configured so that the distance between the centerline and the upper surface is the same as the distance between the centerline and the lower surface at all points along the length of the airfoil. A plurality of such airfoils can be included in a vertical axis wind turbine. These airfoils can be vertically disposed and can rotate about a vertical axis.

  9. Prostate brachytherapy in patients with prior evidence of prostatitis

    International Nuclear Information System (INIS)

    Purpose: To refute a misconception that a prior history of prostatitis is a contraindication to prostate brachytherapy. Methods and Materials: Five patients with clinical or pathologic evidence of prior prostatitis were treated with transperineal brachytherapy. Four of the patients received a single i.v. dose of ciprofloxacin (500 mg) intraoperatively. Postimplant antibiotics were not given. The pretreatment biopsy slides were reviewed. Results: Two of the five patients developed postimplant urinary retention requiring short-term catheterization, and both resolved spontaneously. One patient developed what appeared to be an exacerbation of his chronic prostatitis. Conclusion: We continue to recommend prostate brachytherapy for the treatment of clinically organ-confined cancer, with no concern about prior clinical or pathologic evidence of prostatitis

  10. Cabazitaxel Plus Prednisone With Octreotide For Castration-Resistant Prostate Cancer (CRPC) Previously Treated With Docetaxel

    Science.gov (United States)

    2014-11-21

    Diarrhea; Hormone-resistant Prostate Cancer; Recurrent Prostate Cancer; Stage I Prostate Cancer; Stage IIA Prostate Cancer; Stage IIB Prostate Cancer; Stage III Prostate Cancer; Stage IV Prostate Cancer

  11. KCTD11 tumor suppressor gene expression is reduced in prostate adenocarcinoma.

    Science.gov (United States)

    Zazzeroni, Francesca; Nicosia, Daniela; Tessitore, Alessandra; Gallo, Rita; Verzella, Daniela; Fischietti, Mariafausta; Vecchiotti, Davide; Ventura, Luca; Capece, Daria; Gulino, Alberto; Alesse, Edoardo

    2014-01-01

    Prostate cancer is the most common noncutaneous cancer among men in the United States. A genetic contribution to prostate cancer risk has been documented, but knowledge of the molecular mechanisms involved in prostate cancer initiation is still not well understood. Loss of heterozygosity (LOH) of chromosomal regions is crucial in tumor progression. In human prostate cancer, several chromosomal regions demonstrating a high frequency of LOH have been previously identified. KCTD11 (REN) is a tumor suppressor gene mapping on human chromosome 17p13.2, whose expression is frequently lost in human medulloblastoma and in several other cancer types. KCTD11 acts as a negative regulator of the Hedgehog (Hh) signaling. Here, we demonstrated that KCTD11 LOH is a common genetic lesion in human prostate adenocarcinoma. Indeed, nuclear KCTD11 protein expression is strongly reduced in primary prostate cancer, and this event correlated with overexpression of proteins acting into the Hedgehog pathway. Low levels of KCTD11 mRNA have been also observed in prostatic cancer cells, and ectopic overexpression of KCTD11 led to growth arrest. Our study demonstrates and supports that KCTD11, as well as negatively regulated downstream effectors belonging to Hh signaling, plays a role in prostate cancer pathogenesis. This could be suitable to characterize new diagnostic and therapeutic markers. PMID:25045667

  12. KCTD11 Tumor Suppressor Gene Expression Is Reduced in Prostate Adenocarcinoma

    Directory of Open Access Journals (Sweden)

    Francesca Zazzeroni

    2014-01-01

    Full Text Available Prostate cancer is the most common noncutaneous cancer among men in the United States. A genetic contribution to prostate cancer risk has been documented, but knowledge of the molecular mechanisms involved in prostate cancer initiation is still not well understood. Loss of heterozygosity (LOH of chromosomal regions is crucial in tumor progression. In human prostate cancer, several chromosomal regions demonstrating a high frequency of LOH have been previously identified. KCTD11 (REN is a tumor suppressor gene mapping on human chromosome 17p13.2, whose expression is frequently lost in human medulloblastoma and in several other cancer types. KCTD11 acts as a negative regulator of the Hedgehog (Hh signaling. Here, we demonstrated that KCTD11 LOH is a common genetic lesion in human prostate adenocarcinoma. Indeed, nuclear KCTD11 protein expression is strongly reduced in primary prostate cancer, and this event correlated with overexpression of proteins acting into the Hedgehog pathway. Low levels of KCTD11 mRNA have been also observed in prostatic cancer cells, and ectopic overexpression of KCTD11 led to growth arrest. Our study demonstrates and supports that KCTD11, as well as negatively regulated downstream effectors belonging to Hh signaling, plays a role in prostate cancer pathogenesis. This could be suitable to characterize new diagnostic and therapeutic markers.

  13. Sox2 is an androgen receptor-repressed gene that promotes castration-resistant prostate cancer.

    Directory of Open Access Journals (Sweden)

    Steven Kregel

    Full Text Available Despite advances in detection and therapy, castration-resistant prostate cancer continues to be a major clinical problem. The aberrant activity of stem cell pathways, and their regulation by the Androgen Receptor (AR, has the potential to provide insight into novel mechanisms and pathways to prevent and treat advanced, castrate-resistant prostate cancers. To this end, we investigated the role of the embryonic stem cell regulator Sox2 [SRY (sex determining region Y-box 2] in normal and malignant prostate epithelial cells. In the normal prostate, Sox2 is expressed in a portion of basal epithelial cells. Prostate tumors were either Sox2-positive or Sox2-negative, with the percentage of Sox2-positive tumors increasing with Gleason Score and metastases. In the castration-resistant prostate cancer cell line CWR-R1, endogenous expression of Sox2 was repressed by AR signaling, and AR chromatin-IP shows that AR binds the enhancer element within the Sox2 promoter. Likewise, in normal prostate epithelial cells and human embryonic stem cells, increased AR signaling also decreases Sox2 expression. Resistance to the anti-androgen MDV3100 results in a marked increase in Sox2 expression within three prostate cancer cell lines, and in the castration-sensitive LAPC-4 prostate cancer cell line ectopic expression of Sox2 was sufficient to promote castration-resistant tumor formation. Loss of Sox2 expression in the castration-resistant CWR-R1 prostate cancer cell line inhibited cell growth. Up-regulation of Sox2 was not associated with increased CD133 expression but was associated with increased FGF5 (Fibroblast Growth Factor 5 expression. These data propose a model of elevated Sox2 expression due to loss of AR-mediated repression during castration, and consequent castration-resistance via mechanisms not involving induction of canonical embryonic stem cell pathways.

  14. Culture of mouse prostate organoids

    OpenAIRE

    sprotocols

    2014-01-01

    Authors: Chee Wai Chua, Maho Shibata, Ming Lei, Roxanne Toivanen, LaMont Barlow & Michael Shen ### Abstract This protocol describes a novel three-dimensional “organoid” culture for prostate epithelial cells. We describe the digestion and dissociation of prostate tissue into single-cell suspensions containing both prostatic epithelial and stromal cells, the isolation of epithelial cells from the parental population via fluorescence activated cell sorting, and the plating condition...

  15. Prevention strategies in prostate cancer

    OpenAIRE

    Trottier, Greg; Lawrentschuk, N.; Fleshner, N.E.

    2010-01-01

    Prostate cancer (pca) prevention has been an exciting and controversial topic since the results of the Prostate Cancer Prevention Trial (pcpt) were published. With the recently published results of the reduce (Reduction by Dutasteride of Prostate Cancer Events) trial, interest in this topic is at a peak. Primary pca prevention will be unlikely to affect mortality significantly, but the reduction in overtreatment and the effect on quality of life from the avoidance of a cancer diagnosis are im...

  16. Prostatic Stromal Hyperplasia with Atypia

    Directory of Open Access Journals (Sweden)

    Ryan C. Hutchinson

    2013-01-01

    Full Text Available Prostatic stromal hyperplasia with atypia (PSHA is a rare histologic finding diagnosed incidentally on prostate biopsies, transurethral resection specimens, and radical prostatectomy specimens. PSHA has a bizarre histologic appearance and these lesions often raise concern for sarcoma; however, their clinical course is indolent and does not include extraprostatic progression. We discuss a case of PHSA discovered on prostate biopsy performed for an abnormal digital rectal examination and review the literature on this rare pathologic finding.

  17. Prostatic Stromal Hyperplasia with Atypia

    OpenAIRE

    Hutchinson, Ryan C.; Wu, Kevin J.; Cheville, John C.; Thiel, David D

    2013-01-01

    Prostatic stromal hyperplasia with atypia (PSHA) is a rare histologic finding diagnosed incidentally on prostate biopsies, transurethral resection specimens, and radical prostatectomy specimens. PSHA has a bizarre histologic appearance and these lesions often raise concern for sarcoma; however, their clinical course is indolent and does not include extraprostatic progression. We discuss a case of PHSA discovered on prostate biopsy performed for an abnormal digital rectal examination and revie...

  18. BENIGN PROSTATIC HYPERPLASIA: UPDATED REVIEW

    OpenAIRE

    Praveen.R

    2013-01-01

    Benign Prostatic Hyperplasia (BPH) is one of the commonest medical conditions affecting the geriatric male population. The enlargement of prostate can lead to various clinical symptoms like difficulty in voiding, urinary retention etc. The symptoms are varied depending on the size of enlargement. The International Prostatic Symptom Score (IPSS) is the gold standard and first step in understanding and diagnosing the disease clinically, but in the recent past there are various other newer tools...

  19. Prognostic significance of aberrantly silenced ANPEP expression in prostate cancer

    DEFF Research Database (Denmark)

    Sørensen, Karina Dalsgaard; Abildgaard, Mette Opstrup; Haldrup, Christa;

    2013-01-01

    Background:Novel biomarkers for prostate cancer (PC) are urgently needed. This study investigates the expression, epigenetic regulation, and prognostic potential of ANPEP in PC.Methods:Aminopeptidase N (APN; encoded by ANPEP) expression was analysed by immunohistochemistry using tissue microarrays...

  20. Phosphoproteome Integration Reveals Patient-Specific Networks in Prostate Cancer.

    OpenAIRE

    Drake, JM; Paull, EO; Graham, NA; Lee, JK; Smith, BA; Titz, B; Stoyanova, T; Faltermeier, CM; Uzunangelov, V; Carlin,, R.; Fleming, DT; Wong, CK; Newton, Y; Sudha, S; Vashisht, AA

    2016-01-01

    We used clinical tissue from lethal metastatic castration-resistant prostate cancer (CRPC) patients obtained at rapid autopsy to evaluate diverse genomic, transcriptomic, and phosphoproteomic datasets for pathway analysis. Using Tied Diffusion through Interacting Events (TieDIE), we integrated differentially expressed master transcriptional regulators, functionally mutated genes, and differentially activated kinases in CRPC tissues to synthesize a robust signaling network consisting of drugga...

  1. Neuroendocrine aspects of prostate oncogenesis

    Directory of Open Access Journals (Sweden)

    P.V. Glybochko

    2010-03-01

    Full Text Available The prostate cancer is a widespread disease in Russia with high growth rate and high death rate. Active work in discovery of methods of early diagnostics of prostate cancer is carrying out. it will allow to increase considerably the efficiency of treatment. the data on topography, structural and functional organization, physiology and regulatory effect of neuroendocrine cells and neuroendocrine hormones and peptides of prostate produced by neuroendocrine cells are presented in the review. Neuroendocrine mechanisms of development, prospects of early diagnostics and prognosis of prostate cancer are analyzed

  2. The development of a compact positron tomograph for prostate imaging

    Energy Technology Data Exchange (ETDEWEB)

    Huber, Jennifer S.; Qi, Jinyi; Derenzo, Stephen E.; Moses, William W.; Huesman, Ronald H.; Budinger, Thomas F.

    2002-12-17

    We give design details and expected image results of a compact positron tomograph designed for prostate imaging that centers a patient between a pair of external curved detector banks (ellipse: 45 cm minor, 70 cm major axis). The bottom bank is fixed below the patient bed, and the top bank moves upward for patient access and downward for maximum sensitivity. Each bank is composed of two rows (axially) of 20 CTI PET Systems HR+ block detectors, forming two arcs that can be tilted to minimize attenuation. Compared to a conventional PET system, our camera uses about one-quarter the number of detectors and has almost two times higher solid angle coverage for a central point source, because the detectors are close to the patient. The detectors are read out by modified CTI HRRT data acquisition electronics. The individual detectors are angled in the plane to point towards the prostate to minimize reso

  3. miR-143 interferes with ERK5 signaling, and abrogates prostate cancer progression in mice.

    Directory of Open Access Journals (Sweden)

    Cyrielle Clapé

    Full Text Available BACKGROUND: Micro RNAs are small, non-coding, single-stranded RNAs that negatively regulate gene expression at the post-transcriptional level. Since miR-143 was found to be down-regulated in prostate cancer cells, we wanted to analyze its expression in human prostate cancer, and test the ability of miR-43 to arrest prostate cancer cell growth in vitro and in vivo. RESULTS: Expression of miR-143 was analyzed in human prostate cancers by quantitative PCR, and by in situ hybridization. miR-143 was introduced in cancer cells in vivo by electroporation. Bioinformatics analysis and luciferase-based assays were used to determine miR-143 targets. We show in this study that miR-143 levels are inversely correlated with advanced stages of prostate cancer. Rescue of miR-143 expression in cancer cells results in the arrest of cell proliferation and the abrogation of tumor growth in mice. Furthermore, we show that the effects of miR-143 are mediated, at least in part by the inhibition of extracellular signal-regulated kinase-5 (ERK5 activity. We show here that ERK5 is a miR-143 target in prostate cancer. CONCLUSIONS: miR-143 is as a new target for prostate cancer treatment.

  4. The histology of prostate tissue following prostatic artery embolization for the treatment of benign prostatic hyperplasia

    Directory of Open Access Journals (Sweden)

    George Camara-Lopes

    2013-04-01

    Full Text Available Objective Prostatic artery embolization (PAE for the treatment of patients with symptomatic benign prostatic hyperplasia (BPH is believed to be a safe procedure with a low risk of adverse side effects. Artery embolization is a viable treatment option in patients who are refractory to the classic noninvasive treatments. Knowledge of the histological characteristics of prostate tissue following the procedure is still limited. In this study, we describe the microscopic aspects of the prostate following PAE for BPH. Materials and Methods Two patients underwent transurethral resections of the prostate (TURP after PAE. Embolizations were performed under local anesthesia with an initial pelvic angiography to evaluate the iliac vessels and the prostate arteries using a 2.8 French microcatheter. The prostate was embolized with 300-500µm Microspheres (Embosphere®, using complete blood stasis as the end point. The prostate tissues were analyzed histologically to characterize the effects of the embolization. Results The embolic material within the prostate tissue was easily identified as homogeneous, bright eosin-red spheroids filling the vessel lumens. Ischemic necrosis surrounded or not by chronic inflammatory reactions containing macrophages were considered as a result of the artery embolization. Also, some aspects related to the healing process were observed being fibrotic nodules surrounded by glands with squamous metaplasia of the epithelial lining the most important. In the remaining sections, due to the precocious surgical intervention, the classic findings of BPH were still present with the glandular and stromal hyperplasia associated with nonspecific chronic prostatitis. Conclusions This is the first description of prostate histology in BPH patients treated by PAE, a new procedure that is being used increasingly as a therapeutic intervention. The recognition of the changes caused by this new modality of treatment has become a very important

  5. 78 FR 57505 - World Trade Center Health Program; Addition of Prostate Cancer to the List of WTC-Related Health...

    Science.gov (United States)

    2013-09-19

    ..., Markowitz SB, Moline J, Niu X, Sacks H, Shukla G, Udasin I, Lucchini RG, Boffetta P, Landrigan PJ . Cancer... Concerning Regulations That Significantly Affect Energy Supply, Distribution, or Use) J. Plain Writing Act of... rulemaking (78 FR 39670) proposing to add prostate cancer (malignant neoplasm of the prostate) to the List...

  6. Acupuncture Treatment of Prostatitis

    Institute of Scientific and Technical Information of China (English)

    HU Jin-sheng

    2010-01-01

    @@ MEDICAL HISTORY A male patient, aged 78, a Hong Kong resident, paid his first visit on October 15, 2007. He complained of frequent urination, 5-6 times at night and once every hour during the daytime, and often with urgent urination and urinary incontinence in the previous 10 months. The patient had been diagnosed by a local hospital as having prostatitis and hyperplasia of the prostate, and he had coronary heart disease treated with Aspirin and other western medicines. As he was getting older, he felt deficient stamina, lassitude, lumbago, feeble lower limbs, pain in the left thigh with restricted motion, preference of local warmness, normal appetite, and powerless defecation once every other day. However, the patient was open-minded with good mental state.

  7. Association of Symptomatic Benign Prostatic Hyperplasia and Prostate Cancer: Results from the Prostate Cancer Prevention Trial

    OpenAIRE

    Schenk, Jeannette M.; Kristal, Alan R.; Arnold, Kathryn B.; Tangen, Catherine M.; Neuhouser, Marian L; Lin, Daniel W; White, Emily; Thompson, Ian M

    2011-01-01

    This study examined the association between symptomatic benign prostatic hyperplasia (BPH) and prostate cancer risk in 5,068 placebo-arm participants enrolled in the Prostate Cancer Prevention Trial (1993–2003). These data include 1,225 men whose cancer was detected during the 7-year trial—556 detected for cause (following abnormal prostate-specific antigen or digital rectal examination) and 669 detected not for cause (without indication), as well as 3,843 men who had biopsy-proven absence of...

  8. Comparability of prostate trials

    DEFF Research Database (Denmark)

    Suciu, S; Sylvester, R; Iversen, P;

    1993-01-01

    The present overview of advanced prostate cancer required the identification of randomized clinical trials studying the question of maximal androgen blockade versus the classic castration therapy. The heterogeneity of the trials concerned the type of castration (surgical or chemical) and the type...... of antiandrogen (flutamide, Anandron, or cyproterone acetate) added to castration. This paper reviews the different types of heterogeneity that might exist among trials that are involved in the overview: study design, randomization procedure, treatment evaluation, statistical evaluation, and data maturity...

  9. Prostate Focused Ultrasound Therapy.

    Science.gov (United States)

    Chapelon, Jean-Yves; Rouvière, Olivier; Crouzet, Sébastien; Gelet, Albert

    2016-01-01

    The tremendous progress in engineering and computing power coupled with ultrasound transducer technology and imaging modalities over the past 20 years have encouraged a revival of clinical interest in ultrasound therapy, mainly in High-Intensity Focused Ultrasound (HIFU). So far, the most extensive results from HIFU obtained in urology involve transrectal prostate ablation, which appears to be an effective therapeutic alternative for patients with malignant prostate tumors. Prostate cancer (PCa) is one of the most frequently diagnosed cancers in men. Several treatment options with different therapeutic approaches exist, including HIFU for localized PCa that has been in use for over 15 years. Since the early 2000s, two systems have been marketed for this application, and other devices are currently in clinical trials. HIFU treatment can be used either alone or in combination with (before- or after-) external beam radiotherapy (EBRT) (before or after HIFU) and can be repeated multiple times. HIFU treatment is performed under real-time monitoring with ultrasound or guided by MRI. Two indications are validated today: Primary care treatment and EBRT failure. The results of HIFU for primary care treatment are similar to standard conformal EBRT, even though no randomized comparative studies have been performed and no 10-year follow up data is yet available for HIFU. Salvage HIFU after EBRT failure is increasing with oncological outcomes, similar to those achieved with surgery but with the advantage of fewer adverse effects. HIFU is an evolving technology perfectly adapted for focal treatment. Thus, HIFU focal therapy is another pathway that must be explored when considering the accuracy and reliability for PCa mapping techniques. HIFU would be particularly suited for such a therapy since it is clear that HIFU outcomes and toxicity are relative to the volume of prostate treated. PMID:26486330

  10. The Early Prostate Cancer program: bicalutamide in nonmetastatic prostate cancer

    DEFF Research Database (Denmark)

    Iversen, Peter; Roder, Martin Andreas; Røder, Martin Andreas

    2008-01-01

    The Early Prostate Cancer program is investigating the addition of bicalutamide 150 mg to standard care for localized or locally advanced, nonmetastatic prostate cancer. The third program analysis, at 7.4 years' median follow-up, has shown that bicalutamide 150 mg does not benefit patients...

  11. Predictive value of prostate-specific antigen for prostate cancer

    DEFF Research Database (Denmark)

    Shepherd, Leah; Borges, Alvaro Humberto; Ravn, Lene;

    2014-01-01

    INTRODUCTION: Although prostate cancer (PCa) incidence is lower in HIV+ men than in HIV- men, the usefulness of prostate-specific antigen (PSA) screening in this population is not well defined and may have higher false negative rates than in HIV- men. We aimed to describe the kinetics and predict...

  12. Vertical axis wind turbine acoustics

    OpenAIRE

    Pearson, Charlie

    2014-01-01

    Increasing awareness of the issues of climate change and sustainable energy use has led to growing levels of interest in small-scale, decentralised power generation. Small-scale wind power has seen significant growth in the last ten years, partly due to the political support for renewable energy and the introduction of Feed In Tariffs, which pay home owners for generating their own electricity. Due to their ability to respond quickly to changing wind conditions, small-scale vertical axis...

  13. Serotonergic stimulation of the rat hypothalamo-pituitary-adrenal axis

    DEFF Research Database (Denmark)

    Mikkelsen, Jens D; Hay-Schmidt, Anders; Kiss, Alexander

    2004-01-01

    Acute stimulation of the hypothalamo-pituitary-adrenal (HPA) axis by selective serotonin reuptake inhibitors (SSRIs) is mediated by several postsynaptic 5-HT receptor subtypes. Activation of 5-HT(1A) and 5-HT(2A) receptors increases plasma corticosterone levels, and it is likely that these receptor...... that the two serotonin receptor subtypes affect the HPA axis via a central target. In conclusion, 5-HT(1A) and 5-HT(2A) receptors regulate corticotrophin-releasing hormone (CRH) neurons via distinct but strongly interacting pathways, probably converging on the same neurons in the hypothalamus....

  14. Promoter hypomethylation and upregulation of trefoil factors in prostate cancer

    DEFF Research Database (Denmark)

    Vestergaard, Else Marie; Nexø, Ebba; Tørring, Niels;

    2010-01-01

    Trefoil factors, mucin-associated peptides, are overexpressed in prostate cancer (PC). We hypothesized that promoter methylation contributes to the regulation of trefoil factors (TFF1, TFF2 and TFF3) in human prostate cells. Here we show hypomethylation of promoter regions of TFF1 and TFF3 in PC....... In clinical samples, methylation of the promoter/enhancer regions of TFF1 and TFF3 was significantly lower in PC compared to benign prostatic hyperplasia. The present study shows an inverse relation between promoter methylation and expression of trefoil factors. Preliminary analysis on clinical samples...... suggests that this regulatory mechanism is responsible for the increased levels of TFF1 and TFF3 observed in PC. The overexpression and promoter hypomethylation of trefoil factors may serve as biomarkers in PC....

  15. Preventive Effects of Fermented Brown Rice and Rice Bran against Prostate Carcinogenesis in TRAP Rats.

    Science.gov (United States)

    Kuno, Toshiya; Nagano, Aya; Mori, Yukiko; Kato, Hiroyuki; Nagayasu, Yuko; Naiki-Ito, Aya; Suzuki, Shugo; Mori, Hideki; Takahashi, Satoru

    2016-01-01

    Fermented brown rice and rice bran with Aspergillus oryzae (FBRA) is considered to have the potential to prevent chemically-induced carcinogenesis in multiple organs of rodents. In the present study, we evaluated the possible chemopreventive effects of FBRA against prostate tumorigenesis. Six-week-old male rats of the transgenic rat for adenocarcinoma of prostate (TRAP) strain were fed diets containing 5% or 10% FBRA for 15 weeks. Animals were sacrificed at 21 weeks of age, and the ventral and lateral prostate were removed for histopathological evaluation and immunoblot analyses. FBRA decreased the incidence of adenocarcinoma in the lateral prostate and suppressed the progression of prostate carcinogenesis. Treatment with FBRA induced apoptosis and inhibited cell proliferation in histologically high-grade prostatic intraepithelial neoplasias. Phospho-AMP-activated kinase α (Thr172) was up-regulated in the prostate of rats fed the diet supplemented with FBRA. These results indicate that FBRA controls tumor growth by activating pathways responsive to energy deprivation and suggest that FBRA has translational potential for the prevention of human prostate cancer. PMID:27409632

  16. Effects of cisplatin on the LSD1-mediated invasion and metastasis of prostate cancer cells.

    Science.gov (United States)

    Chen, Zhi-Yuan; Chen, Hui; Qiu, Tao; Weng, Xiao-Dong; Guo, Jia; Wang, Lei; Liu, Xiu-Heng

    2016-09-01

    Prostate cancer poses a major public health problem in men. Metastatic prostate cancer is incurable, and ultimately threatens the life of patients. Lysine‑specific demethylase 1 (LSD1) is an androgen receptor‑interacting protein that exerts a key role in regulating gene expression and is involved in numerous biological processes associated with prostate cancer. Cisplatin, also known as cis‑diamminedichloroplatinum or DDP, is a standard chemotherapeutic agent used to treat prostate cancer; however, it has the disadvantage of various serious side effects. The present study aimed to investigate the effects of LSD1 knockdown, and the interplay between LSD1 and DDP, on prostate cancer cell proliferation, apoptosis and invasion, and, therefore, the potential of LSD1 as a target for prostate cancer therapy. Flow cytometric analysis, Cell Counting kit 8 assay, Transwell assay and western blotting results revealed that LSD1 knockdown, in combination with DDP treatment, exerted antiproliferative, proapoptotic and anti‑invasive effects on PC3 prostate cancer cells. In addition, knockdown of LSD1 acted synergistically with DDP, thereby enhancing the induction of apoptosis, and the inhibition of proliferation and invasion in prostate cancer cells. These results indicated that LSD1 may serve as a potential therapeutic target, and may enhance the sensitivity of PC3 cells to DDP. PMID:27484796

  17. Preventive Effects of Fermented Brown Rice and Rice Bran against Prostate Carcinogenesis in TRAP Rats

    Directory of Open Access Journals (Sweden)

    Toshiya Kuno

    2016-07-01

    Full Text Available Fermented brown rice and rice bran with Aspergillus oryzae (FBRA is considered to have the potential to prevent chemically-induced carcinogenesis in multiple organs of rodents. In the present study, we evaluated the possible chemopreventive effects of FBRA against prostate tumorigenesis. Six-week-old male rats of the transgenic rat for adenocarcinoma of prostate (TRAP strain were fed diets containing 5% or 10% FBRA for 15 weeks. Animals were sacrificed at 21 weeks of age, and the ventral and lateral prostate were removed for histopathological evaluation and immunoblot analyses. FBRA decreased the incidence of adenocarcinoma in the lateral prostate and suppressed the progression of prostate carcinogenesis. Treatment with FBRA induced apoptosis and inhibited cell proliferation in histologically high-grade prostatic intraepithelial neoplasias. Phospho-AMP-activated kinase α (Thr172 was up-regulated in the prostate of rats fed the diet supplemented with FBRA. These results indicate that FBRA controls tumor growth by activating pathways responsive to energy deprivation and suggest that FBRA has translational potential for the prevention of human prostate cancer.

  18. Chemotherapeutic prevention studies of prostate cancer

    DEFF Research Database (Denmark)

    Djavan, Bob; Zlotta, Alexandre; Schulman, Claude;

    2004-01-01

    Despite advances in the detection and management of prostate cancer, this disease remains a major cause of morbidity and mortality in men. Increasing attention has focused on the role of chemoprevention for prostate cancer, ie the administration of agents that inhibit 1 or more steps in the natural...... history of prostate carcinogenesis. We review prostate cancer chemoprevention studies in Europe....

  19. Prevention and early detection of prostate cancer

    NARCIS (Netherlands)

    Cuzick, J.; Thorat, M.A.; Andriole, G.; Brawley, O.W.; Brown, P.H.; Culig, Z.; Eeles, R.A.; Ford, L.G.; Hamdy, F.C.; Holmberg, L.; Ilic, D.; Key, T.J.; Vecchia, C. La; Lilja, H.; Marberger, M.; Meyskens, F.L.; Minasian, L.M.; Parker, C.; Parnes, H.L.; Perner, S.; Rittenhouse, H.; Schalken, J.A.; Schmid, H.P.; Schmitz-Drager, B.J.; Schroder, F.H.; Stenzl, A.; Tombal, B.; Wilt, T.J.; Wolk, A.

    2014-01-01

    Prostate cancer is a common malignancy in men and the worldwide burden of this disease is rising. Lifestyle modifications such as smoking cessation, exercise, and weight control offer opportunities to reduce the risk of developing prostate cancer. Early detection of prostate cancer by prostate-speci

  20. 3D transrectal ultrasound prostate biopsy using a mechanical imaging and needle-guidance system

    Science.gov (United States)

    Bax, Jeffrey; Cool, Derek; Gardi, Lori; Montreuil, Jacques; Gil, Elena; Bluvol, Jeremy; Knight, Kerry; Smith, David; Romagnoli, Cesare; Fenster, Aaron

    2008-03-01

    Prostate biopsy procedures are generally limited to 2D transrectal ultrasound (TRUS) imaging for biopsy needle guidance. This limitation results in needle position ambiguity and an insufficient record of biopsy core locations in cases of prostate re-biopsy. We have developed a multi-jointed mechanical device that supports a commercially available TRUS probe with an integrated needle guide for precision prostate biopsy. The device is fixed at the base, allowing the joints to be manually manipulated while fully supporting its weight throughout its full range of motion. Means are provided to track the needle trajectory and display this trajectory on a corresponding TRUS image. This allows the physician to aim the needle-guide at predefined targets within the prostate, providing true 3D navigation. The tracker has been designed for use with several end-fired transducers that can be rotated about the longitudinal axis of the probe to generate 3D images. The tracker reduces the variability associated with conventional hand-held probes, while preserving user familiarity and procedural workflow. In a prostate phantom, biopsy needles were guided to within 2 mm of their targets, and the 3D location of the biopsy core was accurate to within 3 mm. The 3D navigation system is validated in the presence of prostate motion in a preliminary patient study.

  1. β-catenin is required for prostate development and cooperates with Pten loss to drive invasive carcinoma.

    Directory of Open Access Journals (Sweden)

    Jeffrey C Francis

    Full Text Available Prostate cancer is a major cause of male death in the Western world, but few frequent genetic alterations that drive prostate cancer initiation and progression have been identified. β-Catenin is essential for many developmental processes and has been implicated in tumorigenesis in many tissues, including prostate cancer. However, expression studies on human prostate cancer samples are unclear on the role this protein plays in this disease. We have used in vivo genetic studies in the embryo and adult to extend our understanding of the role of β-Catenin in the normal and neoplastic prostate. Our gene deletion analysis revealed that prostate epithelial β-Catenin is required for embryonic prostate growth and branching but is dispensable in the normal adult organ. During development, β-Catenin controls the number of progenitors in the epithelial buds and regulates a discrete network of genes, including c-Myc and Nkx3.1. Deletion of β-Catenin in a Pten deleted model of castration-resistant prostate cancer demonstrated it is dispensable for disease progression in this setting. Complementary overexpression experiments, through in vivo protein stabilization, showed that β-Catenin promotes the formation of squamous epithelia during prostate development, even in the absence of androgens. β-Catenin overexpression in combination with Pten loss was able to drive progression to invasive carcinoma together with squamous metaplasia. These studies demonstrate that β-Catenin is essential for prostate development and that an inherent property of high levels of this protein in prostate epithelia is to drive squamous fate differentiation. In addition, they show that β-Catenin overexpression can promote invasive prostate cancer in a clinically relevant model of this disease. These data provide novel information on cancer progression pathways that give rise to lethal prostate disease in humans.

  2. Human Prostate Cancer Hallmarks Map.

    Science.gov (United States)

    Datta, Dipamoy; Aftabuddin, Md; Gupta, Dinesh Kumar; Raha, Sanghamitra; Sen, Prosenjit

    2016-01-01

    Human prostate cancer is a complex heterogeneous disease that mainly affects elder male population of the western world with a high rate of mortality. Acquisitions of diverse sets of hallmark capabilities along with an aberrant functioning of androgen receptor signaling are the central driving forces behind prostatic tumorigenesis and its transition into metastatic castration resistant disease. These hallmark capabilities arise due to an intense orchestration of several crucial factors, including deregulation of vital cell physiological processes, inactivation of tumor suppressive activity and disruption of prostate gland specific cellular homeostasis. The molecular complexity and redundancy of oncoproteins signaling in prostate cancer demands for concurrent inhibition of multiple hallmark associated pathways. By an extensive manual curation of the published biomedical literature, we have developed Human Prostate Cancer Hallmarks Map (HPCHM), an onco-functional atlas of human prostate cancer associated signaling and events. It explores molecular architecture of prostate cancer signaling at various levels, namely key protein components, molecular connectivity map, oncogenic signaling pathway map, pathway based functional connectivity map etc. Here, we briefly represent the systems level understanding of the molecular mechanisms associated with prostate tumorigenesis by considering each and individual molecular and cell biological events of this disease process.

  3. Human Prostate Cancer Hallmarks Map.

    Science.gov (United States)

    Datta, Dipamoy; Aftabuddin, Md; Gupta, Dinesh Kumar; Raha, Sanghamitra; Sen, Prosenjit

    2016-01-01

    Human prostate cancer is a complex heterogeneous disease that mainly affects elder male population of the western world with a high rate of mortality. Acquisitions of diverse sets of hallmark capabilities along with an aberrant functioning of androgen receptor signaling are the central driving forces behind prostatic tumorigenesis and its transition into metastatic castration resistant disease. These hallmark capabilities arise due to an intense orchestration of several crucial factors, including deregulation of vital cell physiological processes, inactivation of tumor suppressive activity and disruption of prostate gland specific cellular homeostasis. The molecular complexity and redundancy of oncoproteins signaling in prostate cancer demands for concurrent inhibition of multiple hallmark associated pathways. By an extensive manual curation of the published biomedical literature, we have developed Human Prostate Cancer Hallmarks Map (HPCHM), an onco-functional atlas of human prostate cancer associated signaling and events. It explores molecular architecture of prostate cancer signaling at various levels, namely key protein components, molecular connectivity map, oncogenic signaling pathway map, pathway based functional connectivity map etc. Here, we briefly represent the systems level understanding of the molecular mechanisms associated with prostate tumorigenesis by considering each and individual molecular and cell biological events of this disease process. PMID:27476486

  4. HUMAN PROSTATE CANCER RISK FACTORS

    Science.gov (United States)

    Prostate cancer has the highest prevalence of any non-skin cancer in the human body, with similar likelihood of neoplastic foci found within the prostates of men around the world regardless of diet, occupation, lifestyle, or other factors. Essentially all men with circulating an...

  5. ESUR prostate MR guidelines 2012

    DEFF Research Database (Denmark)

    Barentsz, Jelle O; Richenberg, Jonathan; Clements, Richard;

    2012-01-01

    The aim was to develop clinical guidelines for multi-parametric MRI of the prostate by a group of prostate MRI experts from the European Society of Urogenital Radiology (ESUR), based on literature evidence and consensus expert opinion. True evidence-based guidelines could not be formulated, but a...

  6. Vitamin E and Prostate Cancer

    Science.gov (United States)

    Vitamin E, its metabolites or its analogs, might help prevent prostate cancer initiation or progression. Prostate cancer is the most common non-skin malignancy and the second leading cause of cancer deaths among men in the United States, exceeded only by lung cancer. About 218,890 new cases of prost...

  7. Androgen Control in Prostate Cancer.

    Science.gov (United States)

    Pelekanou, Vasiliki; Castanas, Elias

    2016-10-01

    Research on prostate cancer has extensively advanced in the past decade, through an improved understanding for its genetic basis and risk-stratification. Molecular classification of prostate cancer into distinct subtypes and the recognition of new histologic entities promise the development of tailored-made management strategies of patients. Nowadays, various alternatives are available for clinical management of localized disease ranging from observation alone through radical prostatectomy. In patients with castration-resistant prostate cancer, the approval of new drugs for the management of metastatic disease has offered promising results improving the survival of these patients. In this context, androgen receptors (AR) remain at the epicenter of prostate cancer research holding a prominent role in the biology and therapeutic regimens of prostate cancer. As many of castration-resistant tumors retain hormone-responsiveness, AR is a clinical relevant, druggable target. However, AR paradoxically remains neglected as a prostate cancer biomarker. The great advancements in prostate cancer preclinical and clinical research, imply further improvement in clinical and translational data, for patient selection and treatment optimization. For a precision medicine-guided clinical management of prostate cancer, AR evaluation has to be implemented in companion and complementary diagnostics, as discussed here. J. Cell. Biochem. 117: 2224-2234, 2016. © 2016 Wiley Periodicals, Inc. PMID:27104784

  8. Imaging of recurrent prostate cancer

    NARCIS (Netherlands)

    Futterer, J.J.

    2012-01-01

    Approximately 30\\% of patients who underwent radical prostatectomy or radiation therapy will develop biochemical recurrent disease. Biochemical recurrent disease is defined as an increase in the serum value of prostate-specific antigen (PSA) after reaching the nadir. Prostate recurrence can present

  9. Jointly amplified basal and pulsatile growth hormone (GH) secretion and increased process irregularity in women with anorexia nervosa: indirect evidence for disruption of feedback regulation within the GH-insulin-like growth factor I axis

    DEFF Research Database (Denmark)

    Støving, R K; Veldhuis, J D; Flyvbjerg, A;

    1999-01-01

    pulsatility in AN using the techniques of deconvolution analysis and approximate entropy, which quantify secretory activity and serial irregularity of underlying hormone release not reflected in peak occurrence or amplitudes. To this end, 24-h GH profiles were obtained by continuous blood sampling aliquoted....... Accordingly, GH secretion in AN probably reflects altered neuroendocrine feedback regulation, e.g. associated with increased hypothalamic GHRH discharge superimposed on reduced hypothalamic somatostatinergic tone....

  10. Survey of Differentially Methylated Promoters in Prostate Cancer Cell Lines

    Directory of Open Access Journals (Sweden)

    Yipeng Wang

    2005-08-01

    Full Text Available DNA methylation, copy number in the genomes of three immortalized prostate epithelial, five cancer cell lines (LNCaP, PC3, PC3M, PC3M-Pro4, PC3MLN4 were compared using a microarray-based technique. Genomic DNA is cut with a methylation-sensitive enzyme Hpall, followed by linker ligation, polymerase chain reaction (PCR amplification, labeling, hybridization to an array of promoter sequences. Only those parts of the genomic DNA that have unmethylated restriction sites within a few hundred base pairs generate PCR products detectable on an array. Of 2732 promoter sequences on a test array, 504 (18.5% showed differential hybridization between immortalized prostate epithelial, cancer cell lines. Among candidate hypermethylated genes in cancer-derived lines, there were eight (CD44, CDKN1A, ESR1, PLAU, RARB, SFN, TNFRSF6, TSPY previously observed in prostate cancer, 13 previously known methylation targets in other cancers (ARHI, bcl-2, BRCA1, CDKN2C, GADD45A, MTAP, PGR, SLC26A4, SPARC, SYK, TJP2, UCHL1, WIT-1. The majority of genes that appear to be both differentially methylated, differentially regulated between prostate epithelial, cancer cell lines are novel methylation targets, including PAK6, RAD50, TLX3, PIR51, MAP2K5, INSR, FBN1, GG2-1, representing a rich new source of candidate genes used to study the role of DNA methylation in prostate tumors.

  11. Comparative Metabolomic and Lipidomic Analysis of Phenotype Stratified Prostate Cells.

    Directory of Open Access Journals (Sweden)

    Tanya C Burch

    Full Text Available Prostate cancer (PCa is the most prevalent cancer amongst men and the second most common cause of cancer related-deaths in the USA. Prostate cancer is a heterogeneous disease ranging from indolent asymptomatic cases to very aggressive life threatening forms. The goal of this study was to identify differentially expressed metabolites and lipids in prostate cells with different tumorigenic phenotypes. We have used mass spectrometry metabolomic profiling, lipidomic profiling, bioinformatic and statistical methods to identify, quantify and characterize differentially regulated molecules in five prostate derived cell lines. We have identified potentially interesting species of different lipid subclasses including phosphatidylcholines (PCs, phosphatidylethanolamines (PEs, glycerophosphoinositols (PIs and other metabolites that are significantly upregulated in prostate cancer cells derived from distant metastatic sites. Transcriptomic and biochemical analysis of key enzymes that are involved in lipid metabolism demonstrate the significant upregulation of choline kinase alpha in the metastatic cells compared to the non-malignant and non-metastatic cells. This suggests that different de novo lipogenesis and other specific signal transduction pathways are activated in aggressive metastatic cells as compared to normal and non-metastatic cells.

  12. Losartan sensitizes selectively prostate cancer cell to ionizing radiation.

    Science.gov (United States)

    Yazdannejat, H; Hosseinimehr, S J; Ghasemi, A; Pourfallah, T A; Rafiei, A

    2016-01-11

    Losartan is an angiotensin II receptor (AT-II-R) blocker that is widely used by human for blood pressure regulation. Also, it has antitumor property. In this study, we investigated the radiosensitizing effect of losartan on cellular toxicity induced by ionizing radiation on prostate cancer and non-malignant fibroblast cells. Human prostate cancer (DU-145) and human non-malignant fibroblast cells (HFFF2) were treated with losartan at different concentrations (0.5, 1, 10, 50 and 100 µM) and then these cells were exposed to ionizing radiation. The cell proliferation was determined using MTT assay. Our results showed that losartan exhibited antitumor effect on prostate cancer cells; it was reduced cell survival to 66% at concentration 1 µM. Losartan showed an additive killing effect in combination with ionizing radiation on prostate cancer cell. The cell proliferation was reduced to 54% in the prostate cancer cells treated with losartan at concentration 1 µM in combination with ionizing radiation. Losartan did not exhibit any toxicity on HFFF2 cell. This result shows a promising effect of losartan on enhancement of therapeutic effect of ionizing radiation in patients during therapy.

  13. Androgen receptor: structure, role in prostate cancer and drug discovery.

    Science.gov (United States)

    Tan, M H Eileen; Li, Jun; Xu, H Eric; Melcher, Karsten; Yong, Eu-leong

    2015-01-01

    Androgens and androgen receptors (AR) play a pivotal role in expression of the male phenotype. Several diseases, such as androgen insensitivity syndrome (AIS) and prostate cancer, are associated with alterations in AR functions. Indeed, androgen blockade by drugs that prevent the production of androgens and/or block the action of the AR inhibits prostate cancer growth. However, resistance to these drugs often occurs after 2-3 years as the patients develop castration-resistant prostate cancer (CRPC). In CRPC, a functional AR remains a key regulator. Early studies focused on the functional domains of the AR and its crucial role in the pathology. The elucidation of the structures of the AR DNA binding domain (DBD) and ligand binding domain (LBD) provides a new framework for understanding the functions of this receptor and leads to the development of rational drug design for the treatment of prostate cancer. An overview of androgen receptor structure and activity, its actions in prostate cancer, and how structural information and high-throughput screening have been or can be used for drug discovery are provided herein. PMID:24909511

  14. Differential regulation of LncRNA-SARCC suppresses VHL-mutant RCC cell proliferation yet promotes VHL-normal RCC cell proliferation via modulating androgen receptor/HIF-2α/C-MYC axis under hypoxia.

    Science.gov (United States)

    Zhai, W; Sun, Y; Jiang, M; Wang, M; Gasiewicz, T A; Zheng, J; Chang, C

    2016-09-15

    It is well established that hypoxia contributes to tumor progression in a hypoxia inducible factor-2α (HIF-2α)-dependent manner in renal cell carcinoma (RCC), yet the role of long noncoding RNAs (LncRNAs) involved in hypoxia-mediated RCC progression remains unclear. Here we demonstrate that LncRNA-SARCC (Suppressing Androgen Receptor in Renal Cell Carcinoma) is differentially regulated by hypoxia in a von Hippel-Lindau (VHL)-dependent manner both in RCC cell culture and clinical specimens. LncRNA-SARCC can suppress hypoxic cell cycle progression in the VHL-mutant RCC cells while derepress it in the VHL-restored RCC cells. Mechanism dissection reveals that LncRNA-SARCC can post-transcriptionally regulate androgen receptor (AR) by physically binding and destablizing AR protein to suppress AR/HIF-2α/C-MYC signals. In return, HIF-2α can transcriptionally regulate the LncRNA-SARCC expression via binding to hypoxia-responsive elements on the promoter of LncRNA-SARCC. The negative feedback modulation between LncRNA-SARCC/AR complex and HIF-2α signaling may then lead to differentially modulated RCC progression in a VHL-dependent manner. Together, these results may provide us a new therapeutic approach via targeting this newly identified signal from LncRNA-SARCC to AR-mediated HIF-2α/C-MYC signals against RCC progression.

  15. Association analyses of depression and genes in the hypothalamus-pituitary-adrenal axis

    DEFF Research Database (Denmark)

    Buttenschøn, Henrietta Nørmølle; Krogh, Jesper; Nielsen, Marit Nyholm;

    2016-01-01

    OBJECTIVE: Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis has been reported in depression. The aim was to investigate the potential association between depression and seven genes regulating or interfering with the HPA axis, including the gene encoding angiotensin converting enzyme...

  16. New horizons in prostate cancer imaging

    Energy Technology Data Exchange (ETDEWEB)

    Ravizzini, Gregory; Turkbey, Baris; Kurdziel, Karen [Molecular Imaging Program, National Cancer Institute, National Institutes of Health, Bethesda, MD (United States); Choyke, Peter L. [Molecular Imaging Program, National Cancer Institute, National Institutes of Health, Bethesda, MD (United States)], E-mail: pchoyke@nih.gov

    2009-05-15

    Prostate cancer is the most common non-cutaneous malignancy among American men. Imaging has recently become more important in detection of prostate cancer since screening techniques such as digital rectal examination (DRE), prostate specific and transrectal ultrasound guided biopsy have considerable limitations in diagnosis and localization of prostate cancer. In this manuscript, we reviewed conventional, functional and targeted imaging modalities used in diagnosis and local staging of prostate cancer with exquisite images.

  17. Effect of Obesity on Prostate-Specific Antigen, Prostate Volume, and International Prostate Symptom Score in Patients with Benign Prostatic Hyperplasia

    OpenAIRE

    Kim, Jong Min; Song, Phil Hyun; Kim, Hyun Tae; Moon, Ki Hak

    2011-01-01

    Purpose We examined the correlation between body mass index (BMI) as a marker of obesity and prostate-specific antigen (PSA), prostate volume (PV), and International Prostate Symptom Score (IPSS) in patients with benign prostatic hyperplasia (BPH). Materials and Methods From January 2008 to December 2008, we examined 258 patients diagnosed with BPH. Patients taking 5α-reductase inhibitors or those diagnosed with prostate cancer were excluded from this study. BPH was defined as PV≥25 ml and IP...

  18. Comparison of telomerase activity in prostate cancer, prostatic intraepithelial neoplasia and benign prostatic hyperplasia

    Directory of Open Access Journals (Sweden)

    Soleiman Mahjoub

    2006-11-01

    Full Text Available BACKGROUND: Telomerase is a reverse transcriptase enzyme that synthesizes telomeric DNA on chromosome ends. The enzyme is important for the immortalization of cancer cells because it maintains the telomeres. METHODS: Telomerase activity (TA was measured by fluorescence-based telomeric repeat amplification protocol (FTRAP assay in prostate carcinoma and benign prostatic hyperplasia (BPH. RESULTS: TA was present in 91.4% of 70 prostate cancers, 68.8% of 16 prostatic intraepithelial neoplasia (PIN, 43.3% of 30 BPH*, 21.4% of 14 atrophy and 20% of 15 normal samples adjacent to tumor. There was not any significant correlation between TA, histopathological tumor stage or gleason score. In contrast to high TA in the BPH* tissue from the cancer-bearing gland, only 6.3% of 32 BPH specimens from patients only diagnosed with BPH were telomerase activity-positive. CONCLUSIONS: These results indicate that TA is present in most prostate cancers. The high rate of TA in tissue adjacent to tumor may be attributed either to early molecular alteration of cancer that was histologically unapparent, or to the presence of occult cancer cells. Our findings suggest that the re-expression of telomerase activity could be one step in the transformation of BPH to PIN. KEY WORDS: Telomerase activity, prostate cancer, prostatic intraepithelial neoplasia, benign prostatic hyperplasia.

  19. Role of transurethral resection of the prostate in the management of prostate cancer

    OpenAIRE

    Szollosi Attila; Martha Orsolya; Denes Lorand; Vida Arpad Oliver; Maier Adrian; Pavai Zoltan

    2016-01-01

    Introduction: Prostate cancer is the second most diagnosed cancer in men, after lung cancer. The gold standard procedure in prostate cancer (PCa) diagnosis is the ultrasound guided prostate biopsy. Transurethral resection of the prostate (TURP) used in solving the bladder outlet obstruction, can have a role in detection of PCa. The aim of this retrospective study is to examine the role of transurethral resection of the prostate in the diagnosis and therapy of prostate cancer.

  20. Involvement of extracellular signal-regulated kinase (ERK1/2)-p53-p21 axis in mediating neural stem/progenitor cell cycle arrest in co-morbid HIV-drug abuse exposure.

    Science.gov (United States)

    Malik, Shaily; Saha, Rinki; Seth, Pankaj

    2014-06-01

    Neurological complications in opioid abusing Human Immunodeficiency Virus-1 (HIV-1) patients suggest enhanced neurodegeneration as compared to non-drug abusing HIV-1 infected population. Neural precursor cells (NPCs), the multipotent cells of the mammalian brain, are susceptible to HIV-1 infection and as opiates also perturb their growth kinetics, detailed mechanistic studies for their co-morbid exposure are highly warranted. Using a well characterized in vitro model of human fetal brain-derived neural precursor cells, we investigated alterations in NPC properties at both acute and chronic durations. Chronic morphine and Tat treatment attenuated proliferation in NPCs, with cells stalled at G1-phase of the cell cycle. Furthermore HIV-Tat and morphine exposure increased activation of extracellular signal-regulated kinase-1/2 (ERK1/2), enhanced levels of p53 and p21, and decreased cyclin D1 and Akt levels in NPCs. Regulated by ERK1/2 and p53, p21 was found to be indispensible for Tat and morphine mediated cell cycle arrest. Our study elaborates on the cellular and molecular machinery in NPCs and provides significant mechanistic details into HIV-drug abuse co-morbidity that may have far reaching clinical consequences both in pediatric as well as adult neuroAIDS.

  1. Epidermal growth factor increases LRF/Pokemon expression in human prostate cancer cells.

    Science.gov (United States)

    Aggarwal, Himanshu; Aggarwal, Anshu; Agrawal, Devendra K

    2011-10-01

    Leukemia/lymphoma related factor/POK erythroid myeloid ontogenic factor (LRF/Pokemon) is a member of the POK family of proteins that promotes oncogenesis in several forms of cancer. Recently, we found higher LRF expression in human breast and prostate carcinomas compared to the corresponding normal tissues. The aim of this study was to examine the regulation of LRF expression in human prostate cells. Epidermal growth factor (EGF) and its receptors mediate several tumorigenic cascades that regulate cell differentiation, proliferation, migration and survival of prostate cancer cells. There was significantly higher level of LRF expression in the nucleus of LNCaP and PC-3 cells than RWPE-1 cells. A significant increase in LRF expression was observed with increasing doses of EGF in more aggressive and androgen-sensitive prostate cancer cells suggesting that EGF signaling pathway is critical in upregulating the expression of LRF/Pokemon to promote oncogenesis. PMID:21640721

  2. American Cancer Society Recommendations for Prostate Cancer Early Detection

    Science.gov (United States)

    ... saved articles window. My Saved Articles » My ACS » Prostate Cancer Prevention and Early Detection + - Text Size Download Printable Version [ ... coverage for prostate cancer screening Additional resources for prostate cancer prevention and early detection References: Prostate cancer prevention and ...

  3. A Prospective Randomized Trial of Two Different Prostate Biopsy Schemes

    Science.gov (United States)

    2016-07-03

    Prostate Cancer; Local Anesthesia; Prostate-Specific Antigen/Blood; Biopsy/Methods; Image-guided Biopsy/Methods; Prostatic Neoplasms/Diagnosis; Prostate/Pathology; Prospective Studies; Humans; Male; Ultrasonography, Interventional/Methods

  4. Comparability of prostate trials

    DEFF Research Database (Denmark)

    Suciu, S; Sylvester, R; Iversen, P;

    1993-01-01

    The present overview of advanced prostate cancer required the identification of randomized clinical trials studying the question of maximal androgen blockade versus the classic castration therapy. The heterogeneity of the trials concerned the type of castration (surgical or chemical) and the type...... of antiandrogen (flutamide, Anandron, or cyproterone acetate) added to castration. This paper reviews the different types of heterogeneity that might exist among trials that are involved in the overview: study design, randomization procedure, treatment evaluation, statistical evaluation, and data maturity...... with a larger number of patients and a longer follow-up will contribute more to the overview's results....

  5. A histological study of prostate

    Directory of Open Access Journals (Sweden)

    Ashfaq U. Hassan

    2013-08-01

    Full Text Available The work of anatomists and pathologists in the role of study of prostate has been significant. Starting from earlier times till modern time, the study of prostate has been a dynamic one and the basic anatomical knowledge of the prostate has undergone much change apart from the new techniques, micro invasive procedures and the chemotherapeutic approach for various disorders of the gland. The present study was based on the microscopic examination of Prostatic tissue of individuals with individual tissues of different age groups. The present study involved 40 cases which were further subdivided into various age groups and characteristic histological changes were noted. The study presents an assessment of age changes in prostate in elderly in Kashmiri population with pathological significance. Besides the histological study is of great importance in staging of diseases of prostate and especially in modern era where the incidence and prevalence of prostatic diseases is on rise. [Int J Res Med Sci 2013; 1(4.000: 557-562

  6. Tubulin-Targeting Chemotherapy Impairs Androgen Receptor Activity in Prostate Cancer

    OpenAIRE

    Zhu, Meng-Lei; Horbinski, Craig; Garzotto, Mark; Qian, David Z.; Beer, Tomasz M.; Kyprianou, Natasha

    2010-01-01

    Recent insights into the regulation of the androgen receptor (AR) activity led to novel therapeutic targeting of AR function in prostate cancer patients. Docetaxel is an approved chemotherapy for treatment of castration-resistant-prostate cancer (CRPC), but the mechanism underlying the action of this tubulin-targeting drug is not fully understood. This study investigates the contribution of microtubules and the cytoskeleton to androgen-mediated signaling, and the consequences of their inhibit...

  7. Glutathione S-transferase Pi mediates proliferation of androgen-independent prostate cancer cells

    OpenAIRE

    Hokaiwado, Naomi; Takeshita, Fumitaka; Naiki-Ito, Aya; Asamoto, Makoto; Ochiya, Takahiro; Shirai, Tomoyuki

    2008-01-01

    Prostate cancers generally acquire an androgen-independent growth capacity with progression, resulting in resistance to antiandrogen therapy. Therefore, identification of the genes regulated through this process may be important for understanding the mechanisms of prostate carcinogenesis. We here utilized androgen-dependent/independent transplantable tumors, newly established with the ‘transgenic rat adenocarcinoma in prostate’ (TRAP) model, to analyze their gene expression using microarrays....

  8. Experimental Evidence of Persistent Androgen-Receptor-Dependency in Castration-Resistant Prostate Cancer

    OpenAIRE

    Osamu Ogawa; Tomomi Kamba; Takahiro Inoue; Takashi Kobayashi

    2013-01-01

    In the majority of castration-resistant prostate cancer (CRPC), prostate-specific antigen (PSA), product of a gene that is almost exclusively regulated by the androgen receptor (AR), still acts as a serum marker reflecting disease burden, indicating that AR signaling is activated even under castrate level of serum androgen. Accumulated evidence shows that transcriptional ability of AR is activated both in ligand-dependent and -independent manners in CRPC cells. Some androgen-independent subli...

  9. Epidermal Growth Factor Increases LRF/Pokemon Expression in Human Prostate Cancer Cells

    OpenAIRE

    Aggarwal, Himanshu; Aggarwal, Anshu; Devendra K Agrawal

    2011-01-01

    Leukemia/lymphoma related factor/POK erythroid myeloid ontogenic factor (LRF/Pokemon) is a member of the POK family of proteins that promotes oncogenesis in several forms of cancer. Recently, we found higher LRF expression in human breast and prostate carcinomas compared to the corresponding normal tissues. The aim of this study was to examine the regulation of LRF expression in human prostate cells. Epidermal growth factor (EGF) and its receptors mediate several tumorigenic cascades that reg...

  10. Sildenafil (Viagra) sensitizes prostate cancer cells to doxorubicin-mediated apoptosis through CD95

    OpenAIRE

    Das, Anindita; Durrant, David; Mitchell, Clint; Dent, Paul; Batra, Surinder K.; Kukreja, Rakesh C.

    2015-01-01

    We previously reported that Sildenafil enhances apoptosis and antitumor efficacy of doxorubicin (DOX) while attenuating its cardiotoxic effect in prostate cancer. In the present study, we investigated the mechanism by which sildenafil sensitizes DOX in killing of prostate cancer (PCa) cells, DU145. The death receptor Fas (APO-1 or CD95) induces apoptosis in many carcinoma cells, which is negatively regulated by anti-apoptotic molecules such as FLIP (Fas-associated death domain (FADD) interleu...

  11. Targeting Alternative Sites on the Androgen Receptor to Treat Castration-Resistant Prostate Cancer

    OpenAIRE

    Rennie, Paul S.; Artem Cherkasov; Nada Lallous; Kush Dalal

    2013-01-01

    Recurrent, metastatic prostate cancer continues to be a leading cause of cancer-death in men. The androgen receptor (AR) is a modular, ligand-inducible transcription factor that regulates the expression of genes that can drive the progression of this disease, and as a consequence, this receptor is a key therapeutic target for controlling prostate cancer. The current drugs designed to directly inhibit the AR are called anti-androgens, and all act by competing with androgens for binding to the ...

  12. Clinical Implications of Hedgehog Pathway Signaling in Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Daniel L. Suzman

    2015-09-01

    Full Text Available Activity in the Hedgehog pathway, which regulates GLI-mediated transcription, is important in organogenesis and stem cell regulation in self-renewing organs, but is pathologically elevated in many human malignancies. Mutations leading to constitutive activation of the pathway have been implicated in medulloblastoma and basal cell carcinoma, and inhibition of the pathway has demonstrated clinical responses leading to the approval of the Smoothened inhibitor, vismodegib, for the treatment of advanced basal cell carcinoma. Aberrant Hedgehog pathway signaling has also been noted in prostate cancer with evidence suggesting that it may render prostate epithelial cells tumorigenic, drive the epithelial-to-mesenchymal transition, and contribute towards the development of castration-resistance through autocrine and paracrine signaling within the tumor microenvironment and cross-talk with the androgen pathway. In addition, there are emerging clinical data suggesting that inhibition of the Hedgehog pathway may be effective in the treatment of recurrent and metastatic prostate cancer. Here we will review these data and highlight areas of active clinical research as they relate to Hedgehog pathway inhibition in prostate cancer.

  13. CSR1 suppresses tumor growth and metastasis of prostate cancer.

    Science.gov (United States)

    Yu, Guoying; Tseng, George C; Yu, Yan Ping; Gavel, Tim; Nelson, Joel; Wells, Alan; Michalopoulos, George; Kokkinakis, Demetrius; Luo, Jian-Hua

    2006-02-01

    Prostate cancer is frequent among men over 45 years of age, but it generally only becomes lethal with metastasis. In this study, we identified a gene called cellular stress response 1 (CSR1) that was frequently down-regulated and methylated in prostate cancer samples. Survival analysis indicated that methylation of the CSR1 promoter, and to a lesser extent down-regulation of CSR1 protein expression, was associated with a high rate of prostate cancer metastasis. Forced expression of CSR1 in prostate cancer cell lines DU145 and PC3 resulted in a two- to threefold decrease in colony formation and a 10-fold reduction in anchorage-independent growth. PC3 cells stably expressing CSR1 had an average threefold decrease in their ability to invade in vitro. Expression of CSR1 in PC3 cell xenografts produced a dramatic reduction (>8-fold) in tumor size, rate of invasion (0 versus 31%), and mortality (13 versus 100%). The present findings suggest that CSR1 is a potent tumor sup-pressor gene. PMID:16436673

  14. Abiraterone acetate for prostate cancer: a new era of hormonal therapies

    Institute of Scientific and Technical Information of China (English)

    Emmanuel S Antonarakis

    2011-01-01

    @@ Therapies targeting the androgen receptor (AR) axis have constituted the Holy Grail in the management of advanced prostate cancer for seven decades.1 These hormonal therapies have traditionally taken two main forms: those that suppress gonadal androgen synthesis (e.g.,the gonadotropin releasing hormone agonists/antagonists,such as leuprolide),and those that inhibit the AR directly (e.g.,the anti-androgens,such asbicalutamide).However,although the vast majority of patients with prostate cancer initially respond favorably to androgen-ablative therapies (manifested by tumor regressions and symptomatic improvements),all patients will eventually develop further disease progression after a median of 18-24 months.This transformed disease state,known as castration-resistant prostate cancer (CRPC),is invariably fatal.

  15. The different roles of glucocorticoids in the hippocampus and hypothalamus in chronic stress-induced HPA axis hyperactivity.

    Directory of Open Access Journals (Sweden)

    Li-Juan Zhu

    Full Text Available Hypothalamus-pituitary-adrenal (HPA hyperactivity is observed in many patients suffering from depression and the mechanism underling the dysfunction of HPA axis is not well understood. Chronic stress has a causal relationship with the hyperactivity of HPA axis. Stress induces the over-synthesis of glucocorticoids, which will arrive at all the body containing the brain. It is still complicated whether glucocorticoids account for chronic stress-induced HPA axis hyperactivity and in which part of the brain the glucocorticoids account for chronic stress-induced HPA axis hyperactivity. Here, we demonstrated that glucocorticoids were indispensable and sufficient for chronic stress-induced hyperactivity of HPA axis. Although acute glucocorticoids elevation in the hippocampus and hypothalamus exerted a negative regulation of HPA axis, we found that chronic glucocorticoids elevation in the hippocampus but not in the hypothalamus accounted for chronic stress-induced hyperactivity of HPA axis. Chronic glucocorticoids exposure in the hypothalamus still exerted a negative regulation of HPA axis activity. More importantly, we found mineralocorticoid receptor (MR - neuronal nitric oxide synthesis enzyme (nNOS - nitric oxide (NO pathway mediated the different roles of glucocorticoids in the hippocampus and hypothalamus in regulating HPA axis activity. This study suggests that the glucocorticoids in the hippocampus play an important role in the development of HPA axis hyperactivity and the glucocorticoids in the hypothalamus can't induce hyperactivity of HPA axis, revealing new insights into understanding the mechanism of depression.

  16. The different roles of glucocorticoids in the hippocampus and hypothalamus in chronic stress-induced HPA axis hyperactivity.

    Science.gov (United States)

    Zhu, Li-Juan; Liu, Meng-Ying; Li, Huan; Liu, Xiao; Chen, Chen; Han, Zhou; Wu, Hai-Yin; Jing, Xing; Zhou, Hai-Hui; Suh, Hoonkyo; Zhu, Dong-Ya; Zhou, Qi-Gang

    2014-01-01

    Hypothalamus-pituitary-adrenal (HPA) hyperactivity is observed in many patients suffering from depression and the mechanism underling the dysfunction of HPA axis is not well understood. Chronic stress has a causal relationship with the hyperactivity of HPA axis. Stress induces the over-synthesis of glucocorticoids, which will arrive at all the body containing the brain. It is still complicated whether glucocorticoids account for chronic stress-induced HPA axis hyperactivity and in which part of the brain the glucocorticoids account for chronic stress-induced HPA axis hyperactivity. Here, we demonstrated that glucocorticoids were indispensable and sufficient for chronic stress-induced hyperactivity of HPA axis. Although acute glucocorticoids elevation in the hippocampus and hypothalamus exerted a negative regulation of HPA axis, we found that chronic glucocorticoids elevation in the hippocampus but not in the hypothalamus accounted for chronic stress-induced hyperactivity of HPA axis. Chronic glucocorticoids exposure in the hypothalamus still exerted a negative regulation of HPA axis activity. More importantly, we found mineralocorticoid receptor (MR) - neuronal nitric oxide synthesis enzyme (nNOS) - nitric oxide (NO) pathway mediated the different roles of glucocorticoids in the hippocampus and hypothalamus in regulating HPA axis activity. This study suggests that the glucocorticoids in the hippocampus play an important role in the development of HPA axis hyperactivity and the glucocorticoids in the hypothalamus can't induce hyperactivity of HPA axis, revealing new insights into understanding the mechanism of depression.

  17. ScaphoLunate Axis Method.

    Science.gov (United States)

    Yao, Jeffrey; Zlotolow, Dan A; Lee, Steve K

    2016-03-01

    Background Treating chronic scapholunate ligament injuries without the presence of arthritis remains an unsolved clinical problem facing wrist surgeons. This article highlights a technique for reconstructing the scapholunate ligament using novel fixation, the ScaphoLunate Axis Method (SLAM). Materials and Methods In a preliminary review of the early experience of this technique, 13 patients were evaluated following scapholunate ligament reconstruction utilizing the SLAM technique. Description of Techinque The scapholunate interval is reconstructed utilizing a palmaris longus autograft passed between the scaphoid and lunate along the axis of rotation in the sagittal plane. It is secured in the lunate using a graft anchor and in the scaphoid utilizing an interference screw. The remaining graft is passed dorsally to reconstruct the dorsal scapholunate ligament. Results At an average follow-up of 11 months, the mean postoperative scapholunate gap was 2.1 mm. The mean postoperative scapholunate angle was 59 degrees. The mean postoperative wrist flexion and extension was 45 and 56 degrees, respectively. The mean grip strength was 24.9 kg, or 62% of the contralateral side. The mean pain score (VAS) was 1.7. There was 1 failure with recurrence of the pathologic scapholunate gap and the onset of pain. Conclusion While chronic scapholunate ligament instability remains an unsolved problem facing wrist surgeons, newer techniques are directed toward restoring the normal relationships of the scaphoid and lunate in both the coronal and sagittal planes. The SLAM technique has demonstrated promise in preliminary clinical studies. PMID:26855838

  18. Diagnostic imaging of the prostate

    International Nuclear Information System (INIS)

    Modalities for the diagnostic imaging of the prostate are surveyed. Transrectal sonography is thought to be the best method for the purpose, because of its non-invasive nature, fine picture quality, sufficient reproductivity and less expensive cost. Up-to-date utilizations of the method are described, such as diagnostic capability, staging, monitoring, screening and intervention. CT is less effective but MRI is promising to visualize internal structure inside the prostate. Two very new techniques, namely, ultrasonic Doppler color flow mapping and positron emission CT (PET), of which application to the prostate is being investigated originally in our laboratory, are introduced. (author) 100 refs

  19. Cancer Treatment: Superporous Poly(ethylene glycol) Diacrylate Cryogel with a Defined Elastic Modulus for Prostate Cancer Cell Research (Small 29/2016).

    Science.gov (United States)

    Göppert, Bettina; Sollich, Thomas; Abaffy, Paul; Cecilia, Angelica; Heckmann, Jan; Neeb, Antje; Bäcker, Anne; Baumbach, Tilo; Gruhl, Friederike J; Cato, Andrew C B

    2016-08-01

    On page 3985, F. J. Gruhl, A. C. B. Cato engineer superporous poly(ethylene glycol) diacrylate cryogels that mimic the stiffness of malignant prostate tissues for studies of prostate cancer cell growth and function. Cells grow in an anchorage-dependent manner in this scaffold for three weeks and respond to androgen and antiandrogen treatment. Compared to 2D cell culture system, androgen-dependent prostate target gene expression is highly regulated in this system. PMID:27477259

  20. Analysis of the codon 72 polymorphism of TP53 and human papillomavirus infection in Iranian patients with prostate cancer.

    Science.gov (United States)

    Salehi, Zivar; Hadavi, Mahvash

    2012-09-01

    The TP53 gene is one of the most important tumor suppressor genes controlling DNA transcription and cell regulation. Common polymorphisms in p53 gene may play a role in some cancers. Some studies have reported an association between human papillomavirus (HPV) infections and prostate cancer. The aim of this study was to investigate whether the TP53 codon 72 polymorphism and HPV infection are responsible for susceptibility to prostate cancer in Iranian men. The prostate biopsies were taken during surgery from 68 Iranian prostatic cancer patients, and 85 patients with benign prostate hyperplasia. For genotyping of the p53 polymorphism at codon 72, PCRRFLP methods were used and the PCR products were digested with BstU1. An attempt was also made to detect HPV DNA in benign prostate hyperplasia and prostate cancer specimens. Among cancer cases, the distribution of Arg/Arg, Arg/Pro and Pro/Pro genotypes were 26.5%, 45.4%, and 19.1%, respectively. Among patients with benign prostate hyperplasia, the distribution of Arg/Arg, Arg/Pro, and Pro/Pro genotypes were 27%, 53%, and 20%, respectively. The allele frequencies did not differ significantly between prostate cancer and benign prostate hyperplasia samples. Human papillomavirus was detected only in three patients (4.4%; P = 0.71). The results from this study suggest that the TP53 codon 72 polymorphism and HPV infection do not confer susceptibility to prostate cancer in the Iranian population. Larger population-based studies are needed to clarify the relation between prostate carcinoma and p53 polymorphism and HPV infection. PMID:22825821

  1. A multiscale, mechanism-driven, dynamic model for the effects of 5α-reductase inhibition on prostate maintenance.

    Science.gov (United States)

    Zager, Michael G; Barton, Hugh A

    2012-01-01

    A systems-level mathematical model is presented that describes the effects of inhibiting the enzyme 5α-reductase (5aR) on the ventral prostate of the adult male rat under chronic administration of the 5aR inhibitor, finasteride. 5aR is essential for androgen regulation in males, both in normal conditions and disease states. The hormone kinetics and downstream effects on reproductive organs associated with perturbing androgen regulation are complex and not necessarily intuitive. Inhibition of 5aR decreases the metabolism of testosterone (T) to the potent androgen 5α-dihydrotestosterone (DHT). This results in decreased cell proliferation, fluid production and 5aR expression as well as increased apoptosis in the ventral prostate. These regulatory changes collectively result in decreased prostate size and function, which can be beneficial to men suffering from benign prostatic hyperplasia (BPH) and could play a role in prostate cancer. There are two distinct isoforms of 5aR in male humans and rats, and thus developing a 5aR inhibitor is a challenging pursuit. Several inhibitors are on the market for treatment of BPH, including finasteride and dutasteride. In this effort, comparisons of simulated vs. experimental T and DHT levels and prostate size are depicted, demonstrating the model accurately described an approximate 77% decrease in prostate size and nearly complete depletion of prostatic DHT following 21 days of daily finasteride dosing in rats. This implies T alone is not capable of maintaining a normal prostate size. Further model analysis suggests the possibility of alternative dosing strategies resulting in similar or greater effects on prostate size, due to complex kinetics between T, DHT and gene occupancy. With appropriate scaling and parameterization for humans, this model provides a multiscale modeling platform for drug discovery teams to test and generate hypotheses about drugging strategies for indications like BPH and prostate cancer, such as compound

  2. A multiscale, mechanism-driven, dynamic model for the effects of 5α-reductase inhibition on prostate maintenance.

    Directory of Open Access Journals (Sweden)

    Michael G Zager

    Full Text Available A systems-level mathematical model is presented that describes the effects of inhibiting the enzyme 5α-reductase (5aR on the ventral prostate of the adult male rat under chronic administration of the 5aR inhibitor, finasteride. 5aR is essential for androgen regulation in males, both in normal conditions and disease states. The hormone kinetics and downstream effects on reproductive organs associated with perturbing androgen regulation are complex and not necessarily intuitive. Inhibition of 5aR decreases the metabolism of testosterone (T to the potent androgen 5α-dihydrotestosterone (DHT. This results in decreased cell proliferation, fluid production and 5aR expression as well as increased apoptosis in the ventral prostate. These regulatory changes collectively result in decreased prostate size and function, which can be beneficial to men suffering from benign prostatic hyperplasia (BPH and could play a role in prostate cancer. There are two distinct isoforms of 5aR in male humans and rats, and thus developing a 5aR inhibitor is a challenging pursuit. Several inhibitors are on the market for treatment of BPH, including finasteride and dutasteride. In this effort, comparisons of simulated vs. experimental T and DHT levels and prostate size are depicted, demonstrating the model accurately described an approximate 77% decrease in prostate size and nearly complete depletion of prostatic DHT following 21 days of daily finasteride dosing in rats. This implies T alone is not capable of maintaining a normal prostate size. Further model analysis suggests the possibility of alternative dosing strategies resulting in similar or greater effects on prostate size, due to complex kinetics between T, DHT and gene occupancy. With appropriate scaling and parameterization for humans, this model provides a multiscale modeling platform for drug discovery teams to test and generate hypotheses about drugging strategies for indications like BPH and prostate cancer

  3. MRI of prostate zonal anatomy with an endorectal surface coil

    International Nuclear Information System (INIS)

    The development of an endorectal surface coil now permits a partial study of the anatomical model developed by McNeal. Axial and coronal views, which were used to establish the model can be obtained in a short period of time with fast spin echo sequences. Axial views are performed along the proximal urethra and coronal views are performed along the axis of the distal urethra and the ejaculatory duts. Anatomical boundaries of the transitional zone are well delineated on axial views, illustrating the concept of 'inner gland'. The prostatic capsule and the neuro-vascular bundles, pathways of extension of the cancer out of the prostate are also well delineated. Coronal sections allow a very good anatomical study of the caudal junction of the vas deferens and the seminal vesicles (the so called weak space), pathway of tumor extension to the seminal vesicles. Differences in signal of the prostatic zones make the outer gland cancers very conspicuous as well as some transitional cancers which can show, in some cases, an homogeneous hyposignal. (authors). 15 refs., 14 figs

  4. Initial results of a positron tomograph for prostate imaging

    Energy Technology Data Exchange (ETDEWEB)

    Huber, J.S.; Choong, W.S.; Moses, W.W.; Qi, J.; Hu, J.; Wang,G.C.; Wilson, D.; Oh, S.; Huesman, R.H.; Derenzo, S.E.; Budinger, T.F.

    2004-11-29

    We present the status and initial images of a positrontomograph for prostate imaging that centers a patient between a pair ofexternal curved detector banks (ellipse: 45 cm minor, 70 cm major axis).The distance between detector banks adjusts to allow patient access andto position the detectors as closely as possible for maximum sensitivitywith patients of various sizes. Each bank is composed of two axial rowsof 20 CTI PET Systems HR+ block detectors for a total of 80 modules inthe camera. Compared to an ECAT HR PET system operating in 3D mode, ourcamera uses about one-quarter the number of detectors and hasapproximately the same sensitivity for a central point source, becauseour detectors are close to the patient. The individual detectors areangled in the plane to point towards the prostate to minimize resolutiondegradation in that region. The detectors are read out by modified CTIdata acquisition electronics. We have completed construction of thegantry and electronics, have developed detector calibration and dataacquisition software, and are taking coincidence data. We demonstratethat we can clearly visualize a "prostate" in a simple phantom.Reconstructed images of two phantoms are shown.

  5. Prostate position relative to pelvic bony anatomy based on intraprostatic gold markers and electronic portal imaging

    International Nuclear Information System (INIS)

    Purpose: To describe the relative positions and motions of the prostate, pelvic bony anatomy, and intraprostatic gold fiducial markers during daily electronic portal localization of the prostate. Methods and Materials: Twenty prostate cancer patients were treated supine with definitive external radiotherapy according to an on-line target localization protocol using three or four intraprostatic gold fiducial markers and an electronic portal imaging device. Daily pretherapy and through-treatment electronic portal images (EPIs) were obtained for each of four treatment fields. The patients' pelvic bony anatomy, intraprostatic gold markers, and a best visual match to the target (i.e., prostate) were identified on simulation digitally reconstructed radiographs and during daily treatment setup and delivery. These data provided quantitative inter- and intrafractional analysis of prostate motion, its position relative to the bony anatomy, and the individual intraprostatic fiducial markers. Treatment planning margins, with and without on-line localization, were subsequently compared. Results: A total of 22,266 data points were obtained from daily pretherapy and through-treatment EPIs. The pretherapy three-dimensional (3D) average displacement of the fiducial markers, as a surrogate for the prostate, was 5.6 mm, which improved to 2.8 mm after use of the localization protocol. The bony anatomy 3D average displacement was 4.4 mm both before and after localization to the prostate (p = 0.46). Along the superior-inferior (SI), anterior-posterior (AP), and right-left (RL) axes, the average prostate displacement improved from 2.5, 3.7, and 1.9 mm, respectively, before localization to 1.4, 1.6, and 1.1 mm after (all p < 0.001). The pretherapy to through-treatment position of the bony landmarks worsened from 1.7 to 2.5 mm (p < 0.001) in the SI axis, remained statistically unchanged at 2.8 mm (p = 0.39) in the AP axis, and improved from 2.0 to 1.2 mm in the RL axis (p < 0.001). There

  6. Identification of prostate cancer biomarkers in urinary exosomes.

    Science.gov (United States)

    Øverbye, Anders; Skotland, Tore; Koehler, Christian J; Thiede, Bernd; Seierstad, Therese; Berge, Viktor; Sandvig, Kirsten; Llorente, Alicia

    2015-10-01

    Exosomes have recently appeared as a novel source of non-invasive cancer biomarkers since tumour-specific molecules can be found in exosomes isolated from biological fluids. We have here investigated the proteome of urinary exosomes by using mass spectrometry to identify proteins differentially expressed in prostate cancer patients compared to healthy male controls. In total, 15 control and 16 prostate cancer samples of urinary exosomes were analyzed. Importantly, 246 proteins were differentially expressed in the two groups. The majority of these proteins (221) were up-regulated in exosomes from prostate cancer patients. These proteins were analyzed according to specific criteria to create a focus list that contained 37 proteins. At 100% specificity, 17 of these proteins displayed individual sensitivities above 60%. Even though several of these proteins showed high sensitivity and specificity for prostate cancer as individual biomarkers, combining them in a multi-panel test has the potential for full differentiation of prostate cancer from non-disease controls. The highest sensitivity, 94%, was observed for transmembrane protein 256 (TM256; chromosome 17 open reading frame 61). LAMTOR proteins were also distinctly enriched with very high specificity for patient samples. TM256 and LAMTOR1 could be used to augment the sensitivity to 100%. Other prominent proteins were V-type proton ATPase 16 kDa proteolipid subunit (VATL), adipogenesis regulatory factor (ADIRF), and several Rab-class members and proteasomal proteins. In conclusion, this study clearly shows the potential of using urinary exosomes in the diagnosis and clinical management of prostate cancer.

  7. Potassium channels in prostate and colonic cancer

    OpenAIRE

    Ousingsawat, Jiraporn

    2007-01-01

    Large conductance Ca2+-activated K+ channels in human prostate cancer The KCNMA1 gene encoding the alpha-subunit of BK channels is amplified and BK channel expression is enhanced in late-stage, metastatic and hormone-refractory human prostate cancer tissues, whereas benign prostate tissues show only a weak expression of BK channels. PC-3 hormone-insensitive prostate cancer cells, but not hormone-sensitive prostate cancer cells (LNCaP) and benign prostate hyperplasia cells (BPH-1), show an ...

  8. Dystrophic calcification of the prostate after cryotherapy.

    Science.gov (United States)

    Dru, Christopher; Bender, Leon

    2014-01-01

    We present a previously undocumented complication of dystrophic calcification of the prostate after cryotherapy. An 87-year-old male presented with recurrent lower urinary tract infections and was found to have an obstructing large calcified mass in the right lobe of the prostate. Subsequently, he underwent transurethral resection of the prostate (TURP) and bladder neck with laser lithotripsy to remove the calculus. We propose that chronic inflammation and necrosis of the prostate from cryotherapy resulted in dystrophic calcification of the prostate. As the use of cryotherapy for the treatment of localized prostate cancer continues to increase, it is important that clinicians be aware of this scenario and the technical challenges it poses.

  9. Prostate resonance imaging: morphology and metabolism

    International Nuclear Information System (INIS)

    The cancer of prostate is the most frequent neoplasms and the third cause of death in men, although the average of survival of patients it improved, the cancer of prostate is an important problem in health. The majority of these tumors are of slow growth and the early detection allows high probabilities of definitive treatment. The neoplasms of prostate detected at present are smaller than the detected ones 20 years ago behind, nevertheless exist big differences in the aggressiveness of these tumors. The images are very important in the management of prostate cancer, and the magnetic resonance imaging of the prostate is a new tool in the evaluation of prostate cancer

  10. Oxidative stress in prostate hyperplasia and carcinogenesis.

    Science.gov (United States)

    Udensi, Udensi K; Tchounwou, Paul B

    2016-01-01

    Prostatic hyperplasia (PH) is a common urologic disease that affects mostly elderly men. PH can be classified as benign prostatic hyperplasia (BPH), or prostate cancer (PCa) based on its severity. Oxidative stress (OS) is known to influence the activities of inflammatory mediators and other cellular processes involved in the initiation, promotion and progression of human neoplasms including prostate cancer. Scientific evidence also suggests that micronutrient supplementation may restore the antioxidant status and hence improve the clinical outcomes for patients with BPH and PCa. This review highlights the recent studies on prostate hyperplasia and carcinogenesis, and examines the role of OS on the molecular pathology of prostate cancer progression and treatment. PMID:27609145

  11. Prostate Cancer Genetics: A Review

    Science.gov (United States)

    Wallis, Christopher J.D.

    2015-01-01

    Over the past decades, research has focussed on identifying the genetic underpinnings of prostate cancer. It has been recognized that a number of forms of genetic changes coupled with epigenetic and gene expression changes can increase the prediction to develop prostate cancer. This review outlines the role of somatic copy number alterations (SCNAs), structural rearrangements, point mutations, and single nucleotide polymorphisms (SNPs) as well as miRNAs. Identifying relevant genetic changes offers the ability to develop novel biomarkers to allow early and accurate detection of prostate cancer as well as provide risk stratification of patients following their diagnosis. The concept of personalized or individualized medicine has gained significant attention. Therefore, a better understanding of the genetic and metabolic pathways underlying prostate cancer development offers the opportunity to explore new therapeutic interventions with the possibility of offering patient-specific targeted therapy.

  12. Neuroendocrine differentiation in prostate cancer

    Institute of Scientific and Technical Information of China (English)

    Jiaoti Huang

    2008-01-01

    @@ The treatment of choice for advanced/metastatic prostate cancer(PC) is hormonal therapy. Although patients respond initially to this therapy, the tumor will recur and enter the androgen-independent state, which is the major obstacle in therapy.

  13. Prostate resection - minimally invasive - discharge

    Science.gov (United States)

    ... a burning sensation when you urinate, fever, or chills). Your urine stream is not as strong, or ... pubmed/23234640 . Roehrborn CG. Benign prostatic hyperplasia: Etiology, pathophysiology, epidemiology, and natural history. In: Wein AJ, Kavoussi ...

  14. 6 Common Cancers - Prostate Cancer

    Science.gov (United States)

    ... PSA tests. Read More "6 Common Cancers" Articles Lung Cancer / Breast Cancer / Prostate Cancer / Colorectal Cancer / Skin Cancer / Gynecologic Cancers Spring 2007 Issue: Volume 2 Number 2 Page 10 MedlinePlus | Subscribe | Magazine Information | Contact Us | Viewers & ...

  15. Contemporary Management of Prostate Cancer.

    Science.gov (United States)

    Cotter, Katherine; Konety, Badrinath; Ordonez, Maria A

    2016-01-01

    Prostate cancer represents a spectrum ranging from low-grade, localized tumors to devastating metastatic disease. We discuss the general options for treatment and recent developments in the field. PMID:26949522

  16. Multidrug Resistance in Prostate Cancer

    NARCIS (Netherlands)

    J.P. van Brussel

    2005-01-01

    textabstractAdvanced hormone refractory prostate cancer constitutes a therapeutic challenge, because all available treatment strategies have failed to substantially increase cancer specific survival. Among these strategies, a multitude of chemotherapeutic approaches did not offer a superior life

  17. Treatment Option Overview (Prostate Cancer)

    Science.gov (United States)

    ... This procedure is done to treat benign prostatic hypertrophy and it is sometimes done to relieve symptoms ... or part of the small intestine through weak muscles into the groin ). Inguinal hernia may occur more ...

  18. Enrichment of the Cancer Stem Phenotype in Sphere Cultures of Prostate Cancer Cell Lines Occurs through Activation of Developmental Pathways Mediated by the Transcriptional Regulator ΔNp63α.

    Directory of Open Access Journals (Sweden)

    Roberto Portillo-Lara

    Full Text Available Cancer stem cells (CSC drive prostate cancer tumor survival and metastasis. Nevertheless, the development of specific therapies against CSCs is hindered by the scarcity of these cells in prostate tissues. Suspension culture systems have been reported to enrich CSCs in primary cultures and cell lines. However, the molecular mechanisms underlying this phenomenon have not been fully explored.We describe a prostasphere assay for the enrichment of CD133+ CSCs in four commercial PCa cell lines: 22Rv1, DU145, LNCaP, and PC3. Overexpression of CD133, as determined by flow cytometric analysis, correlated with an increased clonogenic, chemoresistant, and invasive potential in vitro. This phenotype is concordant to that of CSCs in vivo. Gene expression profiling was then carried out using the Cancer Reference panel and the nCounter system from NanoString Technologies. This analysis revealed several upregulated transcripts that can be further explored as potential diagnostic markers or therapeutic targets. Furthermore, functional annotation analysis suggests that ΔNp63α modulates the activation of developmental pathways responsible for the increased stem identity of cells growing in suspension cultures.We conclude that profiling the genetic mechanisms involved in CSC enrichment will help us to better understand the molecular pathways that underlie CSC pathophysiology. This platform can be readily adapted to enrich and assay actual patient samples, in order to design patient-specific therapies that are aimed particularly against CSCs.

  19. Relationship between pathological characteristics of prostate cancer and MACC1, c-Met, Apaf-1 as well as Caspase-9 expression in tumor tissue

    Institute of Scientific and Technical Information of China (English)

    Hang-Yu Ai; Xue-De Qiu

    2016-01-01

    Objective:To study the MACC1, c-Met, Apaf-1 and Caspase-9 expression in prostate cancer tissue and their relationship with the pathological characteristics of tumor.Methods:Prostate cancer and benign prostatic hyperplasia patients who received surgical treatment in our hospital from May 2015 to March 2016 were selected as the research subjects, prostate cancer tissue and benign prostatic hyperplasia tissue were collected during surgery to determine MACC1, c-Met, Apaf-1 and Caspase-9 expression, and serum specimens were collected to determine miR-let7i, -32, -128, -196a and -218 expression levels.Results: mRNA content of MACC1 and c-Met in prostate cancer tissue were significantly higher than those in benign prostatic hyperplasia tissue while mRNA content of Apaf-1 and Caspase-9 were significantly lower than those in benign prostatic hyperplasia tissue, and the higher the Gleason grading and the higher the Whitmore-Prout staging, the higher the mRNA content of MACC1 and c-Met in prostate cancer tissue and the lower the mRNA content of Apaf-1 and Caspase-9; serum miR-32, miR-128 and miR-196a expression levels in prostate cancer patients were significantly higher than those in patients with benign prostatic hyperplasia and negatively correlated with the mRNA content of Apaf-1 and Caspase-9, and the expression levels of miR-let7i and miR-218 were significantly lower than those in patients with benign prostatic hyperplasia and negatively correlated with MACC1 and c-Met.Conclusion: High MACC1 and c-Met expression and low Caspase-9 and Apaf-1 expression are related to the occurrence and progression of prostate cancer, and the MACC1, c-Met, Apaf-1 and Caspase-9 expression in prostate cancer tissue are regulated by miRNAs.

  20. The SWI/SNF ATPase Brm is a gatekeeper of proliferative control in prostate cancer.

    Science.gov (United States)

    Shen, Hui; Powers, Nathan; Saini, Nitin; Comstock, Clay E S; Sharma, Ankur; Weaver, Katherine; Revelo, Monica P; Gerald, William; Williams, Erin; Jessen, Walter J; Aronow, Bruce J; Rosson, Gary; Weissman, Bernard; Muchardt, Christian; Yaniv, Moshe; Knudsen, Karen E

    2008-12-15

    Factors that drive prostate cancer progression remain poorly defined, thus hindering the development of new therapeutic strategies. Disseminated tumors are treated through regimens that ablate androgen signaling, as prostate cancer cells require androgen for growth and survival. However, recurrent, incurable tumors that have bypassed the androgen requirement ultimately arise. This study reveals that the Brm ATPase, a component of selected SWI/SNF complexes, has significant antiproliferative functions in the prostate that protect against these transitions. First, we show that targeted ablation of Brm is causative for the development of prostatic hyperplasia in mice. Second, in vivo challenge revealed that Brm-/- epithelia acquire the capacity for lobe-specific, castration-resistant cellular proliferation. Third, investigation of human specimens revealed that Brm mRNA and protein levels are attenuated in prostate cancer. Fourth, Brm down-regulation was associated with an increased proliferative index, consistent with the mouse model. Lastly, gene expression profiling showed that Brm loss alters factors upstream of E2F1; this was confirmed in murine models, wherein Brm loss induced E2F1 deregulation in a tissue-specific manner. Combined, these data identify Brm as a major effector of serum androgen-induced proliferation in the prostate that is disrupted in human disease, and indicate that loss of Brm confers a proliferative advantage in prostate cancer. PMID:19074882