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Sample records for cancer cell growth

  1. Milk stimulates growth of prostate cancer cells in culture.

    Science.gov (United States)

    Tate, Patricia L; Bibb, Robert; Larcom, Lyndon L

    2011-11-01

    Concern has been expressed about the fact that cows' milk contains estrogens and could stimulate the growth of hormone-sensitive tumors. In this study, organic cows' milk and two commercial substitutes were digested in vitro and tested for their effects on the growth of cultures of prostate and breast cancer cells. Cows' milk stimulated the growth of LNCaP prostate cancer cells in each of 14 separate experiments, producing an average increase in growth rate of over 30%. In contrast, almond milk suppressed the growth of these cells by over 30%. Neither cows' milk nor almond milk affected the growth of MCF-7 breast cancer cells or AsPC-1 pancreatic cancer cells significantly. Soy milk increased the growth rate of the breast cancer cells. These data indicate that prostate and breast cancer patients should be cautioned about the possible promotional effects of commercial dairy products and their substitutes. PMID:22043817

  2. Nonlinear Growth Kinetics of Breast Cancer Stem Cells: Implications for Cancer Stem Cell Targeted Therapy

    OpenAIRE

    Liu, Xinfeng; Johnson, Sara; Liu, Shou; Kanojia, Deepak; Yue, Wei; Singn, Udai; Wang, Qian; Wang, Qi; Nie, Qing; Chen, Hexin

    2013-01-01

    Cancer stem cells (CSCs) have been identified in primary breast cancer tissues and cell lines. The CSC population varies widely among cancerous tissues and cell lines, and is often associated with aggressive breast cancers. Despite of intensive research, how the CSC population is regulated within a tumor is still not well understood so far. In this paper, we present a mathematical model to explore the growth kinetics of CSC population both in vitro and in vivo. Our mathematical models and sup...

  3. Dihydroartemisinin is an inhibitor of ovarian cancer cell growth

    Institute of Scientific and Technical Information of China (English)

    Yang JIAO; Chun-min GE; Qing-hui MENG; Jian-ping CAO; Jian TONG; Sai-jun FAN

    2007-01-01

    Aim: To investigate the anticancer activity of dihydroartemisinin (DHA), a deriva-tive of antimalaria drug artemisinin in a panel of human ovarian cancer cell lines. Methods: Cell growth was determined by the MTT viability assay. Apoptosis and cell cycle progression were evaluated by a DNA fragmentation gel electro-phoresis, flow cytometry assay, and TUNEL assay; protein and mRNA expression were analyzed by Western blotting and RT-PCR assay. Results: Artemisinin and its derivatives, including artesunate, arteether, artemether, arteannuin, and DHA, exhibit anticancer growth activities in human ovarian cancer cells. Among them, DHA is the most effective in inhibiting cell growth. Ovarian cancer cell lines are more sensitive (5-10-fold) to DHA treatment compared to normal ovarian cell lines. DHA at micromolar dose levels exhibits a dose- and time-dependent cyto-toxicity in ovarian cancer cell lines. Furthermore, DHA induced apoptosis and G2 cell cycle arrest, accompanied by a decrease of Bcl-xL and Bcl-2 and an increase of Bax and Bad. Conclusion: The promising results show for the first time that DHA inhibits the growth of human ovarian cancer cells. The selective inhibition of ovarian cancer cell growth, apoptosis induction, and G2 arrest provide in vitro evidence for further studies of DHA as a possible anticancer drug in the clinical treatment of ovarian cancer.

  4. Nonlinear Growth Kinetics of Breast Cancer Stem Cells: Implications for Cancer Stem Cell Targeted Therapy

    Science.gov (United States)

    Liu, Xinfeng; Johnson, Sara; Liu, Shou; Kanojia, Deepak; Yue, Wei; Singn, Udai; Wang, Qian; Wang, Qi; Nie, Qing; Chen, Hexin

    2013-08-01

    Cancer stem cells (CSCs) have been identified in primary breast cancer tissues and cell lines. The CSC population varies widely among cancerous tissues and cell lines, and is often associated with aggressive breast cancers. Despite of intensive research, how the CSC population is regulated within a tumor is still not well understood so far. In this paper, we present a mathematical model to explore the growth kinetics of CSC population both in vitro and in vivo. Our mathematical models and supporting experiments suggest that there exist non-linear growth kinetics of CSCs and negative feedback mechanisms to control the balance between the population of CSCs and that of non-stem cancer cells. The model predictions can help us explain a few long-standing questions in the field of cancer stem cell research, and can be potentially used to predict the efficicacy of anti-cancer therapy.

  5. Nerve Growth Factor in Cancer Cell Death and Survival

    International Nuclear Information System (INIS)

    One of the major challenges for cancer therapeutics is the resistance of many tumor cells to induction of cell death due to pro-survival signaling in the cancer cells. Here we review the growing literature which shows that neurotrophins contribute to pro-survival signaling in many different types of cancer. In particular, nerve growth factor, the archetypal neurotrophin, has been shown to play a role in tumorigenesis over the past decade. Nerve growth factor mediates its effects through its two cognate receptors, TrkA, a receptor tyrosine kinase and p75NTR, a member of the death receptor superfamily. Depending on the tumor origin, pro-survival signaling can be mediated by TrkA receptors or by p75NTR. For example, in breast cancer the aberrant expression of nerve growth factor stimulates proliferative signaling through TrkA and pro-survival signaling through p75NTR. This latter signaling through p75NTR promotes increased resistance to the induction of cell death by chemotherapeutic treatments. In contrast, in prostate cells the p75NTR mediates cell death and prevents metastasis. In prostate cancer, expression of this receptor is lost, which contributes to tumor progression by allowing cells to survive, proliferate and metastasize. This review focuses on our current knowledge of neurotrophin signaling in cancer, with a particular emphasis on nerve growth factor regulation of cell death and survival in cancer

  6. Fentanyl inhibits cell viability in human pancreatic cancer cell line and tumor growth in pancreatic cancer cell-transplanted mice

    OpenAIRE

    Miao, Jianxia; Wang, Liangrong; Chen, Lei; Yang, Tao; Jin, Lida; Lin, Lina

    2015-01-01

    Pancreatic cancer is a kind of devastating disease with a high mortality rate. Fentanyl has been widely applied to anesthesia and analgesia in pancreatic cancer therapy, and is also demonstrated to inhibit the growth of some kinds of cancer cells in existed studies. To investigate the functions of fentanyl in pancreatic cancer, we conducted a series of in vivo and in vitro experiments using human pancreatic cancer cells SW1990 and fentanyl treatment. The cells were transplanted to BALB/c nude...

  7. FH535 inhibited metastasis and growth of pancreatic cancer cells

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    Wu MY

    2015-07-01

    Full Text Available Meng-Yao Wu,1,* Rong-Rui Liang,1,* Kai Chen,1 Meng Shen,1 Ya-Li Tian,1,2 Dao-Ming Li,1 Wei-Ming Duan,1 Qi Gui,1 Fei-Ran Gong,3 Lian Lian,1,2 Wei Li,1,6 Min Tao1,4–61Department of Oncology, The First Affiliated Hospital of Soochow University, 2Department of Oncology, Suzhou Xiangcheng People’s Hospital, 3Department of Hematology, The First Affiliated Hospital of Soochow University, 4Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, 5Institute of Medical Biotechnology, Soochow University, Suzhou, 6PREMED Key Laboratory for Precision Medicine, Soochow University, Suzhou, People’s Republic of China*These authors contributed equally to this workAbstract: FH535 is a small-molecule inhibitor of the Wnt/β-catenin signaling pathway, which a substantial body of evidence has proven is activated in various cancers, including pancreatic cancer. Activation of the Wnt/β-catenin pathway plays an important role in tumor progression and metastasis. We investigated the inhibitory effect of FH535 on the metastasis and growth of pancreatic cancer cells. Western blotting and luciferase reporter gene assay indicated that FH535 markedly inhibited Wnt/β-catenin pathway viability in pancreatic cancer cells. In vitro wound healing, invasion, and adhesion assays revealed that FH535 significantly inhibited pancreatic cancer cell metastasis. We also observed the inhibitory effect of FH535 on pancreatic cancer cell growth via the tetrazolium and plate clone formation assays. Microarray analyses suggested that changes in the expression of multiple genes could be involved in the anti-cancer effect of FH535 on pancreatic cancer cells. Our results indicate for the first time that FH535 inhibits pancreatic cancer cell metastasis and growth, providing new insight into therapy of pancreatic cancer.Keywords: pancreatic cancer, FH535, β-catenin, metastasis, growth

  8. STAMP alters the growth of transformed and ovarian cancer cells

    International Nuclear Information System (INIS)

    Steroid receptors play major roles in the development, differentiation, and homeostasis of normal and malignant tissue. STAMP is a novel coregulator that not only enhances the ability of p160 coactivator family members TIF2 and SRC-1 to increase gene induction by many of the classical steroid receptors but also modulates the potency (or EC50) of agonists and the partial agonist activity of antisteroids. These modulatory activities of STAMP are not limited to gene induction but are also observed for receptor-mediated gene repression. However, a physiological role for STAMP remains unclear. The growth rate of HEK293 cells stably transfected with STAMP plasmid and overexpressing STAMP protein is found to be decreased. We therefore asked whether different STAMP levels might also contribute to the abnormal growth rates of cancer cells. Panels of different stage human cancers were screened for altered levels of STAMP mRNA. Those cancers with the greatest apparent changes in STAMP mRNA were pursued in cultured cancer cell lines. Higher levels of STAMP are shown to have the physiologically relevant function of reducing the growth of HEK293 cells but, unexpectedly, in a steroid-independent manner. STAMP expression was examined in eight human cancer panels. More extensive studies of ovarian cancers suggested the presence of higher levels of STAMP mRNA. Lowering STAMP mRNA levels with siRNAs alters the proliferation of several ovarian cancer tissue culture lines in a cell line-specific manner. This cell line-specific effect of STAMP is not unique and is also seen for the conventional effects of STAMP on glucocorticoid receptor-regulated gene transactivation. This study indicates that a physiological function of STAMP in several settings is to modify cell growth rates in a manner that can be independent of steroid hormones. Studies with eleven tissue culture cell lines of ovarian cancer revealed a cell line-dependent effect of reduced STAMP mRNA on cell growth rates. This cell

  9. Effect of acute exercise on prostate cancer cell growth.

    Directory of Open Access Journals (Sweden)

    Helene Rundqvist

    Full Text Available Physical activity is associated with reduced risk of several cancers, including aggressive prostate cancer. The mechanisms mediating the effects are not yet understood; among the candidates are modifications of endogenous hormone levels. Long-term exercise is known to reduce serum levels of growth stimulating hormones. In contrast, the endocrine effects of acute endurance exercise include increased levels of mitogenic factors such as GH and IGF-1. It can be speculated that the elevation of serum growth factors may be detrimental to prostate cancer progression into malignancy. The incentive of the current study is to evaluate the effect of acute exercise serum on prostate cancer cell growth. We designed an exercise intervention where 10 male individuals performed 60 minutes of bicycle exercise at increasing intensity. Serum samples were obtained before (rest serum and after completed exercise (exercise serum. The established prostate cancer cell line LNCaP was exposed to exercise or rest serum. Exercise serum from 9 out of 10 individuals had a growth inhibitory effect on LNCaP cells. Incubation with pooled exercise serum resulted in a 31% inhibition of LNCaP growth and pre-incubation before subcutaneous injection into SCID mice caused a delay in tumor formation. Serum analyses indicated two possible candidates for the effect; increased levels of IGFBP-1 and reduced levels of EGF. In conclusion, despite the fear of possible detrimental effects of acute exercise serum on tumor cell growth, we show that even the short-term effects seem to add to the overall beneficial influence of exercise on neoplasia.

  10. Metformin inhibits cell growth by upregulating microRNA-26a in renal cancer cells

    OpenAIRE

    Yang, Feng-Qiang; Wang, Ji-Jiao; Yan, Jia-Sheng; Huang, Jian-Hua; Li, Wei; Che, Jian-Ping; Wang, Guang-Chun; Liu, Min; Zheng, Jun-Hua

    2014-01-01

    Accumulating evidence suggests that metformin, a biguanide class of anti-diabetic drugs, possesses anti-cancer properties and may reduce cancer risk and improve prognosis. However, the mechanism by which metformin affects various cancers, including renal cancer still unknown. MiR-26a induces cell growth, cell cycle and cell apoptosis progression via direct targeting of Bcl-2, clyclin D1 and PTEN in cancer cells. In the present study, we used 786-O human renal cancer cell lines to study the ef...

  11. Silencing NOTCH signaling causes growth arrest in both breast cancer stem cells and breast cancer cells

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    Suman, S; Das, T P; Damodaran, C

    2013-01-01

    Background: Breast cancer stem cells (BCSCs) are characterized by high aldehyde dehydrogenase (ALDH) enzyme activity and are refractory to current treatment modalities, show a higher risk for metastasis, and influence the epithelial to mesenchymal transition (EMT), leading to a shorter time to recurrence and death. In this study, we focused on examination of the mechanism of action of a small herbal molecule, psoralidin (Pso) that has been shown to effectively suppress the growth of BSCSs and breast cancer cells (BCCs), in breast cancer (BC) models. Methods: ALDH− and ALDH+ BCCs were isolated from MDA-MB-231 cells, and the anticancer effects of Pso were measured using cell viability, apoptosis, colony formation, invasion, migration, mammosphere formation, immunofluorescence, and western blot analysis. Results: Psoralidin significantly downregulated NOTCH1 signaling, and this downregulation resulted in growth inhibition and induction of apoptosis in both ALDH− and ALDH+ cells. Molecularly, Pso inhibited NOTCH1 signaling, which facilitated inhibition of EMT markers (β-catenin and vimentin) and upregulated E-cadherin expression, resulting in reduced migration and invasion of both ALDH− and ALDH+ cells. Conclusion: Together, our results suggest that inhibition of NOTCH1 by Pso resulted in growth arrest and inhibition of EMT in BCSCs and BCCs. Psoralidin appears to be a novel agent that targets both BCSCs and BCCs. PMID:24129237

  12. Matrix rigidity regulates cancer cell growth and cellular phenotype.

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    Robert W Tilghman

    Full Text Available BACKGROUND: The mechanical properties of the extracellular matrix have an important role in cell growth and differentiation. However, it is unclear as to what extent cancer cells respond to changes in the mechanical properties (rigidity/stiffness of the microenvironment and how this response varies among cancer cell lines. METHODOLOGY/PRINCIPAL FINDINGS: In this study we used a recently developed 96-well plate system that arrays extracellular matrix-conjugated polyacrylamide gels that increase in stiffness by at least 50-fold across the plate. This plate was used to determine how changes in the rigidity of the extracellular matrix modulate the biological properties of tumor cells. The cell lines tested fall into one of two categories based on their proliferation on substrates of differing stiffness: "rigidity dependent" (those which show an increase in cell growth as extracellular rigidity is increased, and "rigidity independent" (those which grow equally on both soft and stiff substrates. Cells which grew poorly on soft gels also showed decreased spreading and migration under these conditions. More importantly, seeding the cell lines into the lungs of nude mice revealed that the ability of cells to grow on soft gels in vitro correlated with their ability to grow in a soft tissue environment in vivo. The lung carcinoma line A549 responded to culture on soft gels by expressing the differentiated epithelial marker E-cadherin and decreasing the expression of the mesenchymal transcription factor Slug. CONCLUSIONS/SIGNIFICANCE: These observations suggest that the mechanical properties of the matrix environment play a significant role in regulating the proliferation and the morphological properties of cancer cells. Further, the multiwell format of the soft-plate assay is a useful and effective adjunct to established 3-dimensional cell culture models.

  13. Meloxicam inhibits the growth of colorectal cancer cells.

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    Goldman, A P; Williams, C S; Sheng, H; Lamps, L W; Williams, V P; Pairet, M; Morrow, J D; DuBois, R N

    1998-12-01

    Cyclooxygenase-2 has been reported to play an important role in colorectal carcinogenesis. The effects of meloxicam (a COX-2 inhibitor) on the growth of two colon cancer cell lines that express COX-2 (HCA-7 and Moser-S) and a COX-2 negative cell line (HCT-116) were evaluated. The growth rate of these cells was measured following treatment with meloxicam. HCA-7 and Moser-S colony size were significantly reduced following treatment with meloxicam; however, there was no significant change in HCT-116 colony size with treatment. In vivo studies were performed to evaluate the effect of meloxicam on the growth of HCA-7 cells when xenografted into nude mice. We observed a 51% reduction in tumor size after 4 weeks of treatment. Analysis of COX-1 and COX-2 protein levels in HCA-7 tumor lysates revealed a slight decrease in COX-2 expression levels in tumors taken from mice treated with meloxicam and no detectable COX-1 expression. Here we report that meloxicam significantly inhibited HCA-7 colony and tumor growth but had no effect on the growth of the COX-2 negative HCT-116 cells. PMID:9886578

  14. Total triterpenoids from Ganoderma Lucidum suppresses prostate cancer cell growth by inducing growth arrest and apoptosis.

    Science.gov (United States)

    Wang, Tao; Xie, Zi-ping; Huang, Zhan-sen; Li, Hao; Wei, An-yang; Di, Jin-ming; Xiao, Heng-jun; Zhang, Zhi-gang; Cai, Liu-hong; Tao, Xin; Qi, Tao; Chen, Di-ling; Chen, Jun

    2015-10-01

    In this study, one immortalized human normal prostatic epithelial cell line (BPH) and four human prostate cancer cell lines (LNCaP, 22Rv1, PC-3, and DU-145) were treated with Ganoderma Lucidum triterpenoids (GLT) at different doses and for different time periods. Cell viability, apoptosis, and cell cycle were analyzed using flow cytometry and chemical assays. Gene expression and binding to DNA were assessed using real-time PCR and Western blotting. It was found that GLT dose-dependently inhibited prostate cancer cell growth through induction of apoptosis and cell cycle arrest at G1 phase. GLT-induced apoptosis was due to activation of Caspases-9 and -3 and turning on the downstream apoptotic events. GLT-induced cell cycle arrest (mainly G1 arrest) was due to up-regulation of p21 expression at the early time and down-regulation of cyclin-dependent kinase 4 (CDK4) and E2F1 expression at the late time. These findings demonstrate that GLT suppresses prostate cancer cell growth by inducing growth arrest and apoptosis, which might suggest that GLT or Ganoderma Lucidum could be used as a potential therapeutic drug for prostate cancer. PMID:26489631

  15. Experimental studies on ultralow frequency pulsed gradient magnetic field inducing apoptosis of cancer cell and inhibiting growth of cancer cell

    Institute of Scientific and Technical Information of China (English)

    曾繁清; 郑从义; 张新晨; 李宗山; 李朝阳; 王川婴; 张新松; 黄晓玲; 张沪生

    2002-01-01

    The morphology characteristics of cell apoptosis of the malignant tumour cells in magnetic field-treated mouse was observed for the first time. The apoptotic cancer cell contracted, became rounder and divorced from adjacent cells; the heterochromatin condensed and coagulated together along the inner side of the nuclear membrane; the endoplasmic reticulums(ER) expanded and fused with the cellular membrane; many apoptotic bodies which were packed by the cellular membrane appeared and were devoured by some lymphocytes and plasma. Apoptosis of cancer cells was detected by terminal deoxynucleotidyl transferase mediated in situ nick end labeling(TUNEL). It was found that the number of apoptosis cancer cells of the sample treated by the magnetic field is more than that of the control sample. The growth of malignant tumour in mice was inhibited and the ability of immune cell to dissolve cancer cells was improved by ultralow frequency(ULF) pulsed gradient magnetic field; the nuclei DNA contents decreased, indicating that magnetic field can block DNA replication and inhibit mitosis of cancer cells. It was suggested that magnetic field could inhibit the metabolism of cancer cell, lower its malignancy, and restrain its rapid and heteromorphic growth. Since ULF pulsed gradient magnetic field can induce apoptosis of cancer cells and inhibit the growth of malignant tumour, it could be used as a new method to treat cancer.

  16. Teroxirone inhibited growth of human non-small cell lung cancer cells by activating p53

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    Wang, Jing-Ping; Lin, Kai-Han; Liu, Chun-Yen; Yu, Ya-Chu; Wu, Pei-Tsun [Department of Life Science, National Taiwan Normal University, Taipei, Taiwan (China); Chiu, Chien-Chih [Department of Biotechnology, Kaohsiung Medical University, Kaohsiung, Taiwan (China); Su, Chun-Li [Department of Human Development and Family Studies, National Taiwan Normal University, Taipei, Taiwan (China); Chen, Kwun-Min [Department of Chemistry, National Taiwan Normal University, Taipei, Taiwan (China); Fang, Kang, E-mail: kangfang@ntnu.edu.tw [Department of Life Science, National Taiwan Normal University, Taipei, Taiwan (China)

    2013-11-15

    In this work, we demonstrated that the growth of human non-small-cell-lung-cancer cells H460 and A549 cells can be inhibited by low concentrations of an epoxide derivative, teroxirone, in both in vitro and in vivo models. The cytotoxicity was mediated by apoptotic cell death through DNA damage. The onset of ultimate apoptosis is dependent on the status of p53. Teroxirone caused transient elevation of p53 that activates downstream p21 and procaspase-3 cleavage. The presence of caspase-3 inhibitor reverted apoptotic phenotype. Furthermore, we showed the cytotoxicity of teroxirone in H1299 cells with stable ectopic expression of p53, but not those of mutant p53. A siRNA-mediated knockdown of p53 expression attenuated drug sensitivity. The in vivo experiments demonstrated that teroxirone suppressed growth of xenograft tumors in nude mice. Being a potential therapeutic agent by restraining cell growth through apoptotic death at low concentrations, teroxirone provides a feasible perspective in reversing tumorigenic phenotype of human lung cancer cells. - Highlights: • Teroxirone repressed tumor cell growth in nude mice of human lung cancer cells. • The apoptotic cell death reverted by caspase-3 inhibitor is related to p53 status. • Teroxirone provides a good candidate for lung cancer treatment.

  17. Teroxirone inhibited growth of human non-small cell lung cancer cells by activating p53

    International Nuclear Information System (INIS)

    In this work, we demonstrated that the growth of human non-small-cell-lung-cancer cells H460 and A549 cells can be inhibited by low concentrations of an epoxide derivative, teroxirone, in both in vitro and in vivo models. The cytotoxicity was mediated by apoptotic cell death through DNA damage. The onset of ultimate apoptosis is dependent on the status of p53. Teroxirone caused transient elevation of p53 that activates downstream p21 and procaspase-3 cleavage. The presence of caspase-3 inhibitor reverted apoptotic phenotype. Furthermore, we showed the cytotoxicity of teroxirone in H1299 cells with stable ectopic expression of p53, but not those of mutant p53. A siRNA-mediated knockdown of p53 expression attenuated drug sensitivity. The in vivo experiments demonstrated that teroxirone suppressed growth of xenograft tumors in nude mice. Being a potential therapeutic agent by restraining cell growth through apoptotic death at low concentrations, teroxirone provides a feasible perspective in reversing tumorigenic phenotype of human lung cancer cells. - Highlights: • Teroxirone repressed tumor cell growth in nude mice of human lung cancer cells. • The apoptotic cell death reverted by caspase-3 inhibitor is related to p53 status. • Teroxirone provides a good candidate for lung cancer treatment

  18. Downregulation of Akt1 Inhibits Anchorage-Independent Cell Growth and Induces Apoptosis in Cancer Cells

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    Xuesong Liu

    2001-01-01

    Full Text Available The serine/threonine kinases, Akti/PKBα, Akt2/PKBβ, and Akt3/PKBγ, play a critical role in preventing cancer cells from undergoing apoptosis. However, the function of individual Akt isoforms in the tumorigenicity of cancer cells is still not well defined. In the current study, we used an AM antisense oligonucleotide (AS to specifically downregulate Akti protein in both cancer and normal cells. Our data indicate that AM AS treatment inhibits the ability of MiaPaCa-2, H460, HCT-15, and HT1080 cells to grow in soft agar. The treatment also induces apoptosis in these cancer cells as demonstrated by FRCS analysis and a caspase activity assay. Conversely, Akti AS treatment has little effect on the cell growth and survival of normal human cells including normal human fibroblast (NHF, fibroblast from muscle (FBM, and mammary gland epithelial 184135 cells. In addition, AM AS specifically sensitizes cancer cells to typical chemotherapeutic agents. Thus, Akti is indispensable for maintaining the tumorigenicity of cancer cells. Inhibition of AM may provide a powerful sensitization agent for chemotherapy specifically in cancer cells.

  19. In vitro effects of recombinant human growth hormone on growth of human gastric cancer cell line BGC823 cells

    Institute of Scientific and Technical Information of China (English)

    Jia-Yong Chen; Dao-Ming Liang; Ping Gan; Yi Zhang; Jie Lin

    2004-01-01

    AIM: To study the effects of recombinant human growth hormone (rhGH) on growth of human gastric cancer cell line in vitro.METHODS: Experiment was divided into control group,rhGH group, oxaliplatin (L-OHP) group and rhGH+L-OHP group. Cell inhibitory rate, cell cycle, cell proliferation index (PI) and DNA inhibitory rate of human gastric cancer line BGC823, at different concentrations of rhGH treatment were studied by cell culture, MTT assay and flow cytometry.RESULTS: The distinctly accelerated effects of rhGH on multiplication of BGC823 cell line were not found in vitro.There was no statistical significance between rhGH group and control group, or between rhGH+L-OHP group and LOHP group (P>0.05). The cell growth curve did not rise.Cell inhibitory rate and cells arrested in G0-G1 phase were obviously increased. Meanwhile, cells in S phase and PI were distinctly decreased and DNA inhibitory rate was obviously increased in rhGH+L-OHP group in comparison with control group and rhGH group, respectively (P<0.01).Cell inhibitory rate showed an increasing trend and PI showed a decreasing trend in rhGH+L-OHP group compared with L-OHP group.CONCLUSION: In vitro rhGH does not accelerate the multiplication of human gastric cancer cells. It may increase the therapeutic efficacy when it is used in combination with anticancer drugs.

  20. Insulin-like growth factor binding protein-5 influences pancreatic cancer cell growth

    Institute of Scientific and Technical Information of China (English)

    Sarah K Johnson; Randy S Haun

    2009-01-01

    AIM: To investigate the functional significance of insulin-like growth factor binding protein-5 (IGFBP-5) overexpression in pancreatic cancer (PaC).METHODS: The effects of IGFBP-5 on cell growth were assessed by stable transfection of BxPC-3 and PANC-1 cell lines and measuring cell number and DNA synthesis. Alterations in the cell cycle were assessed by flow cytometry and immunoblot analyses.Changes in cell survival and signal transduction were evaluated after mitogen activated protein kinase and phosphatidylinositol 3-kinase (PI3K) inhibitor treatment.RESULTS: After serum depr ivat ion, IGFBP-5 expression increased both cell number and DNA synthesis in BxPC-3 cells, but reduced cell number in PANC-1 cells. Consistent with this observation, cell cycle analysis of IGFBP-5-expressing cells revealed accelerated cell cycle progression in BxPC-3 and G2/M arrest of PANC-1 cells. Signal transduction analysis revealed that Akt activation was increased in BxPC-3, but reduced in PANC-1 cells that express IGFBP-5. Inhibition of PI3K with LY294002 suppressed extracellular signal-regulated kinase-1 and -2 (ERK1/2) activation in BxPC-3, but enhanced ERK1/2 activation in PANC-1 cells that express IGFBP-5. When MEK1/2 was blocked, Akt activation remained elevated in IGFBP-5 expressing PaC cells; however, inhibition of PI3K or MEK1/2 abrogated IGFBP-5-mediated cell survival.CONCLUSION: These results indicate that IGFBP-5 expression affects the cell cycle and survival signal pathways and thus it may be an important mediator of PaC cell growth.

  1. SRPK2 promotes the growth and migration of the colon cancer cells.

    Science.gov (United States)

    Wang, Jian; Wu, Hai-Feng; Shen, Wei; Xu, Dong-Yan; Ruan, Ting-Yan; Tao, Guo-Qing; Lu, Pei-Hua

    2016-07-15

    Colon cancer is one of the major causes of cancer-related death in the world. Understanding the molecular mechanism underlying this malignancy will facilitate the diagnosis and treatment. Serine-arginine protein kinase 2 (SRPK2) has been reported to be upregulated in several cancer types. However, its expression and functions in colon cancer remains unknown. In this study, it was found that the expression of SRPK2 was up-regulated in the clinical colon cancer samples. Overexpression of SRPK2 promoted the growth and migration of colon cancer cells, while knocking down the expression of SRPK2 inhibited the growth, migration and tumorigenecity of colon cancer cells. Molecular mechanism studies revealed that SRPK2 activated ERK signaling in colon cancer cells. Taken together, our study demonstrated the tumor promoting roles of SRPK2 in colon cancer cells and SRPK2 might be a promising therapeutic target for colon cancer. PMID:27041240

  2. Effects of space flight exposure on cell growth, tumorigenicity and gene expression in cancer cells

    Science.gov (United States)

    Yang, Cheng; Li, Yuehui; Zhang, Zhijie; Luo, Chen; Tong, Yongqing; Zhou, Guohua; Xie, Pingli; Hu, Jinyue; Li, Guancheng

    2008-12-01

    It is well recognized that harsh outer space environment, consisting of microgravity and radiation, poses significant health risks for human cells. To investigate potential effects of the space environment exposure on cancer cells we examined the biological changes in Caski cells carried by the "Shen Zhou IV" spaceship. After exposure for 7 days in spaceflight, 1440 survival subclonal cell lines were established and 4 cell lines were screened. 44F10 and 17E3 were selected because of their increased cell proliferation and tumorigenesis, while 48A9 and 31F2 had slower cytological events. Experiments with cell proliferation assay, flow cytometry, soft agar assay, tumorigenesis assay and DNA microarray analysis have shown that selected cell lines presented multiple biological changes in cell morphology, cell growth, tumorigenicity and gene expression. These results suggest that space environment exposure can make significant biological impact on cancer cells and provide an entry point to find the immunological target of tumorigenesis.

  3. Pumpkin seed extract: Cell growth inhibition of hyperplastic and cancer cells, independent of steroid hormone receptors.

    Science.gov (United States)

    Medjakovic, Svjetlana; Hobiger, Stefanie; Ardjomand-Woelkart, Karin; Bucar, Franz; Jungbauer, Alois

    2016-04-01

    Pumpkin seeds have been known in folk medicine as remedy for kidney, bladder and prostate disorders since centuries. Nevertheless, pumpkin research provides insufficient data to back up traditional beliefs of ethnomedical practice. The bioactivity of a hydro-ethanolic extract of pumpkin seeds from the Styrian pumpkin, Cucurbita pepo L. subsp. pepo var. styriaca, was investigated. As pumpkin seed extracts are standardized to cucurbitin, this compound was also tested. Transactivational activity was evaluated for human androgen receptor, estrogen receptor and progesterone receptor with in vitro yeast assays. Cell viability tests with prostate cancer cells, breast cancer cells, colorectal adenocarcinoma cells and a hyperplastic cell line from benign prostate hyperplasia tissue were performed. As model for non-hyperplastic cells, effects on cell viability were tested with a human dermal fibroblast cell line (HDF-5). No transactivational activity was found for human androgen receptor, estrogen receptor and progesterone receptor, for both, extract and cucurbitin. A cell growth inhibition of ~40-50% was observed for all cell lines, with the exception of HDF-5, which showed with ~20% much lower cell growth inhibition. Given the receptor status of some cell lines, a steroid-hormone receptor independent growth inhibiting effect can be assumed. The cell growth inhibition for fast growing cells together with the cell growth inhibition of prostate-, breast- and colon cancer cells corroborates the ethnomedical use of pumpkin seeds for a treatment of benign prostate hyperplasia. Moreover, due to the lack of androgenic activity, pumpkin seed applications can be regarded as safe for the prostate. PMID:26976217

  4. HMGCR is up-regulated in gastric cancer and promotes the growth and migration of the cancer cells.

    Science.gov (United States)

    Chushi, Li; Wei, Wu; Kangkang, Xie; Yongzeng, Feng; Ning, Xie; Xiaolei, Chen

    2016-08-01

    Alteration of metabolic profile is one of the hallmarks of cancer cells. Statin, the inhibitors for synthesis of cholesterol, has shown anti-cancer effects on the gastric cancer cells. However, the functions of its target, HMGCR, in the progression of gastric cancer remain unknown. In the present study, we investigated the expression profile and the biological functions of HMGCR in gastric cancer. It was found that the expression of HMGCR was increased in gastric cancer tissues. Over-expression of HMGCR promoted the growth and migration of gastric cancer cells, while knocking down the expression of HMGCR inhibited the growth, migration and tumorigenesis of gastric cancer cells. In the further molecular mechanism study, HMGCR was shown to activate Hedgehog/Gli1 signaling and promoted the expression of Gli1 target genes. Taken together, this study demonstrated the tumor-promoting effects of HMGCR in gastric cancer and suggested HMGCR as a promising therapeutic target. PMID:27085483

  5. Metformin inhibits cell growth by upregulating microRNA-26a in renal cancer cells.

    Science.gov (United States)

    Yang, Feng-Qiang; Wang, Ji-Jiao; Yan, Jia-Sheng; Huang, Jian-Hua; Li, Wei; Che, Jian-Ping; Wang, Guang-Chun; Liu, Min; Zheng, Jun-Hua

    2014-01-01

    Accumulating evidence suggests that metformin, a biguanide class of anti-diabetic drugs, possesses anti-cancer properties and may reduce cancer risk and improve prognosis. However, the mechanism by which metformin affects various cancers, including renal cancer still unknown. MiR-26a induces cell growth, cell cycle and cell apoptosis progression via direct targeting of Bcl-2, clyclin D1 and PTEN in cancer cells. In the present study, we used 786-O human renal cancer cell lines to study the effects and mechanisms of metformin. Metformin treatment inhibited RCC cells proliferation by increasing expression of miR-26a in 786-O cells (P metformin. Also over-expression of miR-26a can inhibited cell proliferation by down-regulating Bcl-2, cyclin D1 and up-regulating PTEN expression. Therefore, these data for the first time provide novel evidence for a mechanism that the anticancer activities of metformin are due to upregulation of miR-26a and affect its downstream target gene. PMID:25419360

  6. Curcumin induces chemo/radio-sensitization in ovarian cancer cells and curcumin nanoparticles inhibit ovarian cancer cell growth

    Directory of Open Access Journals (Sweden)

    Yallapu Murali M

    2010-04-01

    Full Text Available Abstract Background Chemo/radio-resistance is a major obstacle in treating advanced ovarian cancer. The efficacy of current treatments may be improved by increasing the sensitivity of cancer cells to chemo/radiation therapies. Curcumin is a naturally occurring compound with anti-cancer activity in multiple cancers; however, its chemo/radio-sensitizing potential is not well studied in ovarian cancer. Herein, we demonstrate the effectiveness of a curcumin pre-treatment strategy for chemo/radio-sensitizing cisplatin resistant ovarian cancer cells. To improve the efficacy and specificity of curcumin induced chemo/radio sensitization, we developed a curcumin nanoparticle formulation conjugated with a monoclonal antibody specific for cancer cells. Methods Cisplatin resistant A2780CP ovarian cancer cells were pre-treated with curcumin followed by exposure to cisplatin or radiation and the effect on cell growth was determined by MTS and colony formation assays. The effect of curcumin pre-treatment on the expression of apoptosis related proteins and β-catenin was determined by Western blotting or Flow Cytometry. A luciferase reporter assay was used to determine the effect of curcumin on β-catenin transcription activity. The poly(lactic acid-co-glycolic acid (PLGA nanoparticle formulation of curcumin (Nano-CUR was developed by a modified nano-precipitation method and physico-chemical characterization was performed by transmission electron microscopy and dynamic light scattering methods. Results Curcumin pre-treatment considerably reduced the dose of cisplatin and radiation required to inhibit the growth of cisplatin resistant ovarian cancer cells. During the 6 hr pre-treatment, curcumin down regulated the expression of Bcl-XL and Mcl-1 pro-survival proteins. Curcumin pre-treatment followed by exposure to low doses of cisplatin increased apoptosis as indicated by annexin V staining and cleavage of caspase 9 and PARP. Additionally, curcumin pre

  7. Opioid and nicotine receptors affect growth regulation of human lung cancer cell lines

    International Nuclear Information System (INIS)

    Using specific radioactively-labeled ligands, the authors find that lung cancer cell lines of diverse histologic types express multiple, high-affinity membrane receptors for μ, δ, and κ opioid agonists and for nicotine and α-bungarotoxin. These receptors are biologically active because cAMP levels decreased in lung cancer cells after opioid and nicotine application. Nicotine at concentrations found in the blood of smokers had no effect on in vitro lung cancer cell growth, whereas μ, δ, and κ opioid agonists at low concentrations inhibited lung cancer growth in vitro. They also found that lung cancer cells expressed various combinations of immunoreactive opioid peptides (β-endorphin, enkephalin, or dynorphin), suggesting the participation of opioids in a negative autocrine loop or tumor-suppressing system. Due to the almost universal exposure of patients with lung cancer to nicotine, they tested whether nicotine affected the response of lung cancer cell growth to opioids and found that nicotine at concentrations of 100-200 nM partially or totally reversed opioid-induced growth inhibition in 9/14 lung cancer cell lines. These in vitro results for lung cancer cells suggest that opioids could function as part of a tumor suppressor system and that nicotine can function to circumvent this system in the pathogenesis of lung cancer

  8. Somatostatin receptor-1 induces cell cycle arrest and inhibits tumor growth in pancreatic cancer.

    Science.gov (United States)

    Li, Min; Wang, Xiaochi; Li, Wei; Li, Fei; Yang, Hui; Wang, Hao; Brunicardi, F Charles; Chen, Changyi; Yao, Qizhi; Fisher, William E

    2008-11-01

    Functional somatostatin receptors (SSTR) are lost in human pancreatic cancer. Transfection of SSTR-1 inhibited pancreatic cancer cell proliferation in vitro. We hypothesize that stable transfection of SSTR-1 may inhibit pancreatic cancer growth in vivo possibly through cell cycle arrest. In this study, we examined the expression of SSTR-1 mRNA in human pancreatic cancer tissue specimens, and investigated the effect of SSTR-1 overexpression on cell proliferation, cell cycle, and tumor growth in a subcutaneous nude mouse model. We found that SSTR-1 mRNA was downregulated in the majority of pancreatic cancer tissue specimens. Transfection of SSTR-1 caused cell cycle arrest at the G(0)/G(1) growth phase, with a corresponding decline of cells in the S (mitotic) phase. The overexpression of SSTR-1 significantly inhibited subcutaneous tumor size by 71% and 43% (n = 5, P < 0.05, Student's t-test), and inhibited tumor weight by 69% and 47% (n = 5, P < 0.05, Student's t-test), in Panc-SSTR-1 and MIA-SSTR-1 groups, respectively, indicating the potent inhibitory effect of SSTR-1 on pancreatic cancer growth. Our data demonstrate that overexpression of SSTR-1 significantly inhibits pancreatic cancer growth possibly through cell cycle arrest. This study suggests that gene therapy with SSTR-1 may be a potential adjuvant treatment for pancreatic cancer. PMID:18823376

  9. Eugenol and its synthetic analogues inhibit cell growth of human cancer cells (Part I)

    Energy Technology Data Exchange (ETDEWEB)

    Carrasco A, H.; Cardona, W. [Universidad Andres Bello, Vina del Mar (Chile). Dept. de Ciencias Quimicas]. E-mail: hcarrasco@unab.cl; Espinoza C, L.; Gallardo, C.; Catalan M, K. [Universidad Tecnica Federico Santa Maria, Valparaiso (Chile). Dept. de Quimica; Cardile, V.; Lombardo, L. [University of Catania (Italy). Dept. of Physiological Sciences; Cuellar F, M. [Universidad de Valparaiso (Chile). Facultad de Farmacia; Russo, A. [University of Catania (Italy). Dept. of Biological Chemistry, Medical Chemistry and Molecular Biology

    2008-07-01

    Eugenol (4-allyl-2-methoxyphenol) (1) has been reported to possess antioxidant and anticancer properties. In an attempt to enhance intrinsic activity of this natural compound, some derivatives were synthesized. Eugenol was extracted from cloves oil and further, the eugenol analogues (2-6) were obtained through acetylation and nitration reactions. Eugenol (1) and its analogues (2-6) were examined by in vitro model of cancer using two human cancer cell lines: DU-145 (androgeninsensitive prostate cancer cells) and KB (oral squamous carcinoma cells). Cell viability, by tetrazolium salts assay, was measured. Lactic dehydrogenase (LDH) release was also investigated to evaluate the presence of cell toxicity as a result of cell disruption, subsequent to membrane rupture. In the examined cancer cells, all compounds showed cell-growth inhibition activity. The obtained results demonstrate that the compounds 5-allyl-3-nitrobenzene-1,2-diol (3) and 4-allyl- 2-methoxy-5-nitrophenyl acetate (5) were significantly (p < 0,001) more active than eugenol, with IC{sub 50} values in DU-145 cells of 19.02 x 10{sup -6} and 21.5 x 10{sup -6} mol L{sup -1}, respectively, and in KB cells of 18.11 x 10{sup -6} and 21.26 x 10{sup -6} mol L{sup -1}, respectively, suggesting that the presence of nitro and hydroxyl groups could be important in the activity of these compounds. In addition, our results seem to indicate that apoptotic cell demise appears to be induced in KB and DU-145 cells. In fact, in our experimental conditions, no statistically significant increase in LDH release was observed in cancer cells treated with eugenol and its analogues. (author)

  10. Eugenol and its synthetic analogues inhibit cell growth of human cancer cells (Part I)

    International Nuclear Information System (INIS)

    Eugenol (4-allyl-2-methoxyphenol) (1) has been reported to possess antioxidant and anticancer properties. In an attempt to enhance intrinsic activity of this natural compound, some derivatives were synthesized. Eugenol was extracted from cloves oil and further, the eugenol analogues (2-6) were obtained through acetylation and nitration reactions. Eugenol (1) and its analogues (2-6) were examined by in vitro model of cancer using two human cancer cell lines: DU-145 (androgeninsensitive prostate cancer cells) and KB (oral squamous carcinoma cells). Cell viability, by tetrazolium salts assay, was measured. Lactic dehydrogenase (LDH) release was also investigated to evaluate the presence of cell toxicity as a result of cell disruption, subsequent to membrane rupture. In the examined cancer cells, all compounds showed cell-growth inhibition activity. The obtained results demonstrate that the compounds 5-allyl-3-nitrobenzene-1,2-diol (3) and 4-allyl- 2-methoxy-5-nitrophenyl acetate (5) were significantly (p 50 values in DU-145 cells of 19.02 x 10-6 and 21.5 x 10-6 mol L-1, respectively, and in KB cells of 18.11 x 10-6 and 21.26 x 10-6 mol L-1, respectively, suggesting that the presence of nitro and hydroxyl groups could be important in the activity of these compounds. In addition, our results seem to indicate that apoptotic cell demise appears to be induced in KB and DU-145 cells. In fact, in our experimental conditions, no statistically significant increase in LDH release was observed in cancer cells treated with eugenol and its analogues. (author)

  11. Benzimidazoles diminish ERE transcriptional activity and cell growth in breast cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Payton-Stewart, Florastina [Department of Chemistry, College of Arts and Sciences, Xavier University of Louisiana, New Orleans, LA (United States); Tilghman, Syreeta L. [Division of Basic Pharmaceutical Sciences, College of Pharmacy, Xavier University of Louisiana, New Orleans, LA (United States); Williams, LaKeisha G. [Division of Clinical and Administrative Sciences, College of Pharmacy Xavier University of Louisiana, New Orleans, LA (United States); Winfield, Leyte L., E-mail: lwinfield@spelman.edu [Department of Chemistry, Spelman College, Atlanta, GA (United States)

    2014-08-08

    Highlights: • The methyl-substituted benzimidazole was more effective at inhibiting growth in MDA-MB 231 cells. • The naphthyl-substituted benzimidazole was more effective at inhibiting growth in MCF-7 cells than ICI. • The benzimidazole molecules demonstrated a dose-dependent reduction in ERE transcriptional activity. • The benzimidazole molecules had binding mode in ERα and ERβ comparable to that of the co-crystallized ligand. - Abstract: Estrogen receptors (ERα and ERβ) are members of the nuclear receptor superfamily. They regulate the transcription of estrogen-responsive genes and mediate numerous estrogen related diseases (i.e., fertility, osteoporosis, cancer, etc.). As such, ERs are potentially useful targets for developing therapies and diagnostic tools for hormonally responsive human breast cancers. In this work, two benzimidazole-based sulfonamides originally designed to reduce proliferation in prostate cancer, have been evaluated for their ability to modulate growth in estrogen dependent and independent cell lines (MCF-7 and MDA-MB 231) using cell viability assays. The molecules reduced growth in MCF-7 cells, but differed in their impact on the growth of MDA-MB 231 cells. Although both molecules reduced estrogen response element (ERE) transcriptional activity in a dose dependent manner, the contrasting activity in the MDA-MB-231 cells seems to suggest that the molecules may act through alternate ER-mediated pathways. Further, the methyl analog showed modest selectivity for the ERβ receptor in an ER gene expression array panel, while the naphthyl analog did not significantly alter gene expression. The molecules were docked in the ligand binding domains of the ERα-antagonist and ERβ-agonist crystal structures to evaluate the potential of the molecules to interact with the receptors. The computational analysis complimented the results obtained in the assay of transcriptional activity and gene expression suggesting that the molecules

  12. Endothelial cells stimulate growth of normal and cancerous breast epithelial cells in 3D culture

    Directory of Open Access Journals (Sweden)

    Magnusson Magnus K

    2010-07-01

    Full Text Available Abstract Background Epithelial-stromal interaction provides regulatory signals that maintain correct histoarchitecture and homeostasis in the normal breast and facilitates tumor progression in breast cancer. However, research on the regulatory role of the endothelial component in the normal and malignant breast gland has largely been neglected. The aim of the study was to investigate the effects of endothelial cells on growth and differentiation of human breast epithelial cells in a three-dimensional (3D co-culture assay. Methods Breast luminal and myoepithelial cells and endothelial cells were isolated from reduction mammoplasties. Primary cells and established normal and malignant breast cell lines were embedded in reconstituted basement membrane in direct co-culture with endothelial cells and by separation of Transwell filters. Morphogenic and phenotypic profiles of co-cultures was evaluated by phase contrast microscopy, immunostaining and confocal microscopy. Results In co-culture, endothelial cells stimulate proliferation of both luminal- and myoepithelial cells. Furthermore, endothelial cells induce a subpopulation of luminal epithelial cells to form large acini/ducts with a large and clear lumen. Endothelial cells also stimulate growth and cloning efficiency of normal and malignant breast epithelial cell lines. Transwell and gradient co-culture studies show that endothelial derived effects are mediated - at least partially - by soluble factors. Conclusion Breast endothelial cells - beside their role in transporting nutrients and oxygen to tissues - are vital component of the epithelial microenvironment in the breast and provide proliferative signals to the normal and malignant breast epithelium. These growth promoting effects of endothelial cells should be taken into consideration in breast cancer biology.

  13. Expression of the epidermal growth factor receptor in human small cell lung cancer cell lines

    DEFF Research Database (Denmark)

    Damstrup, L; Rygaard, K; Spang-Thomsen, M; Poulsen, H S

    1992-01-01

    Epidermal growth factor (EGF) receptor expression was evaluated in a panel of 21 small cell lung cancer cell lines with radioreceptor assay, affinity labeling, and Northern blotting. We found high-affinity receptors to be expressed in 10 cell lines. Scatchard analysis of the binding data...... lung cancer cell lines express the EGF receptor....... demonstrated that the cells bound between 3 and 52 fmol/mg protein with a KD ranging from 0.5 x 10(-10) to 2.7 x 10(-10) M. EGF binding to the receptor was confirmed by affinity-labeling EGF to the EGF receptor. The cross-linked complex had a M(r) of 170,000-180,000. Northern blotting showed the expression of...

  14. Members of the heat-shock protein 70 family promote cancer cell growth by distinct mechanisms

    DEFF Research Database (Denmark)

    Rohde, Mikkel; Daugaard, Mads; Jensen, Mette Hartvig;

    2005-01-01

    Whereas the stress-inducible heat-shock protein 70 (Hsp70) has gained plenty of attention as a putative target for tumor therapy, little is known about the role of other Hsp70 proteins in cancer. Here we present the first thorough analysis of the expression and function of the cytosolic Hsp70...... survival of tumorigenic as well as nontumorigenic cells depended on Hsc70. Cancer cells depleted for Hsp70 and Hsp70-2 displayed strikingly different morphologies (detached and round vs. flat senescent-like), cell cycle distributions (G2/M vs. G1 arrest) and gene expression profiles. Only Hsp70-2 depletion...... proteins in human cancer cells and identify Hsp70-2, a protein essential for spermatogenesis, as an important regulator of cancer cell growth. Targeted knock-down of the individual family members by RNA interference revealed that both Hsp70 and Hsp70-2 were required for cancer cell growth, whereas the...

  15. Vitamin K2-derived compounds induce growth inhibition in radioresistant cancer cells.

    Science.gov (United States)

    Amalia, Helfi; Sasaki, Ryohei; Suzuki, Yoko; Demizu, Yusuke; Bito, Toshinori; Nishimura, Hideki; Okamoto, Yoshiaki; Yoshida, Kenji; Miyawaki, Daisuke; Kawabe, Tetsuya; Mizushina, Yoshiyuki; Sugimura, Kazuro

    2010-01-01

    A strategy to overcome radioresistance in cancer treatment has been expected. To evaluate the strategy, appropriate experimental models are needed. Radioresistant tumour models were originally established from human colon cancer cells, and we evaluated their molecular basis. Next, the growth inhibitory effects of newly synthesized vitamin K2 (VK2)-related compounds were tested. Here, we showed that these novel compounds have growth inhibitory effects not only on cancer cells of various origins, but also on radioresistant cells, through the generation of reactive oxygen species (ROS). Human colon, lung, and breast cancer cell lines were used for testing the growth inhibitory activities of several chemical compounds. Radioresistant tumour models were established by fractionated radiation exposure. Irradiated cells were selected by a single cell cloning method, and their sensitivity to ionizing radiation was evaluated by a colony-forming assay. The VK2 derivatives (named MQ-1, MQ-2, and MQ-3) were chemically synthesized. To evaluate the generation of ROS, flow cytometer analyses were performed. A radioresistant tumour model was established from the HCT116 human colon cancer cell line. The radioresistant cells from HCT116 also showed resistance to cisplatin. In the radioresistant cells, NF-κB was highly activated. MQ-1, MQ-2, and MQ-3 showed greater growth inhibitory activities than VK2 not only in various cancer cells but also in radioresistant cells through the generation of ROS. In conclusion, a radioresistant tumour model was originally established from colon cancer cell lines through NF-κB activation, and it could be a useful tool for evaluating anti-tumour agents. Newly synthesized VK2 derivatives (MQ-1, MQ-2 and MQ-3) seemed to be potential anti-tumour agents in various cancers and radioresistant cancers. The efficacy of those compounds was related to the generation of ROS. These findings together might pave the way for the treatment of radioresistant or

  16. Expression of a hyperactive androgen receptor leads to androgen-independent growth of prostate cancer cells.

    Science.gov (United States)

    Hsieh, Chen-Lin; Cai, Changmeng; Giwa, Ahmed; Bivins, Aaronica; Chen, Shao-Yong; Sabry, Dina; Govardhan, Kumara; Shemshedini, Lirim

    2008-07-01

    Cellular changes that affect the androgen receptor (AR) can cause prostate cancer to transition from androgen dependent to androgen independent, which is usually lethal. One common change in prostate tumors is overexpression of the AR, which has been shown to lead to androgen-independent growth of prostate cancer cells. This led us to hypothesize that expression of a hyperactive AR would be sufficient for androgen-independent growth of prostate cancer cells. To test this hypothesis, stable lune cancer prostate (LNCaP) cell lines were generated, which express a virion phosphoprotein (VP)16-AR hybrid protein that contains full-length AR fused to the strong viral transcriptional activation domain VP16. This fusion protein elicited as much as a 20-fold stronger transcriptional activity than the natural AR. Stable expression of VP16-AR in LNCaP cells yielded androgen-independent cell proliferation, while under the same growth conditions the parental LNCaP cells exhibited only androgen-dependent growth. These results show that expression of a hyperactive AR is sufficient for androgen-independent growth of prostate cancer cells. To study the molecular basis of this enhanced growth, we measured the expression of soluble guanylyl cyclase-alpha1 (sGCalpha1), a subunit of the sGC, an androgen-regulated gene that has been shown to be involved in prostate cancer cell growth. Interestingly, the expression of sGCalpha1 is androgen independent in VP16-AR-expressing cells, in contrast to its androgen-induced expression in control LNCaP cells. RNA(I)-dependent inhibition of sGCalpha1 expression resulted in significantly reduced proliferation of VP16-AR cells, implicating an important role for sGCalpha1 in the androgen-independent growth of these cells. PMID:18469090

  17. The subcellular localization of IGFBP5 affects its cell growth and migration functions in breast cancer

    OpenAIRE

    Sahin Aysegul; Hu Limei; Akkiprik Mustafa; Hao Xishan; Zhang Wei

    2009-01-01

    Abstract Background Insulin-like growth factor binding protein 5 (IGFBP5) has been shown to be associated with breast cancer metastasis in clinical marker studies. However, a major difficulty in understanding how IGFBP5 functions in this capacity is the paradoxical observation that ectopic overexpression of IGFBP5 in breast cancer cell lines results in suppressed cellular proliferation. In cancer tissues, IGFBP5 resides mainly in the cytoplasm; however, in transfected cells, IGFBP5 is mainly ...

  18. Growth dynamics of cancer cell colonies and their comparison with noncancerous cells

    Science.gov (United States)

    Huergo, M. A. C.; Pasquale, M. A.; González, P. H.; Bolzán, A. E.; Arvia, A. J.

    2012-01-01

    The two-dimensional (2D) growth dynamics of HeLa (cervix cancer) cell colonies was studied following both their growth front and the pattern morphology evolutions utilizing large population colonies exhibiting linearly and radially spreading fronts. In both cases, the colony profile fractal dimension was df=1.20±0.05 and the growth fronts displaced at the constant velocity 0.90±0.05 μm min-1. Colonies showed changes in both cell morphology and average size. As time increased, the formation of large cells at the colony front was observed. Accordingly, the heterogeneity of the colony increased and local driving forces that set in began to influence the dynamics of the colony front. The dynamic scaling analysis of rough colony fronts resulted in a roughness exponent α = 0.50±0.05, a growth exponent β = 0.32±0.04, and a dynamic exponent z=1.5±0.2. The validity of this set of scaling exponents extended from a lower cutoff lc≈60 μm upward, and the exponents agreed with those predicted by the standard Kardar-Parisi-Zhang continuous equation. HeLa data were compared with those previously reported for Vero cell colonies. The value of df and the Kardar-Parisi-Zhang-type 2D front growth dynamics were similar for colonies of both cell lines. This indicates that the cell colony growth dynamics is independent of the genetic background and the tumorigenic nature of the cells. However, one can distinguish some differences between both cell lines during the growth of colonies that may result from specific cooperative effects and the nature of each biosystem.

  19. Growth-inhibitory Effects of Curcumin on Ovary Cancer Cells and Its Mechanisms

    Institute of Scientific and Technical Information of China (English)

    郑丽端; 童强松; 吴翠环

    2004-01-01

    Summary: To study the growth-inhibitory ettects ot curcumin on human ovary cancer A2780 cells in vitro and its molecular mechanisms, the growth inhibition rates of A2780 cancer cells, after being treated with 10 μmol/L-50 μmol/L curcumin for 6-24 h, were examined by MTT method. The morphological changes of cancer cells were observed under inversion microscopy. Cellular apoptotic rates were determined by using TUNEL. The protein expression levels of bcl-2, p53 and MDM2 in cancer cells were examined by SP immunohistochemistry. After being treated by various concentrations of curcumin, the growth of cancer cells was inhibited significantly. Some cancer cells presented characteristic morphological changes of apoptosis. The rates of apoptosis were 6.41% -28.48% (P<0.01). The expression of bcl-2 and p53 was decreased, which depended on the action time (P<0.01). There were no obvious changes in MDM2 expression. It was concluded that curcumin could significantly inhibit the growth of ovary cancer cells. The induction of apoptosis by down-regulating the expression of bcl-2 and p53 was probably one of its molecular mechanisms.

  20. Survivin gene silencing sensitizes prostate cancer cells to selenium growth inhibition

    International Nuclear Information System (INIS)

    Prostate cancer is a leading cause of cancer-related death in men worldwide. Survivin is a member of the inhibitor of apoptosis (IAP) protein family that is expressed in the majority of human tumors including prostate cancer, but is barely detectable in terminally differentiated normal cells. Downregulation of survivin could sensitize prostate cancer cells to chemotherapeutic agents in vitro and in vivo. Selenium is an essential trace element. Several studies have shown that selenium compounds inhibit the growth of prostate cancer cells. The objective of this study is to investigate whether survivin gene silencing in conjunction with selenium treatment could enhance the therapeutic efficacy for prostate cancer and to elucidate the underlying mechanisms. Expression of survivin was analyzed in a collection of normal and malignant prostatic tissues by immunohistochemical staining. In vitro studies were conducted in PC-3M, C4-2B, and 22Rv1 prostate cancer cells. The effect of selenium on survivin expression was analyzed by Western blotting and semi-quantitative RT-PCR. Survivin gene knockdown was carried out by transfecting cells with a short hairpin RNA (shRNA) designed against survivin. Cell proliferation was quantitated by the 3-(4,5-Dimethylthiazol-2-yl)- 2,5-Diphenyltetrazolium Bromide (MTT) assay and apoptosis by propidium iodide staining followed by flow cytometry analysis. Finally, in vivo tumor growth assay was performed by establishing PC-3M xenograft in nude mice and monitoring tumor growth following transfection and treatment. We found that survivin was undetectable in normal prostatic tissues but was highly expressed in prostate cancers. Survivin knockdown or selenium treatment inhibited the growth of prostate cancer cells, but the selenium effect was modest. In contrast to what have been observed in other cell lines, selenium treatment had little or no effect on survivin expression in several androgen-independent prostate cancer cell lines. Survivin

  1. The Inhibitory Effect of Oridonin on the Growth of Fifteen Human Cancer Cell Lines

    Institute of Scientific and Technical Information of China (English)

    Junhui Chen; Shaobin Wang; Dongyang Chen; Guisheng Chang; Qingfeng Xin; Shoujun Yuan; Zhongying Shen

    2007-01-01

    OBJECTIVE To study the inhibitory effect of oridonin on the growth of cancer cells.METHODS Fifteen human cancer cell lines were subjected to various concentrations of oridonin in culture medium.The inhibitory rate of cell growth was measured by the MTT assay.and compared with a negative control and 5-Fu-positive control.RESULTS The 50% inhibiting concentration (IC50) and maximal inhibi tion (Imax) of oridonin shown by studying the growth of the cancer cell lines were as follows:leukemias (HL60 cells:3.9 μg/ml and 73.8%.K562 cells:4.3 μg/ml and 76.2%):esophageal cancers (SHEEC cells:15.4 μg/ml and 99.2%,Eca109 cells:15.1 μg/ml and 84.6%,TE1 cells:4.0 μg/ml and 70.2%):gastric cancers (BGC823 cells:7.6 μg/ml and 98.7%,SGC7901 cells:12.3 μg/ml and 85.7%):colon cancers (HT29 cells:13.6 μg/ml and 97.2%,HCT cells:14.5 μg/ml and 96.5%):liver cancers (Bel7402 cells:15.2 μg/ml and 89.2%,HepG2 cells:7.1 μg/ml and 88.3%):pancreatic cancer (PC3 cells:11.3 μg/ml and 68.4%):lung cancer (A549 cells:18.6 μg/ml and 98.0%):breast cancer (MCF7 cells:18.4 μg/ml and 84.7%):uterine cervix cancer (Hela cells:13.7μg/ml and 98.5%).CONCLUSION Oridonin had a relatively wide anti-tumor spectrum,and a relatively strong inhibitory effect on the growth of the 15 human cancer cells.Inhibitory effects were concentration dependent.

  2. Amygdalin Blocks Bladder Cancer Cell Growth In Vitro by Diminishing Cyclin A and cdk2

    OpenAIRE

    Jasmina Makarević; Jochen Rutz; Eva Juengel; Silke Kaulfuss; Michael Reiter; Igor Tsaur; Georg Bartsch; Axel Haferkamp; Blaheta, Roman A.

    2014-01-01

    Amygdalin, a natural compound, has been used by many cancer patients as an alternative approach to treat their illness. However, whether or not this substance truly exerts an anti-tumor effect has never been settled. An in vitro study was initiated to investigate the influence of amygdalin (1.25-10 mg/ml) on the growth of a panel of bladder cancer cell lines (UMUC-3, RT112 and TCCSUP). Tumor growth, proliferation, clonal growth and cell cycle progression were investigated. The cell cycle regu...

  3. Nerve growth factor: role in growth, differentiation and controlling cancer cell development.

    Science.gov (United States)

    Aloe, Luigi; Rocco, Maria Luisa; Balzamino, Bijorn Omar; Micera, Alessandra

    2016-01-01

    Recent progress in the Nerve Growth Factor (NGF) research has shown that this factor acts not only outside its classical domain of the peripheral and central nervous system, but also on non-neuronal and cancer cells. This latter observation has led to divergent hypothesis about the role of NGF, its specific distribution pattern within the tissues and its implication in induction as well as progression of carcinogenesis. Moreover, other recent studies have shown that NGF has direct clinical relevance in certain human brain neuron degeneration and a number of human ocular disorders. These studies, by suggesting that NGF is involved in a plethora of physiological function in health and disease, warrant further investigation regarding the true role of NGF in carcinogenesis. Based on our long-lasting experience in the physiopathology of NGF, we aimed to review previous and recent in vivo and in vitro NGF studies on tumor cell induction, progression and arrest. Overall, these studies indicate that the only presence of NGF is unable to generate cell carcinogenesis, both in normal neuronal and non-neuronal cells/tissues. However, it cannot be excluded the possibility that the co-expression of NGF and pro-carcinogenic molecules might open to different consequence. Whether NGF plays a direct or an indirect role in cell proliferation during carcinogenesis remains to demonstrate. PMID:27439311

  4. Methylselenol, a selenium metabolite, inhibits colon cancer cell growth and cancer xenografts in C57BL/6 mice

    Science.gov (United States)

    Data indicate that methylselenol is a critical selenium (Se) metabolite for anticancer activity in vivo but its role in colon cancer prevention remains to be characterized. This study tested the hypothesis that methylselenol inhibits the growth of colon cancer cells and tumors. We found that submicr...

  5. Growth Inhibitory and Apoptosis-inducing Effects of Xanthohumol, a Prenylated Chalcone Present in Hops, in Human Prostate Cancer Cells

    OpenAIRE

    DEEB, D.; Gao, X; Jiang, H.; Arbab, A.S.; Dulchavsky, S. A.; Gautam, S.C.

    2010-01-01

    Promotion of apoptosis in cancer cells could potentially lead to the regression and improved prognosis of hormone-refractory prostate cancer. Xanthohumol (XN), a prenylated chalcone-derived from hops, has shown strong antitumorigenic activity towards diverse types of cancer cells. In the present study, the growth-inhibitory and apoptosis-inducing activity of XN was tested in hormone-sensitive and hormone-refractory human prostate cancer cells lines. Cell growth/viability assay (MTS) demonstra...

  6. Functional characterization of Trip10 in cancer cell growth and survival

    Directory of Open Access Journals (Sweden)

    Yan Pearlly S

    2011-02-01

    Full Text Available Abstract Background The Cdc42-interacting protein-4, Trip10 (also known as CIP4, is a multi-domain adaptor protein involved in diverse cellular processes, which functions in a tissue-specific and cell lineage-specific manner. We previously found that Trip10 is highly expressed in estrogen receptor-expressing (ER+ breast cancer cells. Estrogen receptor depletion reduced Trip10 expression by progressively increasing DNA methylation. We hypothesized that Trip10 functions as a tumor suppressor and may be involved in the malignancy of ER-negative (ER- breast cancer. To test this hypothesis and evaluate whether Trip10 is epigenetically regulated by DNA methylation in other cancers, we evaluated DNA methylation of Trip10 in liver cancer, brain tumor, ovarian cancer, and breast cancer. Methods We applied methylation-specific polymerase chain reaction and bisulfite sequencing to determine the DNA methylation of Trip10 in various cancer cell lines and tumor specimens. We also overexpressed Trip10 to observe its effect on colony formation and in vivo tumorigenesis. Results We found that Trip10 is hypermethylated in brain tumor and breast cancer, but hypomethylated in liver cancer. Overexpressed Trip10 was associated with endogenous Cdc42 and huntingtin in IMR-32 brain tumor cells and CP70 ovarian cancer cells. However, overexpression of Trip10 promoted colony formation in IMR-32 cells and tumorigenesis in mice inoculated with IMR-32 cells, whereas overexpressed Trip10 substantially suppressed colony formation in CP70 cells and tumorigenesis in mice inoculated with CP70 cells. Conclusions Trip10 regulates cancer cell growth and death in a cancer type-specific manner. Differential DNA methylation of Trip10 can either promote cell survival or cell death in a cell type-dependent manner.

  7. Plumbagin attenuates cancer cell growth and osteoclast formation in the bone microenvironment of mice

    OpenAIRE

    Yan, Wei; Wang, Ting-Yu; Fan, Qi-ming; Du, Lin; Xu, Jia-ke; Zhai, Zan-jing; Li, Hao-wei; Tang, Ting-ting

    2014-01-01

    Aim: To investigate the effects of plumbagin, a naphthoquinone derived from the medicinal plant Plumbago zeylanica, on human breast cancer cell growth and the cancer cell-induced osteolysis in the bone microenvironment of mice. Methods: Human breast cancer cell subline MDA-MB-231SA with the ability to spread and grow in the bone was tested. The cell proliferation was determined using the CCK-8 assay. Apoptosis was detected with Annexin V/PI double-labeled flow cytometry. Red fluorescent prote...

  8. Growth inhibiting effects of terazosin on androgen-independent prostate cancer cell lines

    Institute of Scientific and Technical Information of China (English)

    许克新; 王向红; 凌明达; 王云川

    2003-01-01

    Objective To study the effects of an α1-adrenoceptor antagonist, terazosin on the androgen-independent prostate cancer cell lines PC-3 and DU145.Methods Two androgen independent cell lines, PC-3 and DU145, were used to determine cell viability, colony-forming ability, as well as cell cycle distribution, after exposure to terazosin. Western blot analysis was used to determine the expression of p21WAF1 and p27KIP1.Results This study shows that terazosin inhibits not only prostate cancer cell growth but also its colony forming ability, both of which are main targets of clinical treatment. In addition, terazosin is shown to inhibit cell growth through G1 phase cell cycle arrest and the up-regulation of p27KIP1.Conclusion This study provides evidence that the α1-adrenoceptor antagonist terazosin may have therapeutic potential in the treatment of advanced hormone refractory prostate cancer.

  9. A novel peptide sansalvamide analogue inhibits pancreatic cancer cell growth through G0/G1 cell-cycle arrest

    International Nuclear Information System (INIS)

    Patients with pancreatic cancer have little hope for cure because no effective therapies are available. Sansalvamide A is a cyclic depsipeptide produced by a marine fungus. We investigated the effect of a novel sansalvamide A analogue on growth, cell-cycle phases, and induction of apoptosis in human pancreatic cancer cells in vitro. The sansalvamide analogue caused marked time- and concentration-dependent inhibition of DNA synthesis and cell proliferation of two human pancreatic cancer cell lines (AsPC-1 and S2-013). The analogue induced G0/G1 phase cell-cycle arrest and morphological changes suggesting induction of apoptosis. Apoptosis was confirmed by annexin V binding. This novel sansalvamide analogue inhibits growth of pancreatic cancer cells through G0/G1 arrest and induces apoptosis. Sansalvamide analogues may be valuable for the treatment of pancreatic cancer

  10. Fatty acid control of growth of human cervical and endometrial cancer cells.

    OpenAIRE

    Gleeson, R P; Ayub, M.; Wright, J T; Wood, C B; Habib, N.A.; Soutter, W P; Sullivan, M. H.; White, J. O.

    1990-01-01

    Stearic acid and iodo-stearic and inhibited cell growth in a cervical cancer cell line (HOG-1) in a dose-related manner, with a half maximal effect at 50 microM stearic acid. Addition of oleic acid abrogated the effect of stearic acid. EGF-stimulated DNA synthesis and growth of HOG-1 cells was inhibited in the presence of stearic acid without any apparent effect on EGF receptor number or affinity.

  11. Cancer Stem Cell Plasticity as Tumor Growth Promoter and Catalyst of Population Collapse

    Directory of Open Access Journals (Sweden)

    Jan Poleszczuk

    2016-01-01

    Full Text Available It is increasingly argued that cancer stem cells are not a cellular phenotype but rather a transient state that cells can acquire, either through intrinsic signaling cascades or in response to environmental cues. While cancer stem cell plasticity is generally associated with increased aggressiveness and treatment resistance, we set out to thoroughly investigate the impact of different rates of plasticity on early and late tumor growth dynamics and the response to therapy. We develop an agent-based model of cancer stem cell driven tumor growth, in which plasticity is defined as a spontaneous transition between stem and nonstem cancer cell states. Simulations of the model show that plasticity can substantially increase tumor growth rate and invasion. At high rates of plasticity, however, the cells get exhausted and the tumor will undergo spontaneous remission in the long term. In a series of in silico trials, we show that such remission can be facilitated through radiotherapy. The presented study suggests that stem cell plasticity has rather complex, nonintuitive implications on tumor growth and treatment response. Further theoretical, experimental, and integrated studies are needed to fully decipher cancer stem cell plasticity and how it can be harnessed for novel therapeutic approaches.

  12. Growth Inhibition and Apoptosis Inducing Mechanisms of Curcumin on Human Ovarian Cancer Cell Line A2780

    Institute of Scientific and Technical Information of China (English)

    ZHENG Li-duan; TONG Qiang-song; WU Cui-huan

    2006-01-01

    Objective: To explore the growth inhibition effects and apoptosis inducing mechanisms of curcumin on human ovarian cancer cell line A2780. Methods: After treatment with 10-50 μmol/L curcumin for 6-24 h, the growth activity of A2780 cancer cells were studied by [ 4, 5-dimethylthiazol-2-yl]-2, 5-diphenyItetrazolium bromide (MTT) colorimetry. Cellular apoptosis was inspected by flow cytometery and acridine orange-ethidium bromide fluorescent staining methods. The fragmentation of cellular chromosome DNA was detected by DNA ladder, the ultrastructural change was observed under a transmission electron microscope,and the protein levels of nuclear factor-kappa B (NF-κB, P65) and cysteinyl aspartate specific protease-3 (Caspase-3) in ovarian cancer cells were measured by immunohistochemistry. Results: After treatment with various concentrations of curcumin, the growth inhibition rates of cancer cells reached 62.05%- 89.24%,with sub-G1 peaks appearing on histogram. Part of the cancer cells showed characteristic morphological changes of apoptosis under fluorescence and electron microscopes, and the rate of apoptosis was 21.5 % -33.5%. The protein expression of NF-κB was decreased, while that of Caspase-3 was increased in a timedependent manner. Conclusion: Curcumin could significantly inhibit the growth of human ovarian cancer cells;inducing apoptosis through up-regulating Caspase-3 and down-regulating gene expression of NF-κB is probably one of its molecular mechanisms.

  13. Insulin-like growth factor binding protein 2 promotes ovarian cancer cell invasion

    OpenAIRE

    Liu Jinsong; Wang Huamin; Shmulevich Ilya; Mircean Cristian; Lee Eun-Ju; Niemistö Antti; Kavanagh John J; Lee Je-Ho; Zhang Wei

    2005-01-01

    Abstract Background Insulin-like growth factor binding protein 2 (IGFBP2) is overexpressed in ovarian malignant tissues and in the serum and cystic fluid of ovarian cancer patients, suggesting an important role of IGFBP2 in the biology of ovarian cancer. The purpose of this study was to assess the role of increased IGFBP2 in ovarian cancer cells. Results Using western blotting and tissue microarray analyses, we showed that IGFBP2 was frequently overexpressed in ovarian carcinomas compared wit...

  14. Andrographolide, an Herbal Medicine, Inhibits Interleukin-6 Expression and Suppresses Prostate Cancer Cell Growth

    OpenAIRE

    Chun, Jae Yeon; Tummala, Ramakumar; Nadiminty, Nagalakshmi; Lou, Wei; Liu, Chengfei; Yang, Joy; Evans, Christopher P.; Zhou, Qinghua; Gao, Allen C.

    2010-01-01

    Elevated interleukin-6 (IL-6), a major mediator of the inflammatory response, has been implicated in androgen receptor (AR) activation, cellular growth and differentiation, plays important roles in the development and progression of prostate cancer, and is a potential target in cancer therapy. Through drug screening using human prostate cancer cells expressing IL-6 autocrine loop, we found that andrographolide, a diterpenoid lactone isolated from a traditional Chinese and Indian medicinal pla...

  15. Ganoderma lucidum (Reishi) Inhibits Cancer Cell Growth and Expression of Key Molecules in Inflammatory Breast Cancer

    OpenAIRE

    Martínez-Montemayor, Michelle M; Acevedo, Raysa Rosario; Otero-Franqui, Elisa; Cubano, Luis A.; Suranganie F. Dharmawardhane

    2011-01-01

    Inflammatory breast cancer (IBC) is the most lethal and least understood form of advanced breast cancer. Its lethality originates from its nature of invading the lymphatic system and absence of a palpable tumor mass. Different from other metastatic breast cancer cells, IBC cells invade by forming tumor spheroids that retain E-cadherin-based cell–cell adhesions. Herein we describe the potential of the medicinal mushroom Ganoderma lucidum (Reishi) as an attractive candidate for anti-IBC therapy...

  16. Identifying anti-growth factors for human cancer cell lines through genome-scale metabolic modeling

    DEFF Research Database (Denmark)

    Ghaffari, Pouyan; Mardinoglu, Adil; Asplund, Anna;

    2015-01-01

    Human cancer cell lines are used as important model systems to study molecular mechanisms associated with tumor growth, hereunder how genomic and biological heterogeneity found in primary tumors affect cellular phenotypes. We reconstructed Genome scale metabolic models (GEMs) for eleven cell lines...... 85 antimetabolites that can inhibit growth of, or even kill, any of the cell lines, while at the same time not being toxic for 83 different healthy human cell types. 60 of these antimetabolites were found to inhibit growth in all cell lines. Finally, we experimentally validated one of the predicted...... antimetabolites using two cell lines with different phenotypic origins, and found that it is effective in inhibiting the growth of these cell lines. Using immunohistochemistry, we also showed high or moderate expression levels of proteins targeted by the validated antimetabolite. Identified anti-growth factors...

  17. Targeting SPARC by lentivirus-mediated RNA interference inhibits cervical cancer cell growth and metastasis

    Directory of Open Access Journals (Sweden)

    Chen Jie

    2012-10-01

    Full Text Available Abstract Background Secreted protein acidic and rich in cysteine (SPARC, a calcium-binding matricellular glycoprotein, is implicated in the progressions of some cancers. However, no information has been available to date regarding the function of SPARC in cervical cancer cell growth and metastasis. Methods In this study, we isolated and established high invasive subclones and low invasive subclones from human cervical cancer cell lines HeLa and SiHa by the limited dilution method. Real-time q-RT-PCR, Western Blot and ICC were performed to investigate SPARC mRNA and protein expressions in high invasive subclones and low invasive subclones. Then lentivirus vector with SPARC shRNA was constructed and infected the highly invasive subclones. Real-time q-RT-PCR, Western Blot and ICC were also performed to investigate the changes of SPARC expression after viral infection. In functional assays, effects of SPARC knockdown on the biological behaviors of cervical cancer cells were investigated. The mechanisms of SPARC in cervical cancer proliferation, apoptosis and invasion were also researched. Results SPARC was over-expressed in the highly invasive subclones compared with the low invasive subclones. Knockdown of SPARC significantly suppressed cervical cancer cell proliferation, and induced cell cycle arrest at the G1/G0 phase through the p53/p21 pathway, also caused cell apoptosis accompanied by the decreased ratio of Bcl-2/Bax, and inhibited cell invasion and metastasis accompanied by down-regulated MMP2 and MMP9 expressions and up-regulated E-cadherin expression. Conclusion SPARC is related to the invasive phenotype of cervical cancer cells. Knockdown of SPARC significantly suppresses cervical cancer cell proliferation, induces cell apoptosis and inhibits cell invasion and metastasis. SPARC as a promoter improves cervical cancer cell growth and metastasis.

  18. Targeting SPARC by lentivirus-mediated RNA interference inhibits cervical cancer cell growth and metastasis

    International Nuclear Information System (INIS)

    Secreted protein acidic and rich in cysteine (SPARC), a calcium-binding matricellular glycoprotein, is implicated in the progressions of some cancers. However, no information has been available to date regarding the function of SPARC in cervical cancer cell growth and metastasis. In this study, we isolated and established high invasive subclones and low invasive subclones from human cervical cancer cell lines HeLa and SiHa by the limited dilution method. Real-time q-RT-PCR, Western Blot and ICC were performed to investigate SPARC mRNA and protein expressions in high invasive subclones and low invasive subclones. Then lentivirus vector with SPARC shRNA was constructed and infected the highly invasive subclones. Real-time q-RT-PCR, Western Blot and ICC were also performed to investigate the changes of SPARC expression after viral infection. In functional assays, effects of SPARC knockdown on the biological behaviors of cervical cancer cells were investigated. The mechanisms of SPARC in cervical cancer proliferation, apoptosis and invasion were also researched. SPARC was over-expressed in the highly invasive subclones compared with the low invasive subclones. Knockdown of SPARC significantly suppressed cervical cancer cell proliferation, and induced cell cycle arrest at the G1/G0 phase through the p53/p21 pathway, also caused cell apoptosis accompanied by the decreased ratio of Bcl-2/Bax, and inhibited cell invasion and metastasis accompanied by down-regulated MMP2 and MMP9 expressions and up-regulated E-cadherin expression. SPARC is related to the invasive phenotype of cervical cancer cells. Knockdown of SPARC significantly suppresses cervical cancer cell proliferation, induces cell apoptosis and inhibits cell invasion and metastasis. SPARC as a promoter improves cervical cancer cell growth and metastasis

  19. Study of wavy laminar growth of human urinary bladder cancer cell line in vitro

    Institute of Scientific and Technical Information of China (English)

    DENG Guo-hong; CONG Yan-guang; LIU Jun-kang; XU Qi-wang; YUAN Ze-tao

    2001-01-01

    To observe the ordered growth behavior of human urinary bladder cancer cell line (BIU) under culture in vitro. Methods: The suspension of BIU cells was spread locally in a culture container. When the cells grew along the wall to form a cellular colony, macroscopic and microscopic observations complemented with measurements of the parameters including expanding diameter, expanding rate, cell shape, average cell density, average cell size, dehydrogenase activity and sensitivity to pH were conducted dynamically. Results: During cell culture, obvious laminar characteristics appeared in localized growing BIU cell colonies and there was difference between the cells of different zones in shape, size, density, dehydrogenase activity and sensitivity to pH. Conclusion: Space closing and bio-dissipation result in self-organization of BIU cells with ordered growth behavior. The present experiment offers a simple, controllable model for the study of wavy growth of human cells.

  20. Angiostatin inhibits pancreatic cancer cell proliferation and growth in nude mice

    Institute of Scientific and Technical Information of China (English)

    Ding-Zhong Yang; Jing He; Ji-Cheng Zhang; Zhuo-Ren Wang

    2005-01-01

    AIM: To observe the biologic behavior of pancreatic cancer cells in vitro and in vivo, and to explore the potential value of angiostatin gene therapy for pancreatic cancer.METHODS: The recombinant vector pcDNA3.1(+)-angiostatin was transfected into human pancreatic cancer cells PC-3 with Lipofectamine 2000, and paralleled with the vector and mock control. Angiostatin transcription and protein expression were determined by immunofluorescence and Western blot. The stable cell line was selected by G418. The supernatant was collected to treat endothelial cells. Cell proliferation and growth in vitro were observed under microscope. Cell growth curves were plotted.The troms-fected or untroms-fected cells overexpressing angiostatin vector were implanted subcutaneously into nude mice. The size of tumors was measured, and microvessel density count (MVD) in tumor tissues was assessed by immunohistochemistry with primary anti-CD34antibody.RESULTS: After transfected into PC-3 with Lipofectamine 2000 and selected by G418, macroscopic resistant cell clones were formed in the experimental group transfected with pcDNA 3.1(+)-angiostatin and vector control. But untreated cells died in the mock control. Angiostatin protein expression was detected in the experimental group by immunofluorescence and Western-blot. Cell proliferation and growth in vitro in the three groups were observed respectively under microscope. After treatment with supernatant, significant differences were observed in endothelial cell (ECV-304) growth in vitro. The cell proliferation and growth were inhibited. In nude mice model, markedly inhibited tumorigenesis and slowed tumor expansion were observed in the experimental group as compared to controls, which was parallel to the decreased microvessel density in and around tumor tissue.CONCLUSION: Angiostatin does not directly inhibit human pancreatic cancer cell proliferation and growth in vitro,but it inhibits endothelial cell growthin vitro. It exerts the anti

  1. Growth inhibiting effects of antisense eukaryotic expression vector of proliferating cell nuclear antigen gene on human bladder cancer cells

    Institute of Scientific and Technical Information of China (English)

    童强松; 曾甫清; 林晨; 赵军; 鲁功成

    2003-01-01

    Objective To explore the growth inhibiting effects on human bladder cancer by antisense RNA targeting the proliferating cell nuclear antigen (PCNA) gene. Methods The eukaryotic expression vector for antisense PCNA cDNA was constructed and transferred into a bladder cancer EJ cell line. The PCNA expression in the cancer cells was detected by RT-PCR and Western blotting assays. The in vitro proliferation activities of the transferred cells were observed by growth curve, tetrazolium bromide (MTT) colorimetry, tritiated thymidine (3H-TdR)incorporation, flow cytometry and clone formation testing, while its in vivo anti-tumor effects were detected on nude mice allograft models.Results After the antisense vector, pLAPSN, was transferred, cellular PCNA expression was inhibited at both protein and mRNA levels. The growth rates of EJ cells were reduced from 27.91% to 62.07% (P<0.01), with an inhibition of DNA synthesis rate by 52.31% (P<0.01). Transferred cells were blocked at G0/G1 phases in cell-cycle assay, with the clone formation ability decreased by 50.81% (P<0.01). The in vivo carcinogenic abilities of the transferred cancer cells were decreased by 54.23% (P<0.05). Conclusions Antisense PCNA gene transfer could inhibit the growth of bladder cancer cells in vitro and in vivo, which provided an ideal strategy for gene therapy of human cancers.

  2. Chondromodulin-1 directly suppresses growth of human cancer cells

    International Nuclear Information System (INIS)

    Chondromodulin-1 (ChM1), an endogenous anti-angiogenic factor expressed in cartilage, has been suggested to inhibit invasion of endothelial cells into cartilage. In addition, the ectopic administration of ChM1 has been reported to suppress tumorigenesis in vivo. However, it is unclear whether the anti-tumor effect is due to not only the anti-vascularization effect of ChM1, but also its direct action against oncocytes. In the present study, we sought to determine whether ChM1 has a direct action on tumor cells. BrdU incorporation assay was performed on human umbilical vein endothelial cells (HUVECs), normal human dermal fibroblasts (NHDFs), HepG2 cells and HeLa cells in the presence or absence of recombinant human ChM1 (rhChM1). An adenovirus that expresses ChM1, Ad-ChM1, was established and applied to the tumor xenografted in vivo, and to in vitro tumor cells cultured on plates or in soft agar. Cell cycle-related proteins and the phosphorylation of Erk, Akt, and GSK3β, the downstream molecules of the extracellular matrix-integrin signaling pathways, in HepG2 cells treated with or without Ad-ChM1 were detected by western blot analysis. Luciferase reporter assays of STAT, GAS, and ISRE, which participate in another cytokine signaling pathway, ware performed in HepG2, HeLa, and HUVEC cells. ChM1 suppressed BrdU incorporation in HUVECs and in HepG2 cells dose-dependently, but did not suppress BrdU incorporation in NHDFs and HeLa cells cultured on plates. In soft agar, however, ChM1 suppressed the growth of HeLa cells, as well as HepG2 cells. Western blot analyses demonstrated that ChM1 decreased the levels of cyclin D1, cyclin D3, and cdk6 and increased those of p21cip1 without affecting the phosphorylation levels of Erk, Akt, and GSK3β in HepG2 cells. The luciferase reporter assay demonstrated that ChM1 suppressed the transcriptional activities of STAT and GAS but not of ISRE. ChM1 directly suppressed the proliferation of tumor cells in an anchorage

  3. Analysis of UHRF1 expression in human ovarian cancer tissues and its regulation in cancer cell growth.

    Science.gov (United States)

    Yan, Feng; Wang, Xiaoming; Shao, Lijia; Ge, Mengyuan; Hu, Xiaoya

    2015-11-01

    Ubiquitin-like with PHD and ring finger domains 1 (UHRF1), known as ICB90 or Np95, has been found to be overexpressed in numerous cancers. In this study, we evaluated the expression level of UHRF1 in ovarian cancer. UHRF1 levels in paired ovarian cancer tissues and adjacent normal tissues from 80 ovarian cancer patients were detected using relative quantitatively PCR and Western blot. Small interfering RNA (siRNA) was introduced in two human ovarian cancer cell lines (SKOV-3 and OVCAR-3) to downregulate the expression of UHRF1. The proliferation of siRNA-treated cells was examined using cell counting kit-8 (CCK-8) assay. The growth of these cells showed a remarkable decrease. Moreover, flow cytometric and Hoechst 33342 assays were used to detect the apoptosis. The diagnostic value of UHRF1 messenger RNA (mRNA) expression in ovarian cancer was estimated by receiver-operator characteristic (ROC) curve. The correlation between UHRF1 mRNA expression and clinicopathologic features of ovarian cancer patients was evaluated by χ (2) test. Our results demonstrated that both UHRF1 mRNA and protein were highly expressed in ovarian cancer tissues and significantly higher than that in adjacent normal tissues. Moreover, the inhibition of UHRF1 may lead to cells to undergo apoptosis. Thus, UHRF1 could act as a new oncogenic factor in ovarian cancer and be a potential molecular target for ovarian cancer gene therapy. PMID:26070868

  4. Advanced Research of Fibroblast Growth Factor Receptor 
in Non-small Cell Lung Cancer

    Directory of Open Access Journals (Sweden)

    Dan PU

    2013-11-01

    Full Text Available Lung cancer is severely threatening human health. In recent years, the treatment for lung adenocarcinoma has made a great progress, targeted therapy has been widely applied in clinic, and benefits amount of patients. However, in squamous cell lung cancer, the incidence of epidermal growth factor receptor (EGFR gene mutant and ALK fusion gene are low,and targeted therapy like Tarceva and crizotinib, can hardly work. Since the fibroblast growth factors (fibroblast growth factor, FGF pathway is considered to be related to tumor cell proliferation, metastasis and angiogenesis, more and more researches proved the amplification of fibroblast growth factor receptor (FGFR in squamous cell lung cancer. Experiments in vivo and in vitro found that blocking FGF pathway could reduce the proliferation of tumor cells and inhibit metastasis. The FGF pathway might be a new target for treatment of squamous cell lung cancer. This article reviews the effect of FGFR in tumorigenesis,as well as the prospect as a therapeutic target in non-small cell lung cancer.

  5. Withaferin-A induces mitotic catastrophe and growth arrest in prostate cancer cells

    OpenAIRE

    Roy, Ram V; Suman, Suman; Das, Trinath P; Luevano, Joe; Damodaran, Chendil

    2013-01-01

    Cell cycle deregulation is strongly associated with the pathogenesis of prostate cancer (CaP). Clinical trials of cell cycle regulators that target either the G0/G1 or G2/M phase to inhibit the growth of cancers including CaP are increasing. In this study, we determined the cell-cycle regulatory potential of the herbal molecule Withaferin-A (WA) on CaP cells. WA induced irreversible G2/M arrest in both CaP cell lines (PC3 and DU145) for 48 h. The G2/M arrest was accompanied by upregulation of...

  6. Puerariae radix isoflavones and their metabolites inhibit growth and induce apoptosis in breast cancer cells

    International Nuclear Information System (INIS)

    Puerariae radix (PR) is a popular natural herb and a traditional food in Asia, which has antithrombotic and anti-allergic properties and stimulates estrogenic activity. In the present study, we investigated the effects of the PR isoflavones puerarin, daidzein, and genistein on the growth of breast cancer cells. Our data revealed that after treatment with PR isoflavones, a dose-dependent inhibition of cell growth occurred in HS578T, MDA-MB-231, and MCF-7 cell lines. Results from cell cycle distribution and apoptosis assays revealed that PR isoflavones induced cell apoptosis through a caspase-3-dependent pathway and mediated cell cycle arrest in the G2/M phase. Furthermore, we observed that the serum metabolites of PR (daidzein sulfates/glucuronides) inhibited proliferation of the breast cancer cells at a 50% cell growth inhibition (GI50) concentration of 2.35 μM. These results indicate that the daidzein constituent of PR can be metabolized to daidzein sulfates or daidzein glucuronides that exhibit anticancer activities. The protein expression levels of the active forms of caspase-9 and Bax in breast cancer cells were significantly increased by treatment with PR metabolites. These metabolites also increased the protein expression levels of p53 and p21. We therefore suggest that PR may act as a chemopreventive and/or chemotherapeutic agent against breast cancer by reducing cell viability and inducing apoptosis.

  7. The cancer growth suppressor gene mda-7 selectively induces apoptosis in human breast cancer cells and inhibits tumor growth in nude mice

    OpenAIRE

    Su, Zao-Zhong; Madireddi, Malavi T.; Lin, Jiao Jiao; Young, Charles S. H.; Kitada, Shinichi; Reed, John C.; Goldstein, Neil I.; Fisher, Paul B.

    1998-01-01

    A differentiation induction subtraction hybridization strategy is being used to identify and clone genes involved in growth control and terminal differentiation in human cancer cells. This scheme identified melanoma differentiation associated gene-7 (mda-7), whose expression is up-regulated as a consequence of terminal differentiation in human melanoma cells. Forced expression of mda-7 is growth inhibitory toward diverse human tumor cells. The present studies elucidate the mechanism by which ...

  8. Ganoderma lucidum (Reishi) inhibits cancer cell growth and expression of key molecules in inflammatory breast cancer.

    Science.gov (United States)

    Martínez-Montemayor, Michelle M; Acevedo, Raysa Rosario; Otero-Franqui, Elisa; Cubano, Luis A; Dharmawardhane, Suranganie F

    2011-01-01

    Inflammatory breast cancer (IBC) is the most lethal and least understood form of advanced breast cancer. Its lethality originates from its nature of invading the lymphatic system and absence of a palpable tumor mass. Different from other metastatic breast cancer cells, IBC cells invade by forming tumor spheroids that retain E-cadherin-based cell-cell adhesions. Herein we describe the potential of the medicinal mushroom Ganoderma lucidum (Reishi) as an attractive candidate for anti-IBC therapy. Reishi contains biological compounds that are cytotoxic against cancer cells. We report the effects of Reishi on viability, apoptosis, invasion, and its mechanism of action in IBC cells (SUM-149). Results show that Reishi selectively inhibits cancer cell viability although it does not affect the viability of noncancerous mammary epithelial cells. Apoptosis induction is consistent with decreased cell viability. Reishi inhibits cell invasion and disrupts the cell spheroids that are characteristic of the IBC invasive pathology. Reishi decreases the expression of genes involved in cancer cell survival and proliferation (BCL-2, TERT, PDGFB), and invasion and metastasis (MMP-9), whereas it increases the expression of IL8. Reishi reduces BCL-2, BCL-XL, E-cadherin, eIF4G, p120-catenin, and c-Myc protein expression and gelatinase activity. These findings suggest that Reishi is an effective anti-IBC therapeutic. PMID:21888505

  9. Effect of NCAM-transfection on growth and invasion of a human cancer cell line

    DEFF Research Database (Denmark)

    Edvardsen, K; Bock, E; Jirus, S;

    1997-01-01

    A cDNA encoding the human transmembrane 140 kDa isoform of the neural cell adhesion molecule (NCAM) was transfected into the highly invasive MDA-MB-231 human breast cancer cell line. Transfectants with a homogeneous expression of NCAM showed a restricted capacity for penetration of an artificial ...... of the NCAM-transfected cells. The fact that NCAM expression influences growth regulation attributes a pivotal role to this cell adhesion molecule during ontogenesis and tumor development....

  10. GROWTH INHIBITION OF HUMAN LARYNGEAL CANCER CELL WITH THE ADENOVIRUS-MEDIATED p53 GENE

    Institute of Scientific and Technical Information of China (English)

    WANG Qi; HAN De-min; WANG Wen-ge; WU Zu-ze; ZHANG Wei

    1999-01-01

    Objective: In most laryngeal cancers, the function of p53 gene is down regulated. To explore the potential use of p53 in gene therapy of laryngeal cancer, by introducing wild-type p53 into laryngeal cancer cell line via a recombinant adenoviral vector, Ad5CMV-p53 and analyzing its effects on cell and tumor growth. Methods: A human laryngeal cancer cell line Hep-2 was used.Recombinant cytomegalovirus-promoted adenoviruses containing human wild-type p53 cDNA was transiently introduced into Hep-2 line. The growth suppression of the Hep-2 cells and established s.c. squamous carcinoma model was examined. The p53 protein expression was detected using immunohistochemical analysis. Results: The transduction efficiencies of Hep-2 cell line were 100% at a multiplicity of 100 or greater. The p53 protein expression peaked on day 2 after infection and lasted far 5 days. In vitro growth assays revealed cell death following Ad5CMV-p53 infected. In vivo studies, Ad5CMV-p53 inhibited the tumorigenicity of Hep-2 cell, and in nude mice with established s.c. squamous carcinoma nodules showed that tumor volumes were significantly reduced in mice that received peritumoral infiltration of Ad5CMV-p53. Conclusion: Adenovirus-mediated antitumor therapy carrying the p53 gene is an efficient method to inhibit laryngeal cancer growth. Transfection of laryngeal cancer cells with the wild-type p53 gene via Ad5CMV-p53 is a potential novel approach to the therapy of laryngeal cancer.

  11. Angiogenin mediates androgen-stimulated growth of prostate cancer cells and correlates with castration resistance

    OpenAIRE

    Li, Shuping; Hu, Miaofen G.; Sun, Yeqing; YOSHIOKA, NORIE; IBARAGI, SOICHIRO; Sheng, Jinghao; Sun, Guangjie; Kishimoto, Koji; Hu, Guo-fu

    2013-01-01

    Androgen receptor (AR) is a critical effector of prostate cancer (PCa) development and progression. Androgen-dependent PCa rely on the function of AR for growth and progression. Many castration-resistant PCa continue to depend on AR signaling for survival and growth. Ribosomal RNA (rRNA) is essential for both androgen-dependent and castration-resistant growth of PCa cells. During androgen-dependent growth of prostate cells, androgen-AR signaling leads to the accumulation of rRNA. However, the...

  12. Vitamin D3 stimulates embryonic stem cells but inhibits migration and growth of ovarian cancer and teratocarcinoma cell lines

    OpenAIRE

    Abdelbaset-Ismail, Ahmed; Pedziwiatr, Daniel; Suszyńska, Ewa; Sluczanowska-Glabowska, Sylwia; Schneider, Gabriela; Kakar, Sham S; Mariusz Z Ratajczak

    2016-01-01

    Background Deficiency in Vitamin D3 (cholecalciferol) may predispose to some malignancies, including gonadal tumors and in experimental models vitamin D3 has been proven to inhibit the growth of cancer cells. To learn more about the potential role of vitamin D3 in cancerogenesis, we evaluated the expression and functionality of the vitamin D receptor (VDR) and its role in metastasis of ovarian cancer cells and of murine and human teratocarcinoma cell lines. Methods In our studies we employed ...

  13. Emodin Inhibits Breast Cancer Growth by Blocking the Tumor-Promoting Feedforward Loop between Cancer Cells and Macrophages.

    Science.gov (United States)

    Iwanowycz, Stephen; Wang, Junfeng; Hodge, Johnie; Wang, Yuzhen; Yu, Fang; Fan, Daping

    2016-08-01

    Macrophage infiltration correlates with severity in many types of cancer. Tumor cells recruit macrophages and educate them to adopt an M2-like phenotype through the secretion of chemokines and growth factors, such as MCP1 and CSF1. Macrophages in turn promote tumor growth through supporting angiogenesis, suppressing antitumor immunity, modulating extracellular matrix remodeling, and promoting tumor cell migration. Thus, tumor cells and macrophages interact to create a feedforward loop supporting tumor growth and metastasis. In this study, we tested the ability of emodin, a Chinese herb-derived compound, to inhibit breast cancer growth in mice and examined the underlying mechanisms. Emodin was used to treat mice bearing EO771 or 4T1 breast tumors. It was shown that emodin attenuated tumor growth by inhibiting macrophage infiltration and M2-like polarization, accompanied by increased T-cell activation and reduced angiogenesis in tumors. The tumor inhibitory effects of emodin were lost in tumor-bearing mice with macrophage depletion. Emodin inhibited IRF4, STAT6, and C/EBPβ signaling and increased inhibitory histone H3 lysine 27 tri-methylation (H3K27m3) on the promoters of M2-related genes in tumor-associated macrophages. In addition, emodin inhibited tumor cell secretion of MCP1 and CSF1, as well as expression of surface anchoring molecule Thy-1, thus suppressing macrophage migration toward and adhesion to tumor cells. These results suggest that emodin acts on both breast cancer cells and macrophages and effectively blocks the tumor-promoting feedforward loop between the two cell types, thereby inhibiting breast cancer growth and metastasis. Mol Cancer Ther; 15(8); 1931-42. ©2016 AACR. PMID:27196773

  14. Inhibition of nuclear factor-kappa B differentially affects thyroid cancer cell growth, apoptosis, and invasion

    Directory of Open Access Journals (Sweden)

    Schweppe Rebecca E

    2010-05-01

    Full Text Available Abstract Background Nuclear factor-κB (NF-κB is constitutively activated in many cancers and plays a key role in promoting cell proliferation, survival, and invasion. Our understanding of NF-κB signaling in thyroid cancer, however, is limited. In this study, we have investigated the role of NF-κB signaling in thyroid cancer cell proliferation, invasion, and apoptosis using selective genetic inhibition of NF-κB in advanced thyroid cancer cell lines. Results Three pharmacologic inhibitors of NF-κB differentially inhibited growth in a panel of advanced thyroid cancer cell lines, suggesting that these NF-κB inhibitors may have off-target effects. We therefore used a selective genetic approach to inhibit NF-κB signaling by overexpression of a dominant-negative IκBα (mIκBα. These studies revealed decreased cell growth in only one of five thyroid cancer cell lines (8505C, which occurred through a block in the S-G2/M transition. Resistance to TNFα-induced apoptosis was observed in all cell lines, likely through an NF-κB-dependent mechanism. Inhibition of NF-κB by mIκBα sensitized a subset of cell lines to TNFα-induced apoptosis. Sensitive cell lines displayed sustained activation of the stress-activated protein kinase/c-Jun NH2-terminal kinase (SAPK/JNK pathway, defining a potential mechanism of response. Finally, NF-κB inhibition by mIκBα expression differentially reduced thyroid cancer cell invasion in these thyroid cancer cell lines. Sensitive cell lines demonstrated approximately a two-fold decrease in invasion, which was associated with differential expression of MMP-13. MMP-9 was reduced by mIκBα expression in all cell lines tested. Conclusions These data indicate that selective inhibition of NF-κB represents an attractive therapeutic target for the treatment of advanced thyroid. However, it is apparent that global regulation of thyroid cancer cell growth and invasion is not achieved by NF-κB signaling alone. Instead, our

  15. Thyroid Growth and Cancer.

    Science.gov (United States)

    Williams, Dillwyn

    2015-09-01

    It is proposed that most papillary thyroid cancers originate in infancy and childhood, based on the early rise in sporadic thyroid carcinoma incidence, the pattern of radiation-induced risk (highest in those exposed as infants), and the high prevalence of sporadic papillary thyroid cancers in children and adolescents (ultrasound screening after the Fukushima accident). The early origin can be linked to the growth pattern of follicular cells, with a high mitotic rate in infancy falling to very low replacement levels in adult life. The cell of origin of thyroid cancers, the differentiated follicular cell, has a limited growth potential. Unlike cancers originating in stem cells, loss of the usually tight link between differentiation and replicative senescence is required for immortalisation. It is suggested that this loss distinguishes larger clinically significant papillary thyroid cancers from micro-papillary thyroid cancers of little clinical significance. Papillary carcinogenesis can then be divided into 3 stages: (1) initiation, the first mutation in the carcinogenic cascade, for radiation-induced papillary thyroid cancers usually a RET rearrangement, (2) progression, acquisition of the additional mutations needed for low-grade malignancy, and (3) escape, further mutations giving immortality and a higher net growth rate. Most papillary thyroid cancers will not have achieved full immortality by adulthood, and remain as so-called micro-carcinomas with a very low growth rate. The use of the term 'cancer' to describe micro-papillary thyroid cancers in older patients encourages overtreatment and alarms patients. Invasive papillary thyroid tumours show a spectrum of malignancy, which at its lowest poses no threat to life. The treatment protocols and nomenclature for small papillary carcinomas need to be reconsidered in the light of the new evidence available, the continuing discovery of smaller lesions, and the model of thyroid carcinogenesis proposed. PMID:26558233

  16. Prolyl oligopeptidase inhibition-induced growth arrest of human gastric cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Suzuki, Kanayo [Laboratory of Cell Biology, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094 (Japan); Sakaguchi, Minoru, E-mail: sakaguti@gly.oups.ac.jp [Laboratory of Cell Biology, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094 (Japan); Tanaka, Satoshi [Laboratory of Cell Biology, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094 (Japan); Yoshimoto, Tadashi [Department of Life Science, Setsunan University, 17-8 Ikeda-Nakamachi, Neyagawa, Osaka 572-8508 (Japan); Takaoka, Masanori [Laboratory of Cell Biology, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094 (Japan)

    2014-01-03

    Highlights: •We examined the effects of prolyl oligopeptidase (POP) inhibition on p53 null gastric cancer cell growth. •POP inhibition-induced cell growth suppression was associated with an increase in a quiescent G{sub 0} state. •POP might regulate the exit from and/or reentry into the cell cycle. -- Abstract: Prolyl oligopeptidase (POP) is a serine endopeptidase that hydrolyzes post-proline peptide bonds in peptides that are <30 amino acids in length. We recently reported that POP inhibition suppressed the growth of human neuroblastoma cells. The growth suppression was associated with pronounced G{sub 0}/G{sub 1} cell cycle arrest and increased levels of the CDK inhibitor p27{sup kip1} and the tumor suppressor p53. In this study, we investigated the mechanism of POP inhibition-induced cell growth arrest using a human gastric cancer cell line, KATO III cells, which had a p53 gene deletion. POP specific inhibitors, 3-((4-[2-(E)-styrylphenoxy]butanoyl)-L-4-hydroxyprolyl)-thiazolidine (SUAM-14746) and benzyloxycarbonyl-thioprolyl-thioprolinal, or RNAi-mediated POP knockdown inhibited the growth of KATO III cells irrespective of their p53 status. SUAM-14746-induced growth inhibition was associated with G{sub 0}/G{sub 1} cell cycle phase arrest and increased levels of p27{sup kip1} in the nuclei and the pRb2/p130 protein expression. Moreover, SUAM-14746-mediated cell cycle arrest of KATO III cells was associated with an increase in the quiescent G{sub 0} state, defined by low level staining for the proliferation marker, Ki-67. These results indicate that POP may be a positive regulator of cell cycle progression by regulating the exit from and/or reentry into the cell cycle by KATO III cells.

  17. The subcellular localization of IGFBP5 affects its cell growth and migration functions in breast cancer

    Directory of Open Access Journals (Sweden)

    Sahin Aysegul

    2009-04-01

    Full Text Available Abstract Background Insulin-like growth factor binding protein 5 (IGFBP5 has been shown to be associated with breast cancer metastasis in clinical marker studies. However, a major difficulty in understanding how IGFBP5 functions in this capacity is the paradoxical observation that ectopic overexpression of IGFBP5 in breast cancer cell lines results in suppressed cellular proliferation. In cancer tissues, IGFBP5 resides mainly in the cytoplasm; however, in transfected cells, IGFBP5 is mainly located in the nucleus. We hypothesized that subcellular localization of IGFBP5 affects its functions in host cells. Methods To test this hypothesis, we generated wild-type and mutant IGFBP5 expression constructs. The mutation occurs within the nuclear localization sequence (NLS of the protein and is generated by site-directed mutagenesis using the wild-type IGFBP5 expression construct as a template. Next, we transfected each expression construct into MDA-MB-435 breast cancer cells to establish stable clones overexpressing either wild-type or mutant IGFBP5. Results Functional analysis revealed that cells overexpressing wild-type IGFBP5 had significantly lower cell growth rate and motility than the vector-transfected cells, whereas cells overexpressing mutant IGFBP5 demonstrated a significantly higher ability to proliferate and migrate. To illustrate the subcellular localization of the proteins, we generated wild-type and mutant IGFBP5-pDsRed fluorescence fusion constructs. Fluorescence microscopy imaging revealed that mutation of the NLS in IGFBP5 switched the accumulation of IGFBP5 from the nucleus to the cytoplasm of the protein. Conclusion Together, these findings imply that the mutant form of IGFBP5 increases proliferation and motility of breast cancer cells and that mutation of the NLS in IGFBP5 results in localization of IGFBP5 in the cytoplasm, suggesting that subcellular localization of IGFBP5 affects its cell growth and migration functions in the

  18. Specific immunotherapy generates CD8(+) CD196(+) T cells to suppress lung cancer growth in mice.

    Science.gov (United States)

    Zhang, Jian; Liu, Jing; Chen, Huiguo; Wu, Weibin; Li, Xiaojun; Wu, Yonghui; Wang, Zhigang; Zhang, Kai; Li, Yun; Weng, Yimin; Liao, Hongying; Gu, Lijia

    2016-08-01

    That specific immunotherapy can inhibit cancer growth has been recognized; its efficiency is to be improved. This study aimed to inhibit lung cancer (LC) growth in a mouse model by using an LC-specific vaccination. In this study, a LC mouse model was created by adoptive transplantation with LC cells. The tumor-bearing mice were vaccinated with LC cell extracts plus adjuvant TNBS or adoptive transplantation with specific CD8(+) CD196(+) T cells. The results showed that the vaccination with LC extracts (LCE)/TNBS markedly inhibited the LC growth and induced CD8(+) CD196(+) T cells in LC tissue and the spleen. These CD8(+) CD196(+) T cells proliferated and produce high levels of perforin upon exposure to LCE and specifically induced LC cell apoptosis. Exposure to TNBS induced RAW264.7 cells to produce macrophage inflammatory protein-3α; the latter activated signal transducer and activator of transcription 3 and further induced perforin expression in the CD8(+) CD196(+) T cells. Adoptive transfer with specific CD8(+) CD196(+) T cells suppressed LC growth in mice. In conclusion, immunization with LC extracts and TNBS can induce LC-specific CD8(+) CD196(+) T cells in LC-bearing mice and inhibit LC growth. PMID:26910585

  19. Amygdalin Blocks Bladder Cancer Cell Growth In Vitro by Diminishing Cyclin A and cdk2

    Science.gov (United States)

    Makarević, Jasmina; Rutz, Jochen; Juengel, Eva; Kaulfuss, Silke; Reiter, Michael; Tsaur, Igor; Bartsch, Georg; Haferkamp, Axel; Blaheta, Roman A.

    2014-01-01

    Amygdalin, a natural compound, has been used by many cancer patients as an alternative approach to treat their illness. However, whether or not this substance truly exerts an anti-tumor effect has never been settled. An in vitro study was initiated to investigate the influence of amygdalin (1.25–10 mg/ml) on the growth of a panel of bladder cancer cell lines (UMUC-3, RT112 and TCCSUP). Tumor growth, proliferation, clonal growth and cell cycle progression were investigated. The cell cycle regulating proteins cdk1, cdk2, cdk4, cyclin A, cyclin B, cyclin D1, p19, p27 as well as the mammalian target of rapamycin (mTOR) related signals phosphoAkt, phosphoRaptor and phosphoRictor were examined. Amygdalin dose-dependently reduced growth and proliferation in all three bladder cancer cell lines, reflected in a significant delay in cell cycle progression and G0/G1 arrest. Molecular evaluation revealed diminished phosphoAkt, phosphoRictor and loss of Cdk and cyclin components. Since the most outstanding effects of amygdalin were observed on the cdk2-cyclin A axis, siRNA knock down studies were carried out, revealing a positive correlation between cdk2/cyclin A expression level and tumor growth. Amygdalin, therefore, may block tumor growth by down-modulating cdk2 and cyclin A. In vivo investigation must follow to assess amygdalin's practical value as an anti-tumor drug. PMID:25136960

  20. Amygdalin blocks bladder cancer cell growth in vitro by diminishing cyclin A and cdk2.

    Directory of Open Access Journals (Sweden)

    Jasmina Makarević

    Full Text Available Amygdalin, a natural compound, has been used by many cancer patients as an alternative approach to treat their illness. However, whether or not this substance truly exerts an anti-tumor effect has never been settled. An in vitro study was initiated to investigate the influence of amygdalin (1.25-10 mg/ml on the growth of a panel of bladder cancer cell lines (UMUC-3, RT112 and TCCSUP. Tumor growth, proliferation, clonal growth and cell cycle progression were investigated. The cell cycle regulating proteins cdk1, cdk2, cdk4, cyclin A, cyclin B, cyclin D1, p19, p27 as well as the mammalian target of rapamycin (mTOR related signals phosphoAkt, phosphoRaptor and phosphoRictor were examined. Amygdalin dose-dependently reduced growth and proliferation in all three bladder cancer cell lines, reflected in a significant delay in cell cycle progression and G0/G1 arrest. Molecular evaluation revealed diminished phosphoAkt, phosphoRictor and loss of Cdk and cyclin components. Since the most outstanding effects of amygdalin were observed on the cdk2-cyclin A axis, siRNA knock down studies were carried out, revealing a positive correlation between cdk2/cyclin A expression level and tumor growth. Amygdalin, therefore, may block tumor growth by down-modulating cdk2 and cyclin A. In vivo investigation must follow to assess amygdalin's practical value as an anti-tumor drug.

  1. Protein disulfide isomerases in the endoplasmic reticulum promote anchorage-independent growth of breast cancer cells.

    Science.gov (United States)

    Wise, Randi; Duhachek-Muggy, Sara; Qi, Yue; Zolkiewski, Michal; Zolkiewska, Anna

    2016-06-01

    Metastatic breast cancer cells are exposed to stress of detachment from the extracellular matrix (ECM). Cultured breast cancer cells that survive this stress and are capable of anchorage-independent proliferation form mammospheres. The purpose of this study was to explore a link between mammosphere growth, ECM gene expression, and the protein quality control system in the endoplasmic reticulum (ER). We compared the mRNA and protein levels of ER folding factors in SUM159PT and MCF10DCIS.com breast cancer cells grown as mammospheres versus adherent conditions. Publicly available gene expression data for mammospheres formed by primary breast cancer cells and for circulating tumor cells (CTCs) were analyzed to assess the status of ECM/ER folding factor genes in clinically relevant samples. Knock-down of selected protein disulfide isomerase (PDI) family members was performed to examine their roles in SUM159PT mammosphere growth. We found that cells grown as mammospheres had elevated expression of ECM genes and ER folding quality control genes. CTC gene expression data for an index patient indicated that upregulation of ECM and ER folding factor genes occurred at the time of acquired therapy resistance and disease progression. Knock-down of PDI, ERp44, or ERp57, three members of the PDI family with elevated protein levels in mammospheres, in SUM159PT cells partially inhibited the mammosphere growth. Thus, breast cancer cell survival and growth under detachment conditions require enhanced assistance of the ER protein folding machinery. Targeting ER folding factors, in particular members of the PDI family, may improve the therapeutic outcomes in metastatic breast cancer. PMID:27161215

  2. Decreased Autocrine EGFR Signaling in Metastatic Breast Cancer Cells Inhibits Tumor Growth in Bone and Mammary Fat Pad

    OpenAIRE

    Nickerson, Nicole K.; Mohammad, Khalid S.; Gilmore, Jennifer L.; Crismore, Erin; Bruzzaniti, Angela; Guise, Theresa A.; Foley, John

    2012-01-01

    Breast cancer metastasis to bone triggers a vicious cycle of tumor growth linked to osteolysis. Breast cancer cells and osteoblasts express the epidermal growth factor receptor (EGFR) and produce ErbB family ligands, suggesting participation of these growth factors in autocrine and paracrine signaling within the bone microenvironment. EGFR ligand expression was profiled in the bone metastatic MDA-MB-231 cells (MDA-231), and agonist-induced signaling was examined in both breast cancer and oste...

  3. 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

  4. Knockdown of RAGE inhibits growth and invasion of gastric cancer cells

    Directory of Open Access Journals (Sweden)

    X.C. Xu

    2013-11-01

    Full Text Available The receptor for advanced glycation endproducts (RAGE is an oncogenic trans-membranous receptor, which is overexpressed in multiple human cancers. However, the role of RAGE in gastric cancer is still elusive. In this study, we investigated the expression and molecular mechanisms of RAGE in gastric cancer cells. Forty cases of gastric cancer and corresponding adjacent non-cancerous tissues (ANCT were collected, and the expression of RAGE was assessed using immunohistochemistry (IHC in biopsy samples. Furthermore, RAGE signaling was blocked by constructed recombinant small hairpin RNA lentiviral vector (Lv-shRAGE used to transfect into human gastric cancer SGC-7901 cells. The expression of AKT, proliferating cell nuclear antigen (PCNA and matrix metallopeptidase-2 (MMP-2 was detected by Real-time PCR and Western blot assays. Cell proliferative activities and invasive capability were respectively determined by MTT and Transwell assays. Cell apoptosis and cycle distribution were analyzed by flow cytometry. As a consequence, RAGE was found highly expressed in cancer tissues compared with the ANCT (70.0% vs 45.0%, P=0.039, and correlated with lymph node metastases (P=0.026. Knockdown of RAGE reduced cell proliferation and invasion of gastric cancer with decreased expression of AKT, PCNA and MMP-2, and induced cell apoptosis and cycle arrest. Altogether, upregulation of RAGE expression is associated with lymph node metastases of gastric cancer, and blockade of RAGE signaling suppresses growth and invasion of gastric cancer cells through AKT pathway, suggesting that RAGE may represent a potential therapeutic target for this aggressive malignancy.

  5. A sulfated polysaccharide of Ecklonia cava inhibits the growth of colon cancer cells by inducing apoptosis

    OpenAIRE

    Ahna, Ginnae; Lee, WonWoo; Kim, Kil-Nam; Lee, Ji-Hyeok; Heo, Soo-Jin; Kang, Nalae; Lee, Seung-Hong; Ahnf, Chang-Bum; Jeon, You-Jin

    2015-01-01

    We investigated anticancer effects of the crude polysaccharides (CPs) isolated from Ecklonia cava enzymatic extracts using AMG, Viscozyme, Protamex, and Alcalase enzyme against a colon cancer cell line, CT26 cells. Among them, the CP of Protamex extract (PCP) contained the highest fucose and sulfated group contents and showed the highest growth inhibitory effect against CT-26 cells. In addition, PCP dose-dependently increased the formation of apoptotic body and the percentage of Sub-G1 DNA co...

  6. LTB4 stimulates growth of human pancreatic cancer cells via MAPK and PI-3 kinase pathways

    International Nuclear Information System (INIS)

    We have previously shown the importance of LTB4 in human pancreatic cancer. LTB4 receptor antagonists block growth and induce apoptosis in pancreatic cancer cells both in vitro and in vivo. Therefore, we investigated the effect of LTB4 on proliferation of human pancreatic cancer cells and the mechanisms involved. LTB4 stimulated DNA synthesis and proliferation of both PANC-1 and AsPC-1 human pancreatic cancer cells, as measured by thymidine incorporation and cell number. LTB4 stimulated rapid and transient activation of MEK and ERK1/2 kinases. The MEK inhibitors, PD98059 and U0126, blocked LTB4-stimulated ERK1/2 activation and cell proliferation. LTB4 also stimulated phosphorylation of p38 MAPK; however, the p38 MAPK inhibitor, SB203580, failed to block LTB4-stimulated growth. The activity of JNK/SAPK was not affected by LTB4 treatment. Phosphorylation of Akt was also induced by LTB4 and this effect was blocked by the PI-3 kinase inhibitor wortmannin, which also partially blocked LTB4-stimulated cell proliferation. In conclusion, LTB4 stimulates proliferation of human pancreatic cancer cells through MEK/ERK and PI-3 kinase/Akt pathways, while p38 MPAK and JNK/SAPK are not involved

  7. Breast cancer tumor growth is efficiently inhibited by dendritic cell transfusion in a murine model

    Directory of Open Access Journals (Sweden)

    Viet Quoc Pham

    2014-03-01

    Full Text Available The ability of dendritic cells to efficiently present tumor-derived antigens when primed with tumor cell lysates makes them attractive as an approach for cancer treatment. This study aimed to evaluate the effects of dendritic cell transfusion dose on breast cancer tumor growth in a murine model. Dendritic cells were produced from allogeneic bone marrow-derived mononuclear cells that were cultured in RPMI 1640 medium supplemented with 20 ng/mL GM-CSF and 20 ng/mL IL-4 for 7 days. These cells were checked for maturation before being primed with a cancer cell-derived antigen. Cancer cell antigens were produced by a rapid freeze-thaw procedure using a 4T1 cell line. Immature dendritic cells were loaded with 4T1 cellderived antigens. Dendritic cells were transfused into mice bearing tumors at three different doses, included 5.104, 105, and 106 cells/mouse with a control consisting of RPMI 1640 media alone. The results showed that dendritic cell therapy inhibited breast cancer tumors in a murine model; however, this effect depended on dendritic cell dose. After 17 days, in the treated groups, tumor size decreased by 43%, 50%, and 87.5% for the doses of 5 and times; 104, 105, and 106 dendritic cells, respectively, while tumor size in the control group decreased by 44%. This result demonstrated that dendritic cell therapy is a promising therapy for breast cancer treatment. [Biomed Res Ther 2014; 1(3.000: 85-92

  8. BMP10 inhibited the growth and migration of gastric cancer cells.

    Science.gov (United States)

    Lei, Haiming; Wang, Jian; Lu, Peihua; Si, Xinghua; Han, Koulan; Ruan, Tingyan; Lu, Junjie

    2016-03-01

    Bone morphogenetic protein 10 (BMP10), a novel member of BMP family, has been identified as an important regulator for angiogenesis. Dysregulation of BMP has been observed in several cancer types. However, its roles in gastric cancer (GC) remain unknown. In this study, the expression of BMP10 was found to be down-regulated in GC samples. Forced expression of BMP10 in GC cells inhibited its growth and migration, while knocking down the expression of BMP10 in GC cells promoted cell growth, migration, and metastasis. BMP10 was shown to negatively regulated beta-catenin/TCF signaling by up-regulating Axin protein level. Taken together, the present study revealed the suppressive function of BMP10 in gastric cancer. PMID:26419594

  9. The role of vascular endothelial growth factor in the tissue specific in vivo growth of prostate cancer cells.

    Science.gov (United States)

    Krupski, T; Harding, M A; Herce, M E; Gulding, K M; Stoler, M H; Theodorescu, D

    2001-01-01

    Despite the fact that cancer cells can be found in many vascular beds, continued growth of the metastatic tumor focus exhibits a significant degree of 'organ tropism', with only certain organs exhibiting the ravages of metastatic disease. Since a limiting factor to the growth of metastases beyond 2 mm in diameter, may be a lack of angiogenesis, we sought to determine whether tumor overexpression of vascular endothelial growth factor (VEGF), a potent angiogenic factor related to prostate cancer metastasis, is causally related to organ specific tumor growth in a prostate cancer xenograft model. LnCaP-C4-2 is a subline of the human prostate cancer cell line LnCaP which unlike its parent, has a predilection for growth in bone, a common site for human prostate cancer metastasis. LnCaP-C4-2, is tumorigenic when injected intrafemorally in mice but requires co-injection of stromal components (Matrigel) to be tumorigenic in the subcutaneous site. Because of this site-specific tumorigenicity profile and relatively low VEGF mRNA and protein expression, this line was transfected with a full length cDNA encoding the 165 isoform of VEGF. Cells either overexpressing or not expressing the transfected gene were selected for study in vivo and in vitro. Overexpression of VEGF did not seem to affect in vitro cell growth. Such overexpression did affect tumorigenicity and in vivo tumor growth rates when cells were inoculated in the subcutaneus site. Interestingly, the dependency of subcutaneous tumorigenicity on Matrigel co-inoculation was still observed in cells overexpressing VEGF. In contrast to the impact that VEGF overexpression has on subcutaneous tumorigenicity, no such effect was observed when cells were inoculated in orthotopic/prostate (primary) or intrafemoral (metastatic) sites. In view of the importance of tumor-stromal interactions in growth of xenografts, we sought to determine if the host strain is important to the observed tumorigenicity effects of VEGF overexpression

  10. Neuroendocrine Cancer-Specific Up-Regulating Mechanism of Insulin-Like Growth Factor Binding Protein-2 in Small Cell Lung Cancer

    OpenAIRE

    Yazawa, Takuya; Sato, Hanako; Shimoyamada, Hiroaki; Okudela, Koji; Woo, Tetsukan; Tajiri, Michihiko; Ogura, Takashi; Ogawa, Nobuo; Suzuki, Takehisa; Mitsui, Hideaki; Ishii, Jun; Miyata, Chie; Sakaeda, Masashi; Goto, Kazuya; Kashiwagi, Korehito

    2009-01-01

    Small cell lung cancer (SCLC) exhibits insulin-like growth factor-dependent growth. SCLC is the most aggressive among known in vivo lung cancers, whereas in vitro growth of SCLC is paradoxically slow as compared with that of non-SCLC (NSCLC). In this study, we demonstrate that SCLC cells overexpress insulin-like growth factor binding protein (IGFBP)-2 via NeuroD, a neuroendocrine cell-specific transcription factor. Chromatin immunoprecipitation, electrophoretic mobility shift, and IGFBP-2 pro...

  11. Biochanin A Modulates Cell Viability, Invasion, and Growth Promoting Signaling Pathways in HER-2-Positive Breast Cancer Cells

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    Vikas Sehdev

    2009-01-01

    Full Text Available Overexpression of HER-2 receptor is associated with poor prognosis and aggressive forms of breast cancer. Scientific literature indicates a preventive role of isoflavones in cancer. Since activation of HER-2 receptor initiates growth-promoting events in cancer cells, we studied the effect of biochanin A (an isoflavone on associated signaling events like receptor activation, downstream signaling, and invasive pathways. HER-2-positive SK-BR-3 breast cancer cells, MCF-10A normal breast epithelial cells, and NIH-3T3 normal fibroblast cells were treated with biochanin A (2–100 μM for 72 hours. Subsequently cell viability assay, western blotting and zymography were carried out. The data indicate that biochanin A inhibits cell viability, signaling pathways, and invasive enzyme expression and activity in SK-BR-3 cancer cells. Biochanin A did not inhibit MCF-10A and NIH-3T3 cell viability. Therefore, biochanin A could be a unique natural anticancer agent which can selectively target cancer cells and inhibit multiple signaling pathways in HER-2-positive breast cancer cells.

  12. Role for chondroitin sulfate glycosaminoglycan in NEDD9-mediated breast cancer cell growth

    NARCIS (Netherlands)

    Iida, J.; Dorchak, J.; Clancy, R.; Slavik, J.; Ellsworth, R.; Katagiri, Y.; Pugacheva, E.N.; Kuppevelt, T.H. van; Mural, R.J.; Cutler, M.L.; Shriver, C.D.

    2015-01-01

    There are lines of evidence demonstrating that NEDD9 (Cas-L, HEF-1) plays a key role in the development, progression, and metastasis of breast cancer cells. We previously reported that NEDD9 plays a critical role for promoting migration and growth of MDA-MB-231. In order to further characterize the

  13. Enhancement of neurite outgrowth in neuron cancer stem cells by growth on 3-D collagen scaffolds

    International Nuclear Information System (INIS)

    Highlights: ► Neuron cancer stem cells (NCSCs) behave high multiply of growth on collagen scaffold. ► Enhancement of NCSCs neurite outgrowth on porous collagen scaffold. ► 3-D collagen culture of NCSCs shows an advance differentiation than 2-D culture. -- Abstract: Collagen is one component of the extracellular matrix that has been widely used for constructive remodeling to facilitate cell growth and differentiation. The 3-D distribution and growth of cells within the porous scaffold suggest a clinical significance for nerve tissue engineering. In the current study, we investigated proliferation and differentiation of neuron cancer stem cells (NCSCs) on a 3-D porous collagen scaffold that mimics the natural extracellular matrix. We first generated green fluorescence protein (GFP) expressing NCSCs using a lentiviral system to instantly monitor the transitions of morphological changes during growth on the 3-D scaffold. We found that proliferation of GFP-NCSCs increased, and a single cell mass rapidly grew with unrestricted expansion between days 3 and 9 in culture. Moreover, immunostaining with neuronal nuclei (NeuN) revealed that NCSCs grown on the 3-D collagen scaffold significantly enhanced neurite outgrowth. Our findings confirmed that the 80 μm porous collagen scaffold could enhance attachment, viability and differentiation of the cancer neural stem cells. This result could provide a new application for nerve tissue engineering and nerve regeneration.

  14. Damaged DNA binding protein 2 plays a role in breast cancer cell growth.

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    Zilal Kattan

    Full Text Available The Damaged DNA binding protein 2 (DDB2, is involved in nucleotide excision repair as well as in other biological processes in normal cells, including transcription and cell cycle regulation. Loss of DDB2 function may be related to tumor susceptibility. However, hypothesis of this study was that DDB2 could play a role in breast cancer cell growth, resulting in its well known interaction with the proliferative marker E2F1 in breast neoplasia. DDB2 gene was overexpressed in estrogen receptor (ER-positive (MCF-7 and T47D, but not in ER-negative breast cancer (MDA-MB231 and SKBR3 or normal mammary epithelial cell lines. In addition, DDB2 expression was significantly (3.0-fold higher in ER-positive than in ER-negative tumor samples (P = 0.0208 from 16 patients with breast carcinoma. Knockdown of DDB2 by small interfering RNA in MCF-7 cells caused a decrease in cancer cell growth and colony formation. Inversely, introduction of the DDB2 gene into MDA-MB231 cells stimulated growth and colony formation. Cell cycle distribution and 5 Bromodeoxyuridine incorporation by flow cytometry analysis showed that the growth-inhibiting effect of DDB2 knockdown was the consequence of a delayed G1/S transition and a slowed progression through the S phase of MCF-7 cells. These results were supported by a strong decrease in the expression of S phase markers (Proliferating Cell Nuclear Antigen, cyclin E and dihydrofolate reductase. These findings demonstrate for the first time that DDB2 can play a role as oncogene and may become a promising candidate as a predictive marker in breast cancer.

  15. A Novel Muscarinic Antagonist R2HBJJ Inhibits Non-Small Cell Lung Cancer Cell Growth and Arrests the Cell Cycle in G0/G1

    OpenAIRE

    Hua, Nan; Wei, Xiaoli; Liu, Xiaoyan; Ma, Xiaoyun; He, Xinhua; Zhuo, Rengong; Zhao, Zhe; Wang, Liyun; Yan, Haitao; Zhong, Bohua; Zheng, Jianquan

    2012-01-01

    Lung cancers express the cholinergic autocrine loop, which facilitates the progression of cancer cells. The antagonists of mAChRs have been demonstrated to depress the growth of small cell lung cancers (SCLCs). In this study we intended to investigate the growth inhibitory effect of R2HBJJ, a novel muscarinic antagonist, on non-small cell lung cancer (NSCLC) cells and the possible mechanisms. The competitive binding assay revealed that R2HBJJ had a high affinity to M3 and M1 AChRs. R2HBJJ pre...

  16. Effect of tumor suppressor in lung cancer-1 on growth inhibition of MG63 cell line

    Institute of Scientific and Technical Information of China (English)

    Li Qin; Yang Lin; Wenjian Chen; Wentao Zhu

    2013-01-01

    Objective: The aim of this study was to establish the osteosarcoma cell sublines which stably expressing tumor suppressor in lung cancer-1 (TSLC1) gene and evaluate its effect on growth inhibition of human osteosarcoma cell line MG63. Methods: The recombinant plasmid pCI-TSLC1 was stably transfected into MG63 cells with Lipofectamine 2000. The positive clones were developed by selection by G418. Biological characteristics of one of the 6 cell lines which highly expressing TSLC1, namely, the M8T were studied. Cell growth was analyzed with MTT assay. 2 × 107 cells suspended in 0.2 mL phosphate buffered saline (PBS) were injected into the two flanks of 5-6-week-old female BALB/C nu/nu athymic nude mice. The volumes of subcutaneous of tumor growth were evaluated and calculated by the formula V= Length × Width × Height × 0.5 once a week. Results: The M8T cell subline which stably expressing TSLC1 was characterized by Western blot. The genetic stability and purity of M8T cells were stable. TSLC1 significantly suppressed the growth of M8T cells in vitro. Moreover, the tumorigenicity of M8T cells was suppressed in vivo. Conclusion: The osteosarcoma cell sublines M8T which stably expressing TSLC1 had been successfully established. The ability of growth and metastasis of M8T was significantly suppressed both in vitro and in vivo.

  17. Withaferin A inhibits in vivo growth of breast cancer cells accelerated by Notch2 knockdown.

    Science.gov (United States)

    Kim, Su-Hyeong; Hahm, Eun-Ryeong; Arlotti, Julie A; Samanta, Suman K; Moura, Michelle B; Thorne, Stephen H; Shuai, Yongli; Anderson, Carolyn J; White, Alexander G; Lokshin, Anna; Lee, Joomin; Singh, Shivendra V

    2016-05-01

    The present study offers novel insights into the molecular circuitry of accelerated in vivo tumor growth by Notch2 knockdown in triple-negative breast cancer (TNBC) cells. Therapeutic vulnerability of Notch2-altered growth to a small molecule (withaferin A, WA) is also demonstrated. MDA-MB-231 and SUM159 cells were used for the xenograft studies. A variety of technologies were deployed to elucidate the mechanisms underlying tumor growth augmentation by Notch2 knockdown and its reversal by WA, including Fluorescence Molecular Tomography for measurement of tumor angiogenesis in live mice, Seahorse Flux analyzer for ex vivo measurement of tumor metabolism, proteomics, and Luminex-based cytokine profiling. Stable knockdown of Notch2 resulted in accelerated in vivo tumor growth in both cells reflected by tumor volume and/or latency. For example, the wet tumor weight from mice bearing Notch2 knockdown MDA-MB-231 cells was about 7.1-fold higher compared with control (P medicinal plant. Molecular underpinnings for tumor growth intensification by Notch2 knockdown included compensatory increase in Notch1 activation, increased cellular proliferation and/or angiogenesis, and increased plasma or tumor levels of growth stimulatory cytokines. WA administration reversed many of these effects providing explanation for its remarkable anti-cancer efficacy. Notch2 functions as a tumor growth suppressor in TNBC and WA offers a novel therapeutic strategy for restoring this function. PMID:27097807

  18. Metformin is an AMP kinase-dependent growth inhibitor for breast cancer cells.

    Science.gov (United States)

    Zakikhani, Mahvash; Dowling, Ryan; Fantus, I George; Sonenberg, Nahum; Pollak, Michael

    2006-11-01

    Recent population studies provide clues that the use of metformin may be associated with reduced incidence and improved prognosis of certain cancers. This drug is widely used in the treatment of type 2 diabetes, where it is often referred to as an "insulin sensitizer" because it not only lowers blood glucose but also reduces the hyperinsulinemia associated with insulin resistance. As insulin and insulin-like growth factors stimulate proliferation of many normal and transformed cell types, agents that facilitate signaling through these receptors would be expected to enhance proliferation. We show here that metformin acts as a growth inhibitor rather than an insulin sensitizer for epithelial cells. Breast cancer cells can be protected against metformin-induced growth inhibition by small interfering RNA against AMP kinase. This shows that AMP kinase pathway activation by metformin, recently shown to be necessary for metformin inhibition of gluconeogenesis in hepatocytes, is also involved in metformin-induced growth inhibition of epithelial cells. The growth inhibition was associated with decreased mammalian target of rapamycin and S6 kinase activation and a general decrease in mRNA translation. These results provide evidence for a mechanism that may contribute to the antineoplastic effects of metformin suggested by recent population studies and justify further work to explore potential roles for activators of AMP kinase in cancer prevention and treatment. PMID:17062558

  19. Involvement of Fatty Acid Binding Protein 5 and PPARβ/δ in Prostate Cancer Cell Growth

    Directory of Open Access Journals (Sweden)

    Elwin Morgan

    2010-01-01

    Full Text Available Fatty acid binding protein 5 (FABP5 delivers ligands from the cytosol directly to the nuclear receptor PPARβ/δ and thus facilitates the ligation and enhances the transcriptional activity of the receptor. We show here that expression levels of both FABP5 and PPARβ/δ are correlated with the tumorigenic potential of prostate cancer cell lines. We show further that FABP5 comprises a direct target gene for PPARβ/δ and thus the binding protein and its cognate receptor are engaged in a positive feedback loop. The observations demonstrate that, similarly to effects observed in mammary carcinomas, activation of the FABP5/PPARβ/δ pathway induces PPARβ/δ target genes involved in cell survival and growth and enhances cell proliferation and anchorage-independent growth in prostate cancer cells. Furthermore, the data show that downregulation of either FABP5 or PPARβ/δ inhibits the growth of the highly malignant prostate cancer PC3M cells. These studies suggest that the FABP5/PPARβ/δ pathway may play a general role in facilitating tumor progression and that inhibition of the pathway may comprise a novel strategy in treatment of cancer.

  20. Programmable models of growth and mutation of cancer-cell populations

    CERN Document Server

    Bortolussi, Luca; 10.4204/EPTCS.67.4

    2011-01-01

    In this paper we propose a systematic approach to construct mathematical models describing populations of cancer-cells at different stages of disease development. The methodology we propose is based on stochastic Concurrent Constraint Programming, a flexible stochastic modelling language. The methodology is tested on (and partially motivated by) the study of prostate cancer. In particular, we prove how our method is suitable to systematically reconstruct different mathematical models of prostate cancer growth - together with interactions with different kinds of hormone therapy - at different levels of refinement.

  1. Human mitochondrial transcription factor A functions in both nuclei and mitochondria and regulates cancer cell growth

    International Nuclear Information System (INIS)

    Highlights: → Mitochondrial transcription factor A (mtTFA) localizes in nuclei and binds tightly to the nuclear chromatin. → mtTFA contains two putative nuclear localization signals (NLS) in the HMG-boxes. → Overexpression of mtTFA enhances the growth of cancer cells, whereas downregulation of mtTFA inhibits their growth by regulating mtTFA target genes, such as baculoviral IAP repeat-containing 5 (BIRC5; also known as survivin). → Knockdown of mtTFA expression induces p21-dependent G1 cell cycle arrest. -- Abstract: Mitochondrial transcription factor A (mtTFA) is one of the high mobility group protein family and is required for both transcription from and maintenance of mitochondrial genomes. However, the roles of mtTFA have not been extensively studied in cancer cells. Here, we firstly reported the nuclear localization of mtTFA. The proportion of nuclear-localized mtTFA varied among different cancer cells. Some mtTFA binds tightly to the nuclear chromatin. DNA microarray and chromatin immunoprecipitation assays showed that mtTFA can regulate the expression of nuclear genes. Overexpression of mtTFA enhanced the growth of cancer cell lines, whereas downregulation of mtTFA inhibited their growth by regulating mtTFA target genes, such as baculoviral IAP repeat-containing 5 (BIRC5; also known as survivin). Knockdown of mtTFA expression induced p21-dependent G1 cell cycle arrest. These results imply that mtTFA functions in both nuclei and mitochondria to promote cell growth.

  2. Vascular Endothelial Growth Factor A Regulates the Secretion of Different Angiogenic Factors in Lung Cancer Cells.

    Science.gov (United States)

    Frezzetti, Daniela; Gallo, Marianna; Roma, Cristin; D'Alessio, Amelia; Maiello, Monica R; Bevilacqua, Simona; Normanno, Nicola; De Luca, Antonella

    2016-07-01

    Vascular endothelial growth factor A (VEGFA) is one of the main mediators of angiogenesis in non-small cell lung cancer (NSCLC). Recently, it has been described an autocrine feed-forward loop in NSCLC cells in which tumor-derived VEGFA promoted the secretion of VEGFA itself, amplifying the proangiogenic signal. In order to investigate the role of VEGFA in lung cancer progression, we assessed the effects of recombinant VEGFA on proliferation, migration, and secretion of other angiogenic factors in A549, H1975, and HCC827 NSCLC cell lines. We found that VEGFA did not affect NSCLC cell proliferation and migration. On the other hand, we demonstrated that VEGFA not only produced a strong and persistent increase of VEGFA itself but also significantly induced the secretion of a variety of angiogenic factors, including follistatin (FST), hepatocyte growth factor (HGF), angiopoietin-2 (ANGPT2), granulocyte-colony stimulating factor (G-CSF), interleukin (IL)-8, leptin (LEP), platelet/endothelial cell adhesion molecule 1 (PECAM-1), and platelet-derived growth factor bb (PDGF-BB). PI3K/AKT, RAS/ERK, and STAT3 signalling pathways were found to mediate the effects of VEGFA in NSCLC cell lines. We also observed that VEGFA regulation mainly occurred at post-transcriptional level and that NSCLC cells expressed different isoforms of VEGFA. Collectively, our data suggested that VEGFA contributes to lung cancer progression by inducing a network of angiogenic factors, which might offer potential for therapeutic intervention. PMID:26542886

  3. Growth inhibition of thyroid follicular cell-derived cancers by the opioid growth factor (OGF - opioid growth factor receptor (OGFr axis

    Directory of Open Access Journals (Sweden)

    Donahue Renee N

    2009-10-01

    Full Text Available Abstract Background Carcinoma of the thyroid gland is an uncommon cancer, but the most frequent malignancy of the endocrine system. Most thyroid cancers are derived from the follicular cell. Follicular carcinoma (FTC is considered more malignant than papillary thyroid carcinoma (PTC, and anaplastic thyroid cancer (ATC is one of the most lethal human cancers. Opioid Growth Factor (OGF; chemical term - [Met5]-enkephalin and its receptor, OGFr, form an inhibitory axis regulating cell proliferation. Both the peptide and receptor have been detected in a wide variety of cancers, and OGF is currently used clinically as a biotherapy for some non-thyroid neoplasias. This study addressed the question of whether the OGF-OGFr axis is present and functional in human thyroid follicular cell - derived cancer. Methods Utilizing human ATC (KAT-18, PTC (KTC-1, and FTC (WRO 82-1 cell lines, immunohistochemistry was employed to ascertain the presence and location of OGF and OGFr. The growth characteristics in the presence of OGF or the opioid antagonist naltrexone (NTX, and the specificity of opioid peptides for proliferation of ATC, were established in KAT-18 cells. Dependence on peptide and receptor were investigated using neutralization studies with antibodies and siRNA experiments, respectively. The mechanism of peptide action on DNA synthesis and cell survival was ascertained. The ubiquity of the OGF-OGFr axis in thyroid follicular cell-derived cancer was assessed in KTC-1 (PTC and WRO 82-1 (FTC tumor cells. Results OGF and OGFr were present in KAT-18 cells. Concentrations of 10-6 M OGF inhibited cell replication up to 30%, whereas NTX increased cell growth up to 35% relative to cultures treated with sterile water. OGF treatment reduced cell number by as much as 38% in KAT-18 ATC in a dose-dependent and receptor-mediated manner. OGF antibodies neutralized the inhibitory effects of OGF, and siRNA knockdown of OGFr negated growth inhibition by OGF. Cell survival

  4. Inhibition of growth and induction of differentiation of colon cancer cells by peach and plum phenolic compounds

    Science.gov (United States)

    The action of extracts from anthocyanin-enriched plums and peaches on growth and differentiation was studied with human colon cancer cells. Growth inhibitory effects were observed in Caco-2, SW1116, HT29 and NCM460 cells. In Caco-2 cells but not in the other cells studied there was evidence for incr...

  5. MicroRNA-181b promotes ovarian cancer cell growth and invasion by targeting LATS2

    International Nuclear Information System (INIS)

    Highlights: • miR-181b is upregulated in human ovarian cancer tissues. • miR-181b promotes ovarian cancer cell proliferation and invasion. • LATS2 is a direct target of miR-181b. • LATS2 is involved in miR-181b-induced ovarian cancer cell growth and invasion. - Abstract: MicroRNAs (miRNAs) are strongly implicated in tumorigenesis and metastasis. In this study, we showed significant upregulation of miR-181b in ovarian cancer tissues, compared with the normal ovarian counterparts. Forced expression of miR-181b led to remarkably enhanced proliferation and invasion of ovarian cancer cells while its knockdown induced significant suppression of these cellular events. The tumor suppressor gene, LATS2 (large tumor suppressor 2), was further identified as a novel direct target of miR-181b. Specifically, miR-181b bound directly to the 3′-untranslated region (UTR) of LATS2 and suppressed its expression. Restoration of LATS2 expression partially reversed the oncogenic effects of miR-181b. Our results indicate that miR-181b promotes proliferation and invasion by targeting LATS2 in ovarian cancer cells. These findings support the utility of miR-181b as a potential diagnostic and therapeutic target for ovarian cancer

  6. MicroRNA-181b promotes ovarian cancer cell growth and invasion by targeting LATS2

    Energy Technology Data Exchange (ETDEWEB)

    Xia, Ying; Gao, Yan, E-mail: gaoyanhdhos@126.com

    2014-05-09

    Highlights: • miR-181b is upregulated in human ovarian cancer tissues. • miR-181b promotes ovarian cancer cell proliferation and invasion. • LATS2 is a direct target of miR-181b. • LATS2 is involved in miR-181b-induced ovarian cancer cell growth and invasion. - Abstract: MicroRNAs (miRNAs) are strongly implicated in tumorigenesis and metastasis. In this study, we showed significant upregulation of miR-181b in ovarian cancer tissues, compared with the normal ovarian counterparts. Forced expression of miR-181b led to remarkably enhanced proliferation and invasion of ovarian cancer cells while its knockdown induced significant suppression of these cellular events. The tumor suppressor gene, LATS2 (large tumor suppressor 2), was further identified as a novel direct target of miR-181b. Specifically, miR-181b bound directly to the 3′-untranslated region (UTR) of LATS2 and suppressed its expression. Restoration of LATS2 expression partially reversed the oncogenic effects of miR-181b. Our results indicate that miR-181b promotes proliferation and invasion by targeting LATS2 in ovarian cancer cells. These findings support the utility of miR-181b as a potential diagnostic and therapeutic target for ovarian cancer.

  7. Elevated expression of protein regulator of cytokinesis 1, involved in the growth of breast cancer cells.

    Science.gov (United States)

    Shimo, Arata; Nishidate, Toshihiko; Ohta, Tomohiko; Fukuda, Mamoru; Nakamura, Yusuke; Katagiri, Toyomasa

    2007-02-01

    To elucidate molecular mechanisms of mammary carcinogenesis and discover novel therapeutic targets for breast cancer, we previously carried out a genome-wide expression profile analysis of 81 breast cancer cases by means of a combination of cDNA microarray and laser microbeam microdissection. Among the upregulated genes, we focused on the functional significance of protein regulator of cytokinesis 1 (PRC1) in the development of breast cancer. Western blot analysis using breast cancer cell lines revealed a significant increase in endogenous PRC1 levels in G(2)/M phase. Treatment of breast cancer cells with small interfering RNA against PRC1 effectively suppressed its expression and inhibited the growth of breast cancer cell lines T47D and HBC5. Furthermore, we found an interaction between PRC1 and kinesin family member 2C/mitotic centromere-associated kinesin (KIF2C/MCAK) by coimmunoprecipitation and immunoblotting using COS-7 cells, in which these molecules were introduced exogenously. These findings suggest the involvement of a PRC1-KIF2C/MCAK complex in breast tumorigenesis, and this complex should be a promising target for the development of novel treatments for breast cancer. PMID:17233835

  8. Highly sensitive quantitative imaging for monitoring single cancer cell growth kinetics and drug response.

    Directory of Open Access Journals (Sweden)

    Mustafa Mir

    Full Text Available The detection and treatment of cancer has advanced significantly in the past several decades, with important improvements in our understanding of the fundamental molecular and genetic basis of the disease. Despite these advancements, drug-screening methodologies have remained essentially unchanged since the introduction of the in vitro human cell line screen in 1990. Although the existing methods provide information on the overall effects of compounds on cell viability, they are restricted by bulk measurements, large sample sizes, and lack capability to measure proliferation kinetics at the individual cell level. To truly understand the nature of cancer cell proliferation and to develop personalized adjuvant therapies, there is a need for new methodologies that provide quantitative information to monitor the effect of drugs on cell growth as well as morphological and phenotypic changes at the single cell level. Here we show that a quantitative phase imaging modality known as spatial light interference microscopy (SLIM addresses these needs and provides additional advantages over existing proliferation assays. We demonstrate these capabilities through measurements on the effects of the hormone estradiol and the antiestrogen ICI182,780 (Faslodex on the growth of MCF-7 breast cancer cells. Along with providing information on changes in the overall growth, SLIM provides additional biologically relevant information. For example, we find that exposure to estradiol results in rapidly growing cells with lower dry mass than the control population. Subsequently blocking the estrogen receptor with ICI results in slower growing cells, with lower dry masses than the control. This ability to measure changes in growth kinetics in response to environmental conditions provides new insight on growth regulation mechanisms. Our results establish the capabilities of SLIM as an advanced drug screening technology that provides information on changes in proliferation

  9. Growth inhibitory effect of 4-phenyl butyric acid on human gastric cancer cells is associated with cell cycle arrest

    Institute of Scientific and Technical Information of China (English)

    Long-Zhu Li; Hong-Xia Deng; Wen-Zhu Lou; Xue-Yan Sun; Meng-Wan Song; Jing Tao; Bing-Xiu Xiao; Jun-Ming Guo

    2012-01-01

    AIM: To investigate the growth effects of 4-phenyl butyric acid (PBA) on human gastric carcinoma cells and their mechanisms. METHODS: Moderately-differentiated human gastric carcinoma SGC-7901 and lowly-differentiated MGC-803 cells were treated with 5, 10, 20, 40, and 60 μmol/L PBA for 1-4 d. Cell proliferation was detected using the MTT colorimetric assay. Cell cycle distributions were examined using flow cytometry. RESULTS: The proliferation of gastric carcinoma cells was inhibited by PBA in a dose- and time-dependent fashion. Flow cytometry showed that SGC-7901 cells treated with low concentrations of PBA were arrested at the G0/G1 phase, whereas cells treated with high concentrations of PBA were arrested at the G2/M phase. Although MGC-803 cells treated with low concentrations of PBA were also arrested at the G0/G1 phase, cells treated with high concentrations of PBA were arrested at the S phase. CONCLUSION: The growth inhibitory effect of PBA on gastric cancer cells is associated with alteration of the cell cycle. For moderately-differentiated gastric cancer cells, the cell cycle was arrested at the G0/G1 and G2/M phases. For lowly-differentiated gastric cancer cells, the cell cycle was arrested at the G0/G1 and S phases.

  10. Novel analogs targeting histone deacetylase suppress aggressive thyroid cancer cell growth and induce re-differentiation.

    Science.gov (United States)

    Jang, S; Yu, X-M; Odorico, S; Clark, M; Jaskula-Sztul, R; Schienebeck, C M; Kupcho, K R; Harrison, A D; Winston-McPherson, G N; Tang, W; Chen, H

    2015-08-01

    To develop novel therapies for aggressive thyroid cancers, we have synthesized a collection of histone deacetylase (HDAC) inhibitor analogs named AB1 to AB13, which have different linkers between a metal chelating group and a hydrophobic cap. The purpose of this study was to screen out the most effective compounds and evaluate the therapeutic efficacy. AB2, AB3 and AB10 demonstrated the lowest half-maximal inhibitory concentration (IC50) values in one metastatic follicular and two anaplastic thyroid cancer cell lines. Treatment with each of the three ABs resulted in an increase in apoptosis markers, including cleaved poly adenosine diphosphate ribose polymerase (PARP) and cleaved caspase 3. Additionally, the expression of cell-cycle regulatory proteins p21(WAF1) and p27(Kip1) increased with the treatment of ABs while cyclin D1 decreased. Furthermore, AB2, AB3 and AB10 were able to induce thyrocyte-specific genes in the three thyroid cancer cell lines indicated by increased expression levels of sodium iodide symporter, paired box gene 8, thyroid transcription factor 1 (TTF1), TTF2 and thyroid-stimulating hormone receptors. AB2, AB3 and AB10 suppress thyroid cancer cell growth via cell-cycle arrest and apoptosis. They also induce cell re-differentiation, which could make aggressive cancer cells more susceptible to radioactive iodine therapy. PMID:26251030

  11. THE EMERGING ROLE OF INSULIN AND INSULIN-LIKE GROWTH FACTOR SIGNALING IN CANCER STEM CELLS

    Directory of Open Access Journals (Sweden)

    Roberta eMalaguarnera

    2014-02-01

    Full Text Available Cancer cells frequently exploit the IGF signaling, a fundamental pathway mediating development, cell growth and survival. As a consequence, several components of the IGF signaling are deregulated in cancer and sustain cancer progression. However, specific targeting of IGF-IR in humans has resulted efficacious only in small subsets of cancers, making researches wondering whether IGF system targeting is still worth pursuing in the clinical setting. Although no definite answer is yet available, it has become increasingly clear that other components of the IGF signaling pathway, such as IR-A, may substitute for the lack of IGF-IR, and induce cancer resistance and/or clonal selection. Moreover, accumulating evidence now indicates that IGF signaling is a central player in the induction/maintenance of epithelial mesenchymal transition (EMT and cell stemness, two strictly related programs, which play a key role in metastatic spread and resistance to cancer treatments. Here we review the evidences indicating that IGF signaling enhances the expression of transcription factors implicated in the EMT program and has extensive crosstalk with specific pathways involved in cell pluripotency and stemness maintenance. In turn, EMT and cell stemness activate positive feed-back mechanisms causing upregulation of various IGF signaling components. These findings may have novel translational implications.

  12. Intercellular redistribution of cAMP underlies selective suppression of cancer cell growth by connexin26.

    Directory of Open Access Journals (Sweden)

    Anjana Chandrasekhar

    Full Text Available Connexins (Cx, which constitute gap junction intercellular channels in vertebrates, have been shown to suppress transformed cell growth and tumorigenesis, but the mechanism(s still remain largely speculative. Here, we define the molecular basis by which Cx26, but less frequently Cx43 or Cx32, selectively confer growth suppression on cancer cells. Functional intercellular coupling is shown to be required, producing partial blocks of the cell cycle due to prolonged activation of several mitogenic kinases. PKA is both necessary and sufficient for the Cx26 induced growth inhibition in low serum and the absence of anchorage. Activation of PKA was not associated with elevated cAMP levels, but appeared to result from a redistribution of cAMP throughout the cell population, eliminating the cell cycle oscillations in cAMP required for efficient cell cycle progression. Cx43 and Cx32 fail to mediate this redistribution as, unlike Cx26, these channels are closed during the G2/M phase of the cell cycle when cAMP levels peak. Comparisons of tumor cell lines indicate that this is a general pattern, with growth suppression by connexins occurring whenever cAMP oscillates with the cell cycle, and the gap junction remain open throughout the cell cycle. Thus, gap junctional coupling, in the absence of any external signals, provides a general means to limit the mitotic rate of cell populations.

  13. Myotubularin-Related Phosphatase 3 Promotes Growth of Colorectal Cancer Cells

    Directory of Open Access Journals (Sweden)

    Bo’an Zheng

    2014-01-01

    Full Text Available Due to changes in lifestyle, particularly changes in dietary habits, colorectal cancer (CRC increased in recent years despite advances in treatment. Nearly one million new cases diagnosed worldwide and half a million deaths make CRC a leading cause of cancer mortality. In the present study, we aimed to investigate the role of myotubularin-related phosphatase 3 (MTMR3 in CRC cell growth via lentivirus-mediated small interfering RNA (siRNA transduction in human colon cancer cell lines HCT116 and SW1116. The effect of MTMR3 knockdown on cell growth was evaluated by MTT, colony formation, and flow cytometry assays. The effect of MTMR3 knockdown on cell apoptosis was evaluated by flow cytometry with Annexin V/7-AAD double staining. The activation of apoptotic markers, Bad and PARP, was detected using Intracellular Signaling Array. Knockdown of MTMR3 resulted in a significant reduction in cell proliferation in both HCT116 and SW1116 cells. Moreover, knockdown of MTMR3 led to S phase cell cycle arrest. Furthermore, knockdown of MTMR3 induced cell apoptosis via phosphorylation of Bad and cleavage of PARP. These results indicate that MTMR3 may play an important role in the progression of CRC and suggest that siRNA mediated silencing of MTMR3 could be an effective tool in CRC treatment.

  14. Pancratistatin selectively targets cancer cell mitochondria and reduces growth of human colon tumor xenografts.

    Science.gov (United States)

    Griffin, Carly; Karnik, Aditya; McNulty, James; Pandey, Siyaram

    2011-01-01

    The naturally occurring Amaryllidaceae alkaloid pancratistatin exhibits potent apoptotic activity against a large panel of cancer cells lines and has an insignificant effect on noncancerous cell lines, although with an elusive cellular target. Many current chemotherapeutics induce apoptosis via genotoxic mechanisms and thus have low selectivity. The observed selectivity of pancratistatin for cancer cells promoted us to consider the hypothesis that this alkaloid targets cancer cell mitochondria rather than DNA or its replicative machinery. In this study, we report that pancratistatin decreased mitochondrial membrane potential and induced apoptotic nuclear morphology in p53-mutant (HT-29) and wild-type p53 (HCT116) colorectal carcinoma cell lines, but not in noncancerous colon fibroblast (CCD-18Co) cells. Interestingly, pancratistatin was found to be ineffective against mtDNA-depleted (ρ(0)) cancer cells. Moreover, pancratistatin induced cell death in a manner independent of Bax and caspase activation, and did not alter β-tubulin polymerization rate nor cause double-stranded DNA breaks. For the first time we report the efficacy of pancratistatin in vivo against human colorectal adenocarcinoma xenografts. Intratumor administration of pancratistatin (3 mg/kg) caused significant reduction in the growth of subcutaneous HT-29 tumors in Nu/Nu mice (n = 6), with no apparent toxicity to the liver or kidneys as indicated by histopathologic analysis and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling. Altogether, this work suggests that pancratistatin may be a novel mitochondria-targeting compound that selectively induces apoptosis in cancer cells and significantly reduces tumor growth. PMID:21220492

  15. STAT6 Mediates Interleukin-4 Growth Inhibition in Human Breast Cancer Cells

    Directory of Open Access Journals (Sweden)

    Jennifer L. Gooch

    2002-01-01

    Full Text Available In addition to acting as a hematopoietic growth factor, interleukin-4 (IL-4 inhibits growth of some transformed cells in vitro and in vivo. In this study, we show that insulin receptor substrate (IRS-1, IRS-2, and signal transducer and activator of transcription 6 (STAT6 are phosphorylated following IL-4 treatment in MCF-7 breast cancer cells. STAT6 DNA binding is enhanced by IL-4 treatment. STAT6 activation occurs even after IRS-1 depletion, suggesting the two pathways are independent. To examine the role of STAT6 in IL-4-mediated growth inhibition and apoptosis, a fulllength STAT6 cDNA was transfected into MCF-7 cells. Transient overexpression of STAT6 resulted in both cytoplasmic and nuclear expression of the protein, increased DNA binding in response to IL-4, and increased transactivation of an IL-4 responsive promoter. In STAT6-transfected cells, basal proliferation was reduced whereas apoptosis was increased. Finally, stable expression of STAT6 resulted in reduced foci formation compared to vector-transfected cells alone. These results suggest STAT6 is required for IL-4mediated growth inhibition and induction of apoptosis in human breast cancer cells.

  16. Nonconventional opioid binding sites mediate growth inhibitory effects of methadone on human lung cancer cells.

    OpenAIRE

    Maneckjee, R; Minna, J D

    1992-01-01

    Methadone was found to significantly inhibit the in vitro and in vivo growth of human lung cancer cells. The in vitro growth inhibition (occurring at 1-100 nM methadone) was associated with changes in cell morphology and viability detectable within 1 hr and was irreversible after a 24-hr exposure to the drug. These effects of methadone could be reversed in the first 6 hr by naltrexone, actinomycin D, and cycloheximide, suggesting involvement of opioid-like receptors and the requirement for de...

  17. SOX7 is involved in aspirin-mediated growth inhibition of human colorectal cancer cells

    Institute of Scientific and Technical Information of China (English)

    Xin Zhou; Shu-Yan Huang; Jing-Xin Feng; Yan-Yan Gao; Li Zhao; Jun Lu; Bai-Qu Huang; Yu Zhang

    2011-01-01

    AIM: To confirm the role of sex-determining region Y-box 7 (Sox7) in aspirin-mediated growth inhibition of COX-independent human colorectal cancer cells.METHODS: The cell survival percentage was examined by MTT (Moto-nuclear cell direc cytotoxicity) assay.SOX7 expression was assessed by using reverse transcription-polymerase chain reaction and Western blotting. SB203580 was used to inhibit the p38MAPK signal pathway. SOX7 promoter activity was detected by Luciferase reporter assay.RESULTS: SOX7 was upregulated by aspirin and was involved in aspirin-mediated growth inhibition of SW480 human colorectal cancer cells. The p38MAPK pathway played a role in aspirin-induced SOX7 expression, during which the AP1 transcription factors c-Jun and c-Fos upregulated SOX7 promoter activities.RESULTS: SOX7 is upregulated by aspirin and is involved in aspirin-mediated growth inhibition of human colorectal cancer SW480 cells.

  18. Signal transducer and activator of transcription 3 activation is associated with bladder cancer cell growth and survival

    Directory of Open Access Journals (Sweden)

    Hsieh Fu-Chuan

    2008-10-01

    Full Text Available Abstract Background Constitutive activation of signal transducer and activator of transcription 3 (Stat3 signaling pathway plays an important role in several human cancers. Activation of Stat3 is dependent on the phosphorylation at the tyrosine residue 705 by upstream kinases and subsequent nuclear translocation after dimerization. It remains unclear whether oncogenic Stat3 signaling pathway is involved in the oncogenesis of bladder cancer. Results We found that elevated Stat3 phosphorylation in 19 of 100 (19% bladder cancer tissues as well as bladder cancer cell lines, WH, UMUC-3 and 253J. To explore whether Stat3 activation is associated with cell growth and survival of bladder cancer, we targeted the Stat3 signaling pathway in bladder cancer cells using an adenovirus-mediated dominant-negative Stat3 (Y705F and a small molecule compound, STA-21. Both prohibited cell growth and induction of apoptosis in these bladder cancer cell lines but not in normal bladder smooth muscle cell (BdSMC. The survival inhibition might be mediated through apoptotic caspase 3, 8 and 9 pathways. Moreover, down-regulation of anti-apoptotic genes (Bcl-2, Bcl-xL and survivin and a cell cycle regulating gene (cyclin D1 was associated with the cell growth inhibition and apoptosis. Conclusion These results indicated that activation of Stat3 is crucial for bladder cancer cell growth and survival. Therefore, interference of Stat3 signaling pathway emerges as a potential therapeutic approach for bladder cancer.

  19. Inhibition of insulin-like growth factor-1 receptor signaling enhances growth-inhibitory and proapoptotic effects of gefitinib (Iressa) in human breast cancer cells

    OpenAIRE

    Camirand, Anne; Zakikhani, Mahvash; Young, Fiona; Pollak, Michael

    2005-01-01

    Introduction Gefitinib (Iressa, ZD 1839, AstraZeneca) blocks the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) and inhibits proliferation of several human cancer cell types including breast cancer. Phase II clinical trials with gefitinib monotherapy showed an objective response of 9 to 19% in non-small-cell lung cancer patients and less than 10% for breast cancer, and phase III results have indicated no benefit of gefitinib in combination with chemotherapy over chemo...

  20. Selective pattern of cancer cell accumulation and growth using UV modulating printing of hydrogels.

    Science.gov (United States)

    Yang, Wenguang; Yu, Haibo; Wei, Fanan; Li, Gongxin; Wang, Yuechao; Liu, Lianqing

    2015-12-01

    Fabrication of extracellular microenvironment for cancer cell growth in vitro is an indispensable technique to precisely control the cell spatial arrangement and proliferation for cell-behavior research. Current micropatterning methods usually require relatively complicated operations, which makes it difficult to investigate the effects of different cell growth patterns. This manuscript proposes a DMD-based projection technique to quickly pattern a poly(ethylene) glycol diacrylate (PEGDA)-based hydrogel on a common glass substrate. Using this method, we can effectively control the growth patterns of cells. Compared with these traditional methods which employ digital dynamic mask, polymerization of PEGDA solution can be used to create arbitrary shaped microstructures with high efficiency, flexibility and repeatability. The duration of UV exposure is less than 10 s through controlling the projected illumination pattern. The ability of patterned PEGDA-coated film to hinder cell adhesion makes it possible to control area over which cells attach. In our experiments, we take advantage of the blank area to pattern cells, which allows cells to grow in various pre-designed shapes and sizes. And the patterning cells have a high viability after culturing for several days. Interestingly, we found that the restricted space could stiffen and strengthen the cells. These results indicate that cells and extracellular microenvironment can influence each other. PMID:26458559

  1. Synthesis and secretion of platelet-derived growth factor by human breast cancer cell lines

    International Nuclear Information System (INIS)

    The authors report that human breast cancer cells secrete a growth factor that is biologically and immunologically similar to platelet-derived growth factor (PDGF). Serum-free medium conditioned by estrogen-independent MDA-MB-231 or estrogen-dependent MCF-7 cells contains a mitogenic or competence activity that is capable of inducing incorporation of [3H] thymidine into quiescent Swiss 3T3 cells in the presence of platelet-poor plasma. Like authentic PDGF, the PDGF-like activity produced by breast cancer cells is stable after acid and heat treatment (950C) and inhibited by reducing agents. The mitogenic activity comigrates with a material of ≅30 kDa on NaDodSO4/polyacrylamide gels. Immunoprecipitation with PDGF antiserum of proteins from metabolically labeled cell lysates and conditioned medium followed by analysis on nonreducing NaDodSO4/polyacrylamide gels identified proteins of 30 and 34 kDa. Upon reduction, the 30- and 34-kDa bands were converted to 15- and 16-kDa bands suggesting that the immunoprecipitated proteins were made up of two disulfide-linked polypeptides similar to PDGF. Hybridization studies with cDNA probes for the A chain PDGF and the B chain of PDGF/SIS identified transcripts for both PDGF chains in the MCF-7 and MDA-MB-231 cells. The data summarized above provide conclusive evidence for the synthesis and hormonally regulated secretion of a PDGF-like mitogen by breast carcinoma cells. Production of a PDGF-like growth factor by breast cancer cell lines may be important in mediating paracrine stimulation of tumor growth

  2. Treatment with kaempferol suppresses breast cancer cell growth caused by estrogen and triclosan in cellular and xenograft breast cancer models.

    Science.gov (United States)

    Kim, Seung-Hee; Hwang, Kyung-A; Choi, Kyung-Chul

    2016-02-01

    As a phytoestrogen, kaempferol (Kaem) is one of bioflavonoids, which are found in a variety of vegetables including broccoli, tea and tomato. In this study, the antiproliferative effects of Kaem in triclosn (TCS)-induced cell growth were examined in MCF-7 breast cancer cells. TCS promoted the cell viability of MCF-7 cells via estrogen receptor α (ERα) as did 17β-estradiol (E2), a positive control. On the other hand, Kaem significantly suppressed E2 or TCS-induced cell growth. To elucidate the molecular mechanisms of TCS and Kaem, alterations in the expressions of cell cycle, apoptosis and metastasis-related genes were identified using western blot assay. The treatment of the cells with TCS up-regulated the protein expressions of cyclin D1, cyclin E and cathepsin D, while down-regulated p21 and bax expressions. Kaem reversed TCS-induced gene expressions in an opposite manner. The phosphorylation of IRS-1, AKT, MEK1/2 and ERK was increased by TCS, indicating that TCS induced MCF-7 cell proliferation via nongenomic ER signaling pathway associated with IGF-1R. Kaem presented an antagonistic activity on this signaling by down-regulating the protein expression of pIRS-1, pAkt and pMEK1/2 promoted by E2 or TCS. In an in vivo xenografted mouse model, tumor growth was induced by treatment with E2 or TCS, which was identified in the measurement of tumor volume, hematoxylin and eosin staining, bromodeoxyuridine and immunohistochemistry assay. On the contrary, E2 or TCS-induced breast tumor growth was inhibited by co-treatment with Kaem, which is consistent with in vitro results. Taken together, these results revealed that Kaem has an anticancer effect against procancer activity of E2 or TCS, a xenoestrogen, in breast cancer and may be suggested as a prominent agent to neutralize breast cancer risk caused by TCS. PMID:26878784

  3. Dietary phenethyl isothiocyanate inhibition of androgen-responsive LNCaP prostate cancer cell tumor growth correlates with decreased angiogenesis

    Science.gov (United States)

    Phenethyl isothiocyanate (PEITC), found in certain cruciferous vegetables, has antitumor activity in several cancer models, including prostate cancer. In our xenograft model, dietary administration of PEITC (100-150 mg/kg/d) inhibited androgen-responsive LNCaP human prostate cancer cell tumor growth...

  4. Bithionol inhibits ovarian cancer cell growth In Vitro - studies on mechanism(s) of action

    International Nuclear Information System (INIS)

    Drug resistance is a cause of ovarian cancer recurrence and low overall survival rates. There is a need for more effective treatment approaches because the development of new drug is expensive and time consuming. Alternatively, the concept of ‘drug repurposing’ is promising. We focused on Bithionol (BT), a clinically approved anti-parasitic drug as an anti-ovarian cancer drug. BT has previously been shown to inhibit solid tumor growth in several preclinical cancer models. A better understanding of the anti-tumor effects and mechanism(s) of action of BT in ovarian cancer cells is essential for further exploring its therapeutic potential against ovarian cancer. The cytotoxic effects of BT against a panel of ovarian cancer cell lines were determined by Presto Blue cell viability assay. Markers of apoptosis such as caspases 3/7, cPARP induction, nuclear condensation and mitochondrial transmembrane depolarization were assessed using microscopic, FACS and immunoblotting methods. Mechanism(s) of action of BT such as cell cycle arrest, reactive oxygen species (ROS) generation, autotaxin (ATX) inhibition and effects on MAPK and NF-kB signalling were determined by FACS analysis, immunoblotting and colorimetric methods. BT caused dose dependent cytotoxicity against all ovarian cancer cell lines tested with IC50 values ranging from 19 μM – 60 μM. Cisplatin-resistant variants of A2780 and IGROV-1 have shown almost similar IC50 values compared to their sensitive counterparts. Apoptotic cell death was shown by expression of caspases 3/7, cPARP, loss of mitochondrial potential, nuclear condensation, and up-regulation of p38 and reduced expression of pAkt, pNF-κB, pIκBα, XIAP, bcl-2 and bcl-xl. BT treatment resulted in cell cycle arrest at G1/M phase and increased ROS generation. Treatment with ascorbic acid resulted in partial restoration of cell viability. In addition, dose and time dependent inhibition of ATX was observed. BT exhibits cytotoxic effects on various

  5. Transfection of promyelocytic leukemia in retrovirus vector inhibits growth of human bladder cancer cells

    Institute of Scientific and Technical Information of China (English)

    Lei LI; Da-lin HE

    2005-01-01

    Aim: To construct a recombinant retrovirus vector carrying human promyelocytic leukemia (PML) cDNA and identify its expression and biology role in bladder cancer UM-UC-2 cells for future gene therapy. Methods: PML full-length cDNA was inserted into the EcoR I and BamHI site of pLXSN vector containing the long terminal repeat (LTR) promoter. The vector was identified by restriction enzyme digestion and then transfected into PA317 packaging cell line by calcium phosphate coprecipitation. PML cDNA was detected by polymerase chain reaction (PCR) and the protein was identified by laser confocal microscopy and Western blot in bladder cancer cells, respectively. The morphology was observed by inverted phase contrast microscope, and MTT assay determined growth curve of the bladder cancer cells. Results: Restriction enzyme digestion proved that a 2.1kb PML cDNA was inserted into the pLXSN vector. PCR assay demonstrated that 304 bp fragments were found in UM-UC-2/pLPMLSN transfects. Laser confocal microscopy showed speck dots fluorescence in the UM-UC-2/pLPMLSN nucleus.A 90 kD specific brand was found by Western blot. MTT assay demonstrated the UM-UC-2/pLPMLSN bladder cancer growth inhibition. Conclusion: The retrovirus pLPMLSN vector was successfully constructed and could generate high effective expression of human PML in bladder cancer cell UM-UC-2, suggesting that PML recombinant retrovirus have potential utility in the gene therapy for bladder cancer.

  6. Tazarotene-induced gene 1 inhibits prostaglandin E2-stimulated HCT116 colon cancer cell growth

    Directory of Open Access Journals (Sweden)

    Tsai Fu-Ming

    2011-11-01

    Full Text Available Abstract Background The tazarotene-induced gene 1 (TIG1 is a putative tumor suppressor gene. We have recently demonstrated both TIG1A and TIG1B isoforms inhibited cell growth and induced the expression of G protein-coupled receptor kinase 5 (GRK5 in colon cancer cells. Because elevated prostaglandin E2 (PGE2 signaling plays a significant role in colorectal carcinogenesis, the objective of this study was to explore the effect of TIG1 on PGE2-induced cellular proliferation and signaling in colon cancer cells. Methods HCT116 cells as well as TIG1A and TIG1B stable cells established from HCT116 colon cancer cells using the GeneSwitch system were used. TIG1 isoform expression was induced by mifepristone treatment in stable cells. Cell growth was determined using the WST-1 cell proliferation assay. Activation of β-catenin/TCF and cyclic adenosine monophosphate (cAMP/CREB signaling pathways were determined using luciferase reporter assays. Expression and subcellular distribution of β-catenin were analyzed using Western blot and confocal microscope. Levels of cAMP were measured using an enzyme immunoassay. RNA interference was used to examine the effects of TIG1- and GRK5-mediated changes. Results PGE2-stimulated cell growth was reduced in inducible TIG1A- and TIG1B-stable HCT116 cells. GRK5 expression was upregulated by both TIG1A and TIG1B isoforms, and its expression suppressed PGE2-stimulated HCT116 cell growth. GRK5, TIG1A, and TIG1B expression significantly inhibited PGE2-stimulated β-catenin/TCF and cAMP signaling pathway reporters and cAMP. Also, PGE2-stimulated nuclear localization of β-catenin was inhibited by expression of TIG1A and TIG1B, which was ameliorated by both TIG1 and GRK5 siRNAs. Conclusions TIG1 suppressed PGE2-stimulated Wnt and cAMP signaling pathways in colon cancer cells through GRK5.

  7. Mullerian Inhibiting Substance inhibits cervical cancer cell growth via a pathway involving p130 and p107

    OpenAIRE

    Barbie, Thanh U.; Barbie, David A; MacLaughlin, David T.; Maheswaran, Shyamala; Donahoe, Patricia K.

    2003-01-01

    In addition to causing regression of the Mullerian duct in the male embryo, Mullerian Inhibiting Substance (MIS) inhibits the growth of epithelial ovarian cancer cells, which are known to be of Mullerian origin. Because the uterine cervix is derived from the same Mullerian duct precursor as the epithelium of the ovary, we tested the hypothesis that cervical cancer cells might also respond to MIS. A number of cervical cancer cell lines express the MIS type II receptor, and MIS inhibits the gro...

  8. Combined MET inhibition and topoisomerase I inhibition block cell growth of small cell lung cancer.

    Science.gov (United States)

    Rolle, Cleo E; Kanteti, Rajani; Surati, Mosmi; Nandi, Suvobroto; Dhanasingh, Immanuel; Yala, Soheil; Tretiakova, Maria; Arif, Qudsia; Hembrough, Todd; Brand, Toni M; Wheeler, Deric L; Husain, Aliya N; Vokes, Everett E; Bharti, Ajit; Salgia, Ravi

    2014-03-01

    Small cell lung cancer (SCLC) is a devastating disease, and current therapies have not greatly improved the 5-year survival rates. Topoisomerase (Top) inhibition is a treatment modality for SCLC; however, the response is short lived. Consequently, our research has focused on improving SCLC therapeutics through the identification of novel targets. Previously, we identified MNNG HOS transforming gene (MET) to be overexpressed and functional in SCLC. Herein, we investigated the therapeutic potential of combinatorial targeting of MET using SU11274 and Top1 using 7-ethyl-10-hydroxycamptothecin (SN-38). MET and TOP1 gene copy numbers and protein expression were determined in 29 patients with limited (n = 11) and extensive (n = 18) disease. MET gene copy number was significantly increased (>6 copies) in extensive disease compared with limited disease (P = 0.015). Similar TOP1 gene copy numbers were detected in limited and extensive disease. Immunohistochemical staining revealed a significantly higher Top1 nuclear expression in extensive (0.93) versus limited (0.15) disease (P = 0.04). Interestingly, a significant positive correlation was detected between MET gene copy number and Top1 nuclear expression (r = 0.5). In vitro stimulation of H82 cells revealed hepatocyte growth factor (HGF)-induced nuclear colocalization of p-MET and Top1. Furthermore, activation of the HGF/MET axis enhanced Top1 activity, which was abrogated by SU11274. Combination of SN-38 with SU11274 dramatically decreased SCLC growth as compared with either drug alone. Collectively, these findings suggest that the combinatorial inhibition of MET and Top1 is a potentially efficacious treatment strategy for SCLC. PMID:24327519

  9. Aspirin inhibits colon cancer cell and tumor growth and downregulates specificity protein (Sp transcription factors.

    Directory of Open Access Journals (Sweden)

    Satya Pathi

    Full Text Available Acetylsalicylic acid (aspirin is highly effective for treating colon cancer patients postdiagnosis; however, the mechanisms of action of aspirin in colon cancer are not well defined. Aspirin and its major metabolite sodium salicylate induced apoptosis and decreased colon cancer cell growth and the sodium salt of aspirin also inhibited tumor growth in an athymic nude mouse xenograft model. Colon cancer cell growth inhibition was accompanied by downregulation of Sp1, Sp3 and Sp4 proteins and decreased expression of Sp-regulated gene products including bcl-2, survivin, VEGF, VEGFR1, cyclin D1, c-MET and p65 (NFκB. Moreover, we also showed by RNA interference that β-catenin, an important target of aspirin in some studies, is an Sp-regulated gene. Aspirin induced nuclear caspase-dependent cleavage of Sp1, Sp3 and Sp4 proteins and this response was related to sequestration of zinc ions since addition of zinc sulfate blocked aspirin-mediated apoptosis and repression of Sp proteins. The results demonstrate an important underlying mechanism of action of aspirin as an anticancer agent and, based on the rapid metabolism of aspirin to salicylate in humans and the high salicylate/aspirin ratios in serum, it is likely that the anticancer activity of aspirin is also due to the salicylate metabolite.

  10. ING1 and 5-Azacytidine Act Synergistically to Block Breast Cancer Cell Growth

    Science.gov (United States)

    Thakur, Satbir; Feng, Xiaolan; Qiao Shi, Zhong; Ganapathy, Amudha; Kumar Mishra, Manoj; Atadja, Peter; Morris, Don; Riabowol, Karl

    2012-01-01

    Background Inhibitor of Growth (ING) proteins are epigenetic “readers” that recognize trimethylated lysine 4 of histone H3 (H3K4Me3) and target histone acetyl transferase (HAT) and histone deacetylase (HDAC) complexes to chromatin. Methods and Principal Findings Here we asked whether dysregulating two epigenetic pathways with chemical inhibitors showed synergistic effects on breast cancer cell line killing. We also tested whether ING1 could synergize better with chemotherapeutics that target the same epigenetic mechanism such as the HDAC inhibitor LBH589 (Panobinostat) or a different epigenetic mechanism such as 5-azacytidine (5azaC), which inhibits DNA methyl transferases. Simultaneous treatment of breast cancer cell lines with LBH589 and 5azaC did not show significant synergy in killing cells. However, combination treatment of ING1 with either LBH589 or 5azaC did show synergy. The combination of ING1b with 5azaC, which targets two distinct epigenetic mechanisms, was more effective at lower doses and enhanced apoptosis as determined by Annexin V staining and cleavage of caspase 3 and poly-ADP-ribose polymerase (PARP). ING1b plus 5azaC also acted synergistically to increase γH2AX staining indicating significant levels of DNA damage were induced. Adenoviral delivery of ING1b with 5azaC also inhibited cancer cell growth in a murine xenograft model and led to tumor regression when viral concentration was optimized in vivo. Conclusions These data show that targeting distinct epigenetic pathways can be more effective in blocking cancer cell line growth than targeting the same pathway with multiple agents, and that using viral delivery of epigenetic regulators can be more effective in synergizing with a chemical agent than using two chemotherapeutic agents. This study also indicates that the ING1 epigenetic regulator may have additional activities in the cell when expressed at high levels. PMID:22916295

  11. ING1 and 5-azacytidine act synergistically to block breast cancer cell growth.

    Directory of Open Access Journals (Sweden)

    Satbir Thakur

    Full Text Available BACKGROUND: Inhibitor of Growth (ING proteins are epigenetic "readers" that recognize trimethylated lysine 4 of histone H3 (H3K4Me3 and target histone acetyl transferase (HAT and histone deacetylase (HDAC complexes to chromatin. METHODS AND PRINCIPAL FINDINGS: Here we asked whether dysregulating two epigenetic pathways with chemical inhibitors showed synergistic effects on breast cancer cell line killing. We also tested whether ING1 could synergize better with chemotherapeutics that target the same epigenetic mechanism such as the HDAC inhibitor LBH589 (Panobinostat or a different epigenetic mechanism such as 5-azacytidine (5azaC, which inhibits DNA methyl transferases. Simultaneous treatment of breast cancer cell lines with LBH589 and 5azaC did not show significant synergy in killing cells. However, combination treatment of ING1 with either LBH589 or 5azaC did show synergy. The combination of ING1b with 5azaC, which targets two distinct epigenetic mechanisms, was more effective at lower doses and enhanced apoptosis as determined by Annexin V staining and cleavage of caspase 3 and poly-ADP-ribose polymerase (PARP. ING1b plus 5azaC also acted synergistically to increase γH2AX staining indicating significant levels of DNA damage were induced. Adenoviral delivery of ING1b with 5azaC also inhibited cancer cell growth in a murine xenograft model and led to tumor regression when viral concentration was optimized in vivo. CONCLUSIONS: These data show that targeting distinct epigenetic pathways can be more effective in blocking cancer cell line growth than targeting the same pathway with multiple agents, and that using viral delivery of epigenetic regulators can be more effective in synergizing with a chemical agent than using two chemotherapeutic agents. This study also indicates that the ING1 epigenetic regulator may have additional activities in the cell when expressed at high levels.

  12. Lysine-specific demethylase 1 mediates epidermal growth factor signaling to promote cell migration in ovarian cancer cells

    OpenAIRE

    Genbao Shao; Jie Wang; Yuanxia Li; Xiuwen Liu; Xiaodong Xie; Xiaolei Wan; Meina Yan; Jie Jin; Qiong Lin; Haitao Zhu; Liuping Zhang; Aihua Gong; Qixiang Shao; Chaoyang Wu

    2015-01-01

    Epigenetic abnormalities play a vital role in the progression of ovarian cancer. Lysine-specific demethylase 1 (LSD1/KDM1A) acts as an epigenetic regulator and is overexpressed in ovarian tumors. However, the upstream regulator of LSD1 expression in this cancer remains elusive. Here, we show that epidermal growth factor (EGF) signaling upregulates LSD1 protein levels in SKOV3 and HO8910 ovarian cancer cells overexpressing both LSD1 and the EGF receptor. This effect is correlated with a decrea...

  13. Optimal Therapeutic Strategy for Non-small Cell Lung Cancer with Mutated Epidermal Growth Factor Receptor

    Directory of Open Access Journals (Sweden)

    Zhong SHI

    2015-02-01

    Full Text Available Although epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs have been widely used in non-small cell lung cancer (NSCLC patients, it is still controversial about how to combine EGFR-TKI with chemotherapy and other targeted drugs. We have made a summary on the current therapeutic models of EGFR-TKI combined with chemotherapy/bevacizumab in this review and aimed to find the optimal therapeutic strategy for NSCLC patients with EGFR mutation.

  14. 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...

  15. ING1 and 5-Azacytidine Act Synergistically to Block Breast Cancer Cell Growth

    OpenAIRE

    Satbir Thakur; Xiaolan Feng; Zhong Qiao Shi; Amudha Ganapathy; Manoj Kumar Mishra; Peter Atadja; Don Morris; Karl Riabowol

    2012-01-01

    BACKGROUND: Inhibitor of Growth (ING) proteins are epigenetic "readers" that recognize trimethylated lysine 4 of histone H3 (H3K4Me3) and target histone acetyl transferase (HAT) and histone deacetylase (HDAC) complexes to chromatin. METHODS AND PRINCIPAL FINDINGS: Here we asked whether dysregulating two epigenetic pathways with chemical inhibitors showed synergistic effects on breast cancer cell line killing. We also tested whether ING1 could synergize better with chemotherapeutics that targe...

  16. Metformin inhibits pancreatic cancer cell and tumor growth and downregulates Sp transcription factors.

    Science.gov (United States)

    Nair, Vijayalekshmi; Pathi, Satya; Jutooru, Indira; Sreevalsan, Sandeep; Basha, Riyaz; Abdelrahim, Maen; Samudio, Ismael; Safe, Stephen

    2013-12-01

    Metformin is a widely used antidiabetic drug, and epidemiology studies for pancreatic and other cancers indicate that metformin exhibits both chemopreventive and chemotherapeutic activities. Several metformin-induced responses and genes are similar to those observed after knockdown of specificity protein (Sp) transcription factors Sp1, Sp3 and Sp4 by RNA interference, and we hypothesized that the mechanism of action of metformin in pancreatic cancer cells was due, in part, to downregulation of Sp transcription factors. Treatment of Panc1, L3.6pL and Panc28 pancreatic cancer cells with metformin downregulated Sp1, Sp3 and Sp4 proteins and several pro-oncogenic Sp-regulated genes including bcl-2, survivin, cyclin D1, vascular endothelial growth factor and its receptor, and fatty acid synthase. Metformin induced proteasome-dependent degradation of Sps in L3.6pL and Panc28 cells, whereas in Panc1 cells metformin decreased microRNA-27a and induced the Sp repressor, ZBTB10, and disruption of miR-27a:ZBTB10 by metformin was phosphatase dependent. Metformin also inhibited pancreatic tumor growth and downregulated Sp1, Sp3 and Sp4 in tumors in an orthotopic model where L3.6pL cells were injected directly into the pancreas. The results demonstrate for the first time that the anticancer activities of metformin are also due, in part, to downregulation of Sp transcription factors and Sp-regulated genes. PMID:23803693

  17. Silymarin suppressed lung cancer growth in mice via inhibiting myeloid-derived suppressor cells.

    Science.gov (United States)

    Wu, Tiancong; Liu, Wen; Guo, Wenjie; Zhu, Xixu

    2016-07-01

    In this study, we investigated the antitumor activity of Silymarin in a mouse model of colon cancer xenograft of Lewis lung cancer (LLC) cells. Silymarin significantly suppressed tumor growth and induced apoptosis of cells in tumor tissues at a dose of 25 and 50mg/kg. Silymarin treatment enhanced the infiltration and function of CD8(+) T cells. In the meantime, Silymarin decreased the level of IL-10 while elevated the level of IL-2 and IFN-γ in the serum of tumor-bearing mice. Finally, Silymarin reduced the proportion of myeloid-derived suppressor cells (MDSC) in the tumor tissue and also the mRNA expressions of inducible nitric oxide synthases-2 (iNOS2), arginase-1 (Arg-1) and MMP9, which indicated that the function of MDSC in tumor tissues were suppressed. Altogether, our data here showed that Silymarin inhibited the MDSC and promoted the infiltration and function of CD8(+) T cells thus suppressed the growth of LLC xenografts, which provides evidence for the possible use of Silymarin against lung cancer. PMID:27261626

  18. Calmidazolium chloride inhibits growth of murine embryonal carcinoma cells, a model of cancer stem-like cells.

    Science.gov (United States)

    Lee, Jina; Kim, Min Seong; Kim, Min Aeh; Jang, Yeun Kyu

    2016-09-01

    Calmidazolium chloride (CMZ) is widely used as a calmodulin (CaM) antagonist, but is also known to induce apoptosis in certain cancer cell lines. However, in spite of the importance of cancer stem cells (CSCs) in cancer therapy, the effects of CMZ on CSCs are not yet well understood. We investigated the effects of CMZ on the F9 embryonal carcinoma cell (ECC) line as a surrogate model of CSCs. To avoid bias due to culture conditions, F9 ECCs and E14 embryonic stem cells (ESCs) were grown in the same culture medium. Results obtained using a cell-counting kit showed that CMZ significantly inhibited growth in F9 ECCs compared with growth in E14 ESCs. CMZ also induced apoptosis of F9 ECCs, but not of E14 ESCs, which was associated with caspase-3 activation and an increased fraction of the sub-G1 cell population. In addition, our data revealed that the expression of stemness-related genes including c-Myc was selectively down regulated in CMZ-treated F9 ECCs. Our results suggest that CMZ can inhibit the growth of ECCs by inducing apoptosis and down regulating stemness-related genes, without causing any harm to normal stem cells. These findings indicate a potential application of CMZ in the development of anti-CSC therapeutics. PMID:27247146

  19. Wwox suppresses breast cancer cell growth through modulation of the hedgehog–GLI1 signaling pathway

    Energy Technology Data Exchange (ETDEWEB)

    Xiong, Anwen [Department of Oncology, Changhai Hospital, Second Military Medical University, Shanghai (China); Wei, Li [Department of Oncology, Changhai Hospital, Second Military Medical University, Shanghai (China); Department of Oncology, NO. 401 hospital of PLA, Qingdao, Shandong (China); Ying, Mingzhen; Wu, Hongmei; Hua, Jin [Department of Oncology, Changhai Hospital, Second Military Medical University, Shanghai (China); Wang, Yajie, E-mail: yajiewang@live.com [Department of Oncology, Changhai Hospital, Second Military Medical University, Shanghai (China)

    2014-01-24

    Highlights: • We investigated Gli1 as a novel partner of Wwox. • We observed a physical association between Wwox and the Gli1. • Wwox–Gli1 interaction affects Gli1 intracellular localization. • Gli1 Blocks Wwox-induced growth inhibition and apoptosis in T47D cells. - Abstract: Wwox is a tumor suppressor that is frequently deleted or altered in several cancer types, including breast cancer. Previous studies have shown that ectopic expression of Wwox inhibits proliferation of breast cancer cells. However, the underlying mechanism remains unclear. To better understand the molecular mechanisms of Wwox function, we investigated novel partners of this protein. Utilizing the coimmunoprecipitation assay, we observed a physical association between Wwox and the Gli1 zinc-finger transcription factor involved in the hedgehog pathway. Our results further demonstrated that Wwox expression triggered redistribution of nuclear Gli1 to the cytoplasm. Additionally, ectopic expression of Wwox reduced Gli1 expression in vitro. Furthermore, Gli1 Blocks Wwox-induced breast cancer cell growth inhibition. These findings suggest a functional crosstalk between Wwox and hedgehog–GLI1 signaling pathway in tumorigenesis.

  20. 3D cell culture systems modeling tumor growth determinants in cancer target discovery.

    Science.gov (United States)

    Thoma, Claudio R; Zimmermann, Miriam; Agarkova, Irina; Kelm, Jens M; Krek, Wilhelm

    2014-04-01

    Phenotypic heterogeneity of cancer cells, cell biological context, heterotypic crosstalk and the microenvironment are key determinants of the multistep process of tumor development. They sign responsible, to a significant extent, for the limited response and resistance of cancer cells to molecular-targeted therapies. Better functional knowledge of the complex intra- and intercellular signaling circuits underlying communication between the different cell types populating a tumor tissue and of the systemic and local factors that shape the tumor microenvironment is therefore imperative. Sophisticated 3D multicellular tumor spheroid (MCTS) systems provide an emerging tool to model the phenotypic and cellular heterogeneity as well as microenvironmental aspects of in vivo tumor growth. In this review we discuss the cellular, chemical and physical factors contributing to zonation and cellular crosstalk within tumor masses. On this basis, we further describe 3D cell culture technologies for growth of MCTS as advanced tools for exploring molecular tumor growth determinants and facilitating drug discovery efforts. We conclude with a synopsis on technological aspects for on-line analysis and post-processing of 3D MCTS models. PMID:24636868

  1. Effects of recombinant epidermal growth factor receptor antisense adenovirus combined with irradiation on breast cancer cells

    International Nuclear Information System (INIS)

    Objective: To investigate the effects of a recombinant antisense adenovirus for epidermal growth factor receptor (EGFR) combined with irradiation on breast cancer cells. Methods: Human EGFR cDNA fragment was subcloned in the opposite orientation to the cytomegaloviral promoter and inserted into a E1/E3-deleted type 5 adenoviral vector to obtain AdE5 construct which expresses EGFR antisense RNA. Combined with γ-ray irradiation, its effects on clonogenicity and cell cycle phase distribution were studied in a human breast cancer line MDA-MB-23. Results: EGFR protein expression was dramatically inhibited in MDA-MB-231 cells after AdE5 infection. The post-irradiation clonogenicity was reduced by AdE5 in a viral and irradiation dose-dependent manner. Further cytometric analysis showed that AdE5 infection at a MOI of 300 pfu/cell induced a cell cycle progression from radio-resistant G0 + G1 phases to radiosensitive G2 + M phases, resulting in a synergistic effect after combination of these two treatments. Conclusions: The transduction of EGFR antisense RNA by adenoviral vector is effective for antisense strategy targeting EGFR, and increases the cell-killing effect of ionizing radiation on breast cancer cells.(authors)

  2. Novel STAT3 phosphorylation inhibitors exhibit potent growth suppressive activity in pancreatic and breast cancer cells

    Science.gov (United States)

    Lin, Li; Hutzen, Brian; Zuo, Mingxin; Ball, Sarah; Deangelis, Stephanie; Foust, Elizabeth; Pandit, Bulbul; Ihnat, Michael A.; Shenoy, Satyendra S.; Kulp, Samuel; Li, Pui-Kai; Li, Chenglong; Fuchs, James; Lin, Jiayuh

    2010-01-01

    The constitutive activation of Signal Transducer and Activator of Transcription 3 (STAT3) is frequently detected in most types of human cancer where it plays important roles in survival, drug-resistance, angiogenesis, and other functions. Targeting constitutive STAT3 signaling is thus an attractive therapeutic approach for these cancers. We have recently developed novel small molecule STAT3 inhibitors known as FLLL31 and FLLL32, which are derived from curcumin (the primary bioactive compound of turmeric). These compounds are designed to bind selectively to Janus Kinase 2 (JAK2) and the STAT3 SH2 domain, which serves crucial roles in STAT3 dimerization and signal transduction. Here we show that FLLL31 and FLLL32 are effective inhibitors of STAT3 phosphorylation, DNA binding activity, and transactivation in vitro, leading to the impediment of multiple oncogenic processes and the induction of apoptosis in pancreatic and breast cancer cell lines. FLLL31 and FLLL32 also inhibit colony formation in soft agar, cell invasion, and exhibit synergy with the anti-cancer drug doxorubicin against breast cancer cells. In addition, we show that FLLL32 can inhibit the induction of STAT3 phosphorylation by Interferon-α (IFNα) and Interleukin-6 (IL-6) in breast cancer cells. We also demonstrate that administration of FLLL32 can inhibit tumor growth and vascularity in chicken embryo xenografts as well as substantially reduce tumor volumes in mouse xenografts. Our findings highlight the potential of these new compounds and their efficacy in targeting pancreatic and breast cancers that exhibit constitutive STAT3 signaling. PMID:20215512

  3. Effect of specific silencing of EMMPRIN on the growth and cell cycle distribution of MCF-7 breast cancer cells.

    Science.gov (United States)

    Yang, X Q; Yang, J; Wang, R; Zhang, S; Tan, Q W; Lv, Q; Meng, W T; Mo, X M; Li, H J

    2015-01-01

    The extracellular matrix metalloproteinase inducer (EMMPRIN, CD147) is a member of the immunoglobulin family and shows increased expression in tumor cells. We examined the effect of RNAi-mediated EMMPRIN gene silencing induced by lentiviral on the growth and cycle distribution of MCF-7 breast cancer cells. Lentiviral expressing EMMPRIN-short hairpin RNA were packaged to infect MCF-7 cells. The inhibition efficiency of EMMPRIN was validated by real-time fluorescent quantitation polymerase chain reaction and western blotting. The effect of EMMPRIN on cell proliferation ability was detected using the MTT assay and clone formation experiments. Changes in cell cycle were detected by flow cytometry. EMMPRIN-short hairpin RNA-packaged lentiviral significantly down-regulated EMMPRIN mRNA and protein expression, significantly inhibited cell proliferation and in vitro tumorigenicity, and induced cell cycle abnormalities. Cells in the G0/G1 and G2/M phases were increased, while cells in the S phase were decreased after infection of MCF-7 cells for 3 days. The EMMPRIN gene facilitates breast cancer cell malignant proliferation by regulating cell cycle distribution and may be a molecular target for breast cancer gene therapy. PMID:26634540

  4. RRR-α-tocopheryl succinate inhibits human gastric cancer SGC-7901 cell growth by inducing apoptosis and DNA synthesis arrest

    OpenAIRE

    Wu, Kun; ZHAO Yan; Liu, Bai-He; Li, Yao; Liu, Fang; Guo, Jian; Yu, Wei-Ping

    2002-01-01

    AIM: To investigate the effects of growth inhibition of human gastric cancer SGC-7901 cell with RRR-α-tocopheryl succinate (VES), a derivative of natural Vitamin E, via inducing apoptosis and DNA synthesis arrest.

  5. MUC4 potentiates invasion and metastasis of pancreatic cancer cells through stabilization of fibroblast growth factor receptor 1

    OpenAIRE

    Rachagani, Satyanarayana; Muzafar A Macha; Moorthy P Ponnusamy; Haridas, Dhanya; Kaur, Sukhwinder; Jain, Maneesh; Batra, Surinder K.

    2012-01-01

    MUC4 is a type-1 transmembrane mucin differentially expressed in multiple cancers and has previously been shown to potentiate progression and metastasis of pancreatic cancer. In this study, we investigated the molecular mechanisms associated with the MUC4-induced invasion and metastasis in pancreatic cancer. Stable silencing of MUC4 in multiple pancreatic cancer cells resulted in the downregulation of N-cadherin and its interacting partner fibroblast growth factor receptor 1 (FGFR1) through d...

  6. Insulin-like growth factor binding protein 2 is a marker for antiestrogen resistant human breast cancer cell lines but is not a major growth regulator

    DEFF Research Database (Denmark)

    Juncker-Jensen, A; Lykkesfeldt, A E; Worm, J;

    2006-01-01

    Antiestrogens target the estrogen receptor and counteract the growth stimulatory action of estrogen on human breast cancer. However, acquired resistance to antiestrogens is a major clinical problem in endocrine treatment of breast cancer patients. To mimic acquired resistance, we have used a mode...... resistant cell growth was observed. Thus, we were able to establish IGFBP-2 as a marker for antiestrogen resistant breast cancer cell lines, although IGFBP-2 was not a major contributor to the resistant cell growth.......Antiestrogens target the estrogen receptor and counteract the growth stimulatory action of estrogen on human breast cancer. However, acquired resistance to antiestrogens is a major clinical problem in endocrine treatment of breast cancer patients. To mimic acquired resistance, we have used a model...... system with the antiestrogen sensitive human breast cancer cell line MCF-7 and several antiestrogen resistant cell lines derived from the parental MCF-7 cell line. This model system was used to study the expression and possible involvement in resistant cell growth of insulin-like growth factor binding...

  7. Silibinin inhibits accumulation of myeloid-derived suppressor cells and tumor growth of murine breast cancer

    International Nuclear Information System (INIS)

    Myeloid-derived suppressor cells (MDSC)s increase in blood and accumulate in the tumor microenvironment of tumor-bearing animals, contributing to immune suppression in cancer. Silibinin, a natural flavonoid from the seeds of milk thistle, has been developed as an anti-inflammatory agent and supportive care agent to reduce the toxicity of cancer chemotherapy. The goals of this study were to evaluate the effect of silibinin on MDSCs in tumor-bearing mice and antitumor activity of silibinin in a mouse model of breast cancer. 4T1 luciferase-transfected mammary carcinoma cells were injected into in the mammary fat pad female BALB/c mice, and female CB17-Prkdc Scid/J mice. Silibinin treatment started on day 4 or day 14 after tumor inoculation continued every other day. Tumor growth was monitored by bioluminescent imaging (BLI) measuring total photon flux. Flow cytometry measured total leukocytes, CD11b+ Gr-1+ MDSC, and T cells in the blood and tumors of tumor-bearing mice. The effects of silibinin on 4T1 cell viability in vitro were measured by BLI. Treatment with silibinin increased overall survival in mice harboring tumors derived from the 4T1-luciferase breast cancer cell line, and reduced tumor volumes and numbers of CD11b+Gr-1+ MDSCs in the blood and tumor, and increased the content of T cells in the tumor microenvironment. Silibinin failed to inhibit tumor growth in immunocompromised severe combined immunodeficiency mice, supporting the hypothesis that anticancer effect of silibinin is immune-mediated. The antitumor activity of silibinin requires an intact host immune system and is associated with decreased accumulation of blood and tumor-associated MDSCs

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

    International Nuclear Information System (INIS)

    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. 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. 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 laminin-binding integrins, nor can they be linked to

  9. 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

  10. Tocotrienol-adjuvanted dendritic cells inhibit tumor growth and metastasis: a murine model of breast cancer.

    Directory of Open Access Journals (Sweden)

    Sitti Rahma Abdul Hafid

    Full Text Available Tocotrienol-rich fraction (TRF from palm oil is reported to possess anti-cancer and immune-enhancing effects. In this study, TRF supplementation was used as an adjuvant to enhance the anti-cancer effects of dendritic cells (DC-based cancer vaccine in a syngeneic mouse model of breast cancer. Female BALB/c mice were inoculated with 4T1 cells in mammary pad to induce tumor. When the tumor was palpable, the mice in the experimental groups were injected subcutaneously with DC-pulsed with tumor lysate (TL from 4T1 cells (DC+TL once a week for three weeks and fed daily with 1 mg TRF or vehicle. Control mice received unpulsed DC and were fed with vehicle. The combined therapy of using DC+TL injections and TRF supplementation (DC+TL+TRF inhibited (p<0.05 tumor growth and metastasis. Splenocytes from the DC+TL+TRF group cultured with mitomycin-C (MMC-treated 4T1 cells produced higher (p<0.05 levels of IFN-γ and IL-12. The cytotoxic T-lymphocyte (CTL assay also showed enhanced tumor-specific killing (p<0.05 by CD8(+ T-lymphocytes isolated from mice in the DC+TL+TRF group. This study shows that TRF has the potential to be used as an adjuvant to enhance effectiveness of DC-based vaccines.

  11. Downregulation of myosin VI reduced cell growth and increased apoptosis in human colorectal cancer.

    Science.gov (United States)

    You, Weiqiang; Tan, Gewen; Sheng, Nengquan; Gong, Jianfeng; Yan, Jun; Chen, Di; Zhang, Huizhen; Wang, Zhigang

    2016-05-01

    Colorectal cancer (CRC) is the third most commonly diagnosed cancer worldwide, with the mortality increasing steadily over the last decade. Myosin VI (MYO6) expression is found to be elevated in some types of human carcinoma cell types, suggesting that it may be a sensitive biomarker for the diagnosis and follow-up. In this study, we first used the Oncomine database to explore the expression of MYO6 in CRC tissues, and then constructed a plasmid of RNA interference targeting MYO6 gene. After transfection of lentivirus targeting MYO6 into SW1116 cells, cell viability and proliferation were measured with 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and colony formation assay. Cell cycle distribution was assayed by flow cytometry and apoptosis was evaluated by Annexin V. MYO6 expression was detected by quantitative real-time polymerase chain reaction and western blot analysis. It was found that MYO6 mRNA was upregulated in CRC tissues using data mining of public Oncomine microarray datasets. Depletion of MYO6 significantly inhibited cell proliferation and colony formation. In addition, knockdown of MYO6 slightly arrested cell cycle in G0/G1 phase, but remarkably increased the proportion of the sub-G1 phase of cell with the increase of apoptotic cells. These results suggest that MYO6 may promote cell growth and may be used as a potential target for anticancer therapy of CRC. PMID:27044563

  12. Withaferin-A induces mitotic catastrophe and growth arrest in prostate cancer cells

    Science.gov (United States)

    Roy, Ram V; Suman, Suman; Das, Trinath P.; Luevano, Joe; Damodaran, Chendil

    2014-01-01

    Cell cycle deregulation is strongly associated with the pathogenesis of prostate cancer (CaP). Clinical trials of cell cycle regulators that target either the G0/G1 or G2/M phase to inhibit the growth of cancers including CaP are increasing. In this study, we determined the cell-cycle regulatory potential of the herbal molecule Withaferin-A (WA) on CaP cells. WA induced irreversible G2/M arrest in both CaP cell lines (PC3 and DU145) for 48 h. The G2/M arrest was accompanied by upregulation of phosphorylated Wee1, phophorylated histone H3, p21 and Aurora-B. On the other hand, downregulation of cyclins (E2, A, and B1) and phorphorylated Cdc2 (Tyr15) was observed in WA-treated CaP cells. In addition, decreased levels of phosphorylated Chk1 (Ser345) and Chk2 (Thr68) were evident in WA-treated CaP cells. Our results suggest that activation of Cdc2 leads to accumulation in M-phase, with abnormal duplication, and initiation of mitotic catastrophe that results in cell death. In conclusion, these results clearly highlight the potential of WA as a regulator of the G2/M phase of the cell cycle and as a therapeutic agent for CaP. PMID:24079846

  13. Antiprogestin mifepristone inhibits the growth of cancer cells of reproductive and non-reproductive origin regardless of progesterone receptor expression

    Directory of Open Access Journals (Sweden)

    Ortbahn Casey T

    2011-05-01

    Full Text Available Abstract Background Mifepristone (MF has been largely used in reproductive medicine due to its capacity to modulate the progesterone receptor (PR. The study of MF has been expanded to the field of oncology; yet it remains unclear whether the expression of PR is required for MF to act as an anti-cancer agent. Our laboratory has shown that MF is a potent inhibitor of ovarian cancer cell growth. In this study we questioned whether the growth inhibitory properties of MF observed in ovarian cancer cells would translate to other cancers of reproductive and non-reproductive origin and, importantly, whether its efficacy is related to the expression of cognate PR. Methods Dose-response experiments were conducted with cancer cell lines of the nervous system, breast, prostate, ovary, and bone. Cultures were exposed to vehicle or increasing concentrations of MF for 72 h and analysed for cell number and cell cycle traverse, and hypodiploid DNA content characteristic of apoptotic cell death. For all cell lines, expression of steroid hormone receptors upon treatment with vehicle or cytostatic doses of MF for 24 h was studied by Western blot, whereas the activity of the G1/S regulatory protein Cdk2 in both treatment groups was monitored in vitro by the capacity of Cdk2 to phosphorylate histone H1. Results MF growth inhibited all cancer cell lines regardless of tissue of origin and hormone responsiveness, and reduced the activity of Cdk2. Cancer cells in which MF induced G1 growth arrest were less susceptible to lethality in the presence of high concentrations of MF, when compared to cancer cells that did not accumulate in G1. While all cancer cell lines were growth inhibited by MF, only the breast cancer MCF-7 cells expressed cognate PR. Conclusions Antiprogestin MF inhibits the growth of different cancer cell lines with a cytostatic effect at lower concentrations in association with a decline in the activity of the cell cycle regulatory protein Cdk2, and

  14. Antiprogestin mifepristone inhibits the growth of cancer cells of reproductive and non-reproductive origin regardless of progesterone receptor expression

    International Nuclear Information System (INIS)

    Mifepristone (MF) has been largely used in reproductive medicine due to its capacity to modulate the progesterone receptor (PR). The study of MF has been expanded to the field of oncology; yet it remains unclear whether the expression of PR is required for MF to act as an anti-cancer agent. Our laboratory has shown that MF is a potent inhibitor of ovarian cancer cell growth. In this study we questioned whether the growth inhibitory properties of MF observed in ovarian cancer cells would translate to other cancers of reproductive and non-reproductive origin and, importantly, whether its efficacy is related to the expression of cognate PR. Dose-response experiments were conducted with cancer cell lines of the nervous system, breast, prostate, ovary, and bone. Cultures were exposed to vehicle or increasing concentrations of MF for 72 h and analysed for cell number and cell cycle traverse, and hypodiploid DNA content characteristic of apoptotic cell death. For all cell lines, expression of steroid hormone receptors upon treatment with vehicle or cytostatic doses of MF for 24 h was studied by Western blot, whereas the activity of the G1/S regulatory protein Cdk2 in both treatment groups was monitored in vitro by the capacity of Cdk2 to phosphorylate histone H1. MF growth inhibited all cancer cell lines regardless of tissue of origin and hormone responsiveness, and reduced the activity of Cdk2. Cancer cells in which MF induced G1 growth arrest were less susceptible to lethality in the presence of high concentrations of MF, when compared to cancer cells that did not accumulate in G1. While all cancer cell lines were growth inhibited by MF, only the breast cancer MCF-7 cells expressed cognate PR. Antiprogestin MF inhibits the growth of different cancer cell lines with a cytostatic effect at lower concentrations in association with a decline in the activity of the cell cycle regulatory protein Cdk2, and apoptotic lethality at higher doses in association with increased

  15. Acetoacetate reduces growth and ATP concentration in cancer cell lines which over-express uncoupling protein 2

    Directory of Open Access Journals (Sweden)

    Quadros Edward V

    2009-05-01

    Full Text Available Abstract Background Recent evidence suggests that several human cancers are capable of uncoupling of mitochondrial ATP generation in the presence of intact tricarboxylic acid (TCA enzymes. The goal of the current study was to test the hypothesis that ketone bodies can inhibit cell growth in aggressive cancers and that expression of uncoupling protein 2 is a contributing factor. The proposed mechanism involves inhibition of glycolytic ATP production via a Randle-like cycle while increased uncoupling renders cancers unable to produce compensatory ATP from respiration. Methods Seven aggressive human cancer cell lines, and three control fibroblast lines were grown in vitro in either 10 mM glucose medium (GM, or in glucose plus 10 mM acetoacetate [G+AcA]. The cells were assayed for cell growth, ATP production and expression of UCP2. Results There was a high correlation of cell growth with ATP concentration (r = 0.948 in a continuum across all cell lines. Controls demonstrated normal cell growth and ATP with the lowest density of mitochondrial UCP2 staining while all cancer lines demonstrated proportionally inhibited growth and ATP, and over-expression of UCP2 (p Conclusion Seven human cancer cell lines grown in glucose plus acetoacetate medium showed tightly coupled reduction of growth and ATP concentration. The findings were not observed in control fibroblasts. The observed over-expression of UCP2 in cancer lines, but not in controls, provides a plausible molecular mechanism by which acetoacetate spares normal cells but suppresses growth in cancer lines. The results bear on the hypothesized potential for ketogenic diets as therapeutic strategies.

  16. Genistein inhibits prostate cancer cell growth by targeting miR-34a and oncogenic HOTAIR.

    Directory of Open Access Journals (Sweden)

    Takeshi Chiyomaru

    Full Text Available OBJECTIVE: Genistein is a soy isoflavone that has antitumor activity both in vitro and in vivo. It has been shown that genistein inhibits many type of cancers including prostate cancer (PCa by regulating several cell signaling pathways and microRNAs (miRNAs. Recent studies suggest that the long non-coding RNAs (lncRNAs are also involved in many cellular processes. At present there are no reports about the relationship between gensitein, miRNAs and lncRNAs. In this study, we focused on miRNAs, lncRNA that are regulated by genistein and investigated their functional role in PCa. METHOD: Microarray (SurePrint G3 Human GE 8×60K was used for expression profiling of genistein treated and control PCa cells (PC3 and DU145. Functional assay (cell proliferation, migration, invasion, apoptosis and cell cycle assays were performed with the PCa cell lines, PC3 and DU145. Both in vitro and in vivo (nude mouse models were used for growth assays. Luciferase reporter assays were used for binding of miR-34a to HOTAIR. RESULTS: LncRNA profiling showed that HOTAIR was highly regulated by genistein and its expression was higher in castration-resistant PCa cell lines than in normal prostate cells. Knockdown (siRNA of HOTAIR decreased PCa cell proliferation, migration and invasion and induced apoptosis and cell cycle arrest. miR-34a was also up-regulated by genistein and may directly target HOTAIR in both PC3 and DU145 PCa cells. CONCLUSIONS: Our results indicated that genistein inhibited PCa cell growth through down-regulation of oncogenic HOTAIR that is also targeted by tumor suppressor miR-34a. These findings enhance understanding of how genistein regulates lncRNA HOTAIR and miR-34a in PCa.

  17. Benzopyrene exposure disrupts DNA methylation and growth dynamics in breast cancer cells

    International Nuclear Information System (INIS)

    Exposures to environmental carcinogens and unhealthy lifestyle choices increase the incidence of breast cancer. One such compound, benzo(a)pyrene (BaP), leads to covalent DNA modifications and the deregulation of gene expression. To date, these mechanisms of BaP-induced carcinogenesis are poorly understood, particularly in the case of breast cancer. We tested the effects of BaP exposure on cellular growth dynamics and DNA methylation in four breast cancer cell lines since disruptions in DNA methylation lead to deregulated gene expression and the loss of genomic integrity. We observed robust time- and concentration-dependent loss of proliferation, S phase and G2M accumulation and apoptosis in p53 positive MCF-7 and T47-D cells. We observed minimal responses in p53 negative HCC-1086 and MDA MB 231 cells. Furthermore, BaP increased p53 levels in both p53 positive cell lines, as well as p21 levels in MCF-7 cells, an effect that was prevented by the p53-specific inhibitor pifithrin-α. No changes in global levels of DNA methylation levels induced by BaP were detected by the methyl acceptor assay (MAA) in any cell line, however, methylation profiling by AIMS (amplification of intermethylated sites) analysis showed dynamic, sequence-specific hypo- and hypermethylation events in all cell lines. We also identified BaP-induced hypomethylation events at a number of genomic repeats. Our data confirm the p53-specific disruption of the cell cycle as well as the disruption of DNA methylation as a consequence of BaP treatment, thus reinforcing the link between environmental exposures, DNA methylation and breast cancer

  18. Proteomic analysis of pathways involved in estrogen-induced growth and apoptosis of breast cancer cells.

    Directory of Open Access Journals (Sweden)

    Zhang-Zhi Hu

    Full Text Available BACKGROUND: Estrogen is a known growth promoter for estrogen receptor (ER-positive breast cancer cells. Paradoxically, in breast cancer cells that have been chronically deprived of estrogen stimulation, re-introduction of the hormone can induce apoptosis. METHODOLOGY/PRINCIPAL FINDINGS: Here, we sought to identify signaling networks that are triggered by estradiol (E2 in isogenic MCF-7 breast cancer cells that undergo apoptosis (MCF-7:5C versus cells that proliferate upon exposure to E2 (MCF-7. The nuclear receptor co-activator AIB1 (Amplified in Breast Cancer-1 is known to be rate-limiting for E2-induced cell survival responses in MCF-7 cells and was found here to also be required for the induction of apoptosis by E2 in the MCF-7:5C cells. Proteins that interact with AIB1 as well as complexes that contain tyrosine phosphorylated proteins were isolated by immunoprecipitation and identified by mass spectrometry (MS at baseline and after a brief exposure to E2 for two hours. Bioinformatic network analyses of the identified protein interactions were then used to analyze E2 signaling pathways that trigger apoptosis versus survival. Comparison of MS data with a computationally-predicted AIB1 interaction network showed that 26 proteins identified in this study are within this network, and are involved in signal transduction, transcription, cell cycle regulation and protein degradation. CONCLUSIONS: G-protein-coupled receptors, PI3 kinase, Wnt and Notch signaling pathways were most strongly associated with E2-induced proliferation or apoptosis and are integrated here into a global AIB1 signaling network that controls qualitatively distinct responses to estrogen.

  19. Insulin like growth factor 2 regulation of aryl hydrocarbon receptor in MCF-7 breast cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Tomblin, Justin K.; Salisbury, Travis B., E-mail: salisburyt@marshall.edu

    2014-01-17

    Highlights: •IGF-2 stimulates concurrent increases in AHR and CCND1 expression. •IGF-2 promotes the binding of AHR to the endogenous cyclin D1 promoter. •AHR knockdown inhibits IGF-2 stimulated increases in CCND1 mRNA and protein. •AHR knockdown inhibits IGF-2 stimulated increases in MCF-7 proliferation. -- Abstract: Insulin like growth factor (IGF)-1 and IGF-2 stimulate normal growth, development and breast cancer cell proliferation. Cyclin D1 (CCND1) promotes cell cycle by inhibiting retinoblastoma protein (RB1). The aryl hydrocarbon receptor (AHR) is a major xenobiotic receptor that also regulates cell cycle. The purpose of this study was to investigate whether IGF-2 promotes MCF-7 breast cancer proliferation by inducing AHR. Western blot and quantitative real time PCR (Q-PCR) analysis revealed that IGF-2 induced an approximately 2-fold increase (P < .001) in the expression of AHR and CCND1. Chromatin immunoprecipitation (ChIP), followed by Q-PCR indicated that IGF-2 promoted (P < .001) a 7-fold increase in AHR binding on the CCND1 promoter. AHR knockdown significantly (P < .001) inhibited IGF-2 stimulated increases in CCND1 mRNA and protein. AHR knockdown cells were less (P < .001) responsive to the proliferative effects of IGF-2 than control cells. Collectively, our findings have revealed a new regulatory mechanism by which IGF-2 induction of AHR promotes the expression of CCND1 and the proliferation of MCF-7 cells. This previously uncharacterized pathway could be important for the proliferation of IGF responsive cancer cells that also express AHR.

  20. Exercise-induced muscle-derived cytokines inhibit mammary cancer cell growth.

    Science.gov (United States)

    Hojman, Pernille; Dethlefsen, Christine; Brandt, Claus; Hansen, Jakob; Pedersen, Line; Pedersen, Bente Klarlund

    2011-09-01

    Regular physical activity protects against the development of breast and colon cancer, since it reduces the risk of developing these by 25-30%. During exercise, humoral factors are released from the working muscles for endocrinal signaling to other organs. We hypothesized that these myokines mediate some of the inhibitory effects of exercise on mammary cancer cell proliferation. Serum and muscles were collected from mice after an exercise bout. Incubation with exercise-conditioned serum inhibited MCF-7 cell proliferation by 52% and increased caspase activity by 54%. A similar increase in caspase activity was found after incubation of MCF-7 cells with conditioned media from electrically stimulated myotubes. PCR array analysis (CAPM-0838E; SABiosciences) revealed that seven genes were upregulated in the muscles after exercise, and of these oncostatin M (OSM) proved to inhibit MCF-7 proliferation by 42%, increase caspase activity by 46%, and induce apoptosis. Blocking OSM signaling with anti-OSM antibodies reduced the induction of caspase activity by 51%. To verify that OSM was a myokine, we showed that it was significantly upregulated in serum and in three muscles, tibialis cranialis, gastronemius, and soleus, after an exercise bout. In contrast, OSM expression remained unchanged in subcutaneous and visceral adipose tissue, liver, and spleen (mononuclear cells). We conclude that postexercise serum inhibits mammary cancer cell proliferation and induces apoptosis of these cells. We suggest that one or more myokines secreted from working muscles may be mediating this effect and that OSM is a possible candidate. These findings emphasize that role of physical activity in cancer treatment, showing a direct link between exercise-induced humoral factors and decreased tumor cell growth. PMID:21653222

  1. Withaferin-A Inhibits Colon Cancer Cell Growth by Blocking STAT3 Transcriptional Activity

    OpenAIRE

    Choi, Bu Young; Kim, Bong-Woo

    2015-01-01

    Background: Withania somnifera (known as Ashwagandha) is a medicinal plant used in the ayurvedic medicines in India. Withaferin-A, a withanolide derived from the leaf extract of W. somnifera, has been reported to exhibit anti-tumor activity against various cancer cells, such as leukemia, breast cancer and colon cancer cells. Methods: We investigated the anti-cancer effects of withaferin-A on the proliferation and migration of human colorectal cancer (HCT116) cells. And we evaluated the effect...

  2. Hispolon inhibits the growth of estrogen receptor positive human breast cancer cells through modulation of estrogen receptor alpha

    Energy Technology Data Exchange (ETDEWEB)

    Jang, Eun Hyang; Jang, Soon Young; Cho, In-Hye [Department of Pharmacy, Graduate School, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 130-701 (Korea, Republic of); Hong, Darong [Department of Life and Nanopharmaceutical Science, Graduate School, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 130-701 (Korea, Republic of); Jung, Bom; Park, Min-Ju [Department of Pharmacy, Graduate School, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 130-701 (Korea, Republic of); Kim, Jong-Ho, E-mail: jonghokim@khu.ac.kr [Department of Pharmacy, Graduate School, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 130-701 (Korea, Republic of)

    2015-08-07

    Human estrogen receptor α (ERα) is a nuclear transcription factor that is a major therapeutic target in breast cancer. The transcriptional activity of ERα is regulated by certain estrogen-receptor modulators. Hispolon, isolated from Phellinus linteus, a traditional medicinal mushroom called Sanghwang in Korea, has been used to treat various pathologies, such as inflammation, gastroenteric disorders, lymphatic diseases, and cancers. In this latter context, Hispolon has been reported to exhibit therapeutic efficacy against various cancer cells, including melanoma, leukemia, hepatocarcinoma, bladder cancer, and gastric cancer cells. However, ERα regulation by Hispolon has not been reported. In this study, we investigated the effects of Hispolon on the growth of breast cancer cells. We found that Hispolon decreased expression of ERα at both mRNA and the protein levels in MCF7 and T47D human breast cancer cells. Luciferase reporter assays showed that Hispolon decreased the transcriptional activity of ERα. Hispolon treatment also inhibited expression of the ERα target gene pS2. We propose that Hispolon, an anticancer drug extracted from natural sources, inhibits cell growth through modulation of ERα in estrogen-positive breast cancer cells and is a candidate for use in human breast cancer chemotherapy. - Highlights: • Hispolon decreased ERα expression at both mRNA and protein levels. • Hispolon decreased ERα transcriptional activity. • Hispolon treatment inhibited expression of ERα target gene pS2. • Shikonin is a candidate chemotherapeutic target in the treatment of human breast cancer.

  3. Hispolon inhibits the growth of estrogen receptor positive human breast cancer cells through modulation of estrogen receptor alpha

    International Nuclear Information System (INIS)

    Human estrogen receptor α (ERα) is a nuclear transcription factor that is a major therapeutic target in breast cancer. The transcriptional activity of ERα is regulated by certain estrogen-receptor modulators. Hispolon, isolated from Phellinus linteus, a traditional medicinal mushroom called Sanghwang in Korea, has been used to treat various pathologies, such as inflammation, gastroenteric disorders, lymphatic diseases, and cancers. In this latter context, Hispolon has been reported to exhibit therapeutic efficacy against various cancer cells, including melanoma, leukemia, hepatocarcinoma, bladder cancer, and gastric cancer cells. However, ERα regulation by Hispolon has not been reported. In this study, we investigated the effects of Hispolon on the growth of breast cancer cells. We found that Hispolon decreased expression of ERα at both mRNA and the protein levels in MCF7 and T47D human breast cancer cells. Luciferase reporter assays showed that Hispolon decreased the transcriptional activity of ERα. Hispolon treatment also inhibited expression of the ERα target gene pS2. We propose that Hispolon, an anticancer drug extracted from natural sources, inhibits cell growth through modulation of ERα in estrogen-positive breast cancer cells and is a candidate for use in human breast cancer chemotherapy. - Highlights: • Hispolon decreased ERα expression at both mRNA and protein levels. • Hispolon decreased ERα transcriptional activity. • Hispolon treatment inhibited expression of ERα target gene pS2. • Shikonin is a candidate chemotherapeutic target in the treatment of human breast cancer

  4. Adenovirus-mediated expression of SSAT inhibits colorectal cancer cell growth in vitro

    Institute of Scientific and Technical Information of China (English)

    Hui SUN; Bin LIU; Ya-pei YANG; Chun-xiao XU; Yun-fei YAN; Wei WANG; Xian-xi LIU

    2008-01-01

    Aim: To construct a recombinant adenovirus that can express human spermidine/ spermine N1-acetyltransferase (SSAT) and detect its inhibitory effect on colorectal cancer cell growth in vitro. Methods: A 516 bp eDNA of SSAT was amplified and cloned into a pGL3-hTERT plasmid. The pGL3-hTERT-SSAT recombinant was digested, and the small fragment was cloned into the shuttle vector pAdTrack. The pAdTrack-hTERT-SSAT plasmids were recombined with pAdEasy-1 vectors in AdEasy-1 cells. Positive clones were selected and transfected into the HEK293 packaging cells (transformed human embryonic kidney cells) after they were lin-earized by PacI. The process of adenovirus packaging and amplification was monitored by green fluorescent protein (GFP) expression. The SSAT protein levels were determined by Western blotting, and the intracellular polyamine con-tent was detected by reverse-phase high performance liquid chromatography. The MTS (3-(4, 5-dimethylthiaol-2-yl)-5-(3-carboxy-methoxyphenyl)-2-(-4-sulfophenyl)-2H-tetrazolium, inner salt) and colony-forming assays were used to analyze the gene transduction efficiency and effect on the growth of HT-29 and LoVo cells. A viable cell count was used to determine the cell growth with or without exogenous polyamines. Results: The GFP expression in 293 cells during virus packing and amplification was observed by fluorescence microscopy. Western blotting results demonstrated that Ad-hTERT-SSAT could increase the expres-sion of SSAT, and consequently, spermidine and spermine were reduced to low levels. The MTS and colony-forming assay results showed that HT-29 and LoVo cell growth were significantly inhibited, and the inhibitory effect could be partially reversed by exogenous spermidine and spermine. Conclusion: The successfully constructed recombinant adenovirus Ad-hTERT-SSAT could accelerate polyamine catabolism and inhibit the colorectal cell growth in vitro. It also has therapeutic potential in the treatment of colorectal cancer.

  5. S100A4 is frequently overexpressed in lung cancer cells and promotes cell growth and cell motility

    International Nuclear Information System (INIS)

    Highlights: • We observed frequent overexpression of S100A4 in lung cancer cell lines. • Knockdown of S100A4 suppressed proliferation in lung cancer cells. • Forced expression of S100A4 accelerated cell motility in lung cancer cells. • PRDM2 was found to be one of the downstream suppressed genes of S100A4. - Abstract: S100A4, a small calcium-binding protein belonging to the S100 protein family, is commonly overexpressed in a variety of tumor types and is widely accepted to associate with metastasis by regulating the motility and invasiveness of cancer cells. However, its biological role in lung carcinogenesis is largely unknown. In this study, we found that S100A4 was frequently overexpressed in lung cancer cells, irrespective of histological subtype. Then we performed knockdown and forced expression of S100A4 in lung cancer cell lines and found that specific knockdown of S100A4 effectively suppressed cell proliferation only in lung cancer cells with S100A4-overexpression; forced expression of S100A4 accelerated cell motility only in S100A4 low-expressing lung cancer cells. PRDM2 and VASH1, identified as novel upregulated genes by microarray after specific knockdown of S100A4 in pancreatic cancer, were also analyzed, and we found that PRDM2 was significantly upregulated after S100A4-knockdown in one of two analyzed S100A4-overexpressing lung cancer cells. Our present results suggest that S100A4 plays an important role in lung carcinogenesis by means of cell proliferation and motility by a pathway similar to that in pancreatic cancer

  6. S100A4 is frequently overexpressed in lung cancer cells and promotes cell growth and cell motility

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Na; Sato, Daisuke; Saiki, Yuriko; Sunamura, Makoto; Fukushige, Shinichi; Horii, Akira, E-mail: horii@med.tohoku.ac.jp

    2014-05-09

    Highlights: • We observed frequent overexpression of S100A4 in lung cancer cell lines. • Knockdown of S100A4 suppressed proliferation in lung cancer cells. • Forced expression of S100A4 accelerated cell motility in lung cancer cells. • PRDM2 was found to be one of the downstream suppressed genes of S100A4. - Abstract: S100A4, a small calcium-binding protein belonging to the S100 protein family, is commonly overexpressed in a variety of tumor types and is widely accepted to associate with metastasis by regulating the motility and invasiveness of cancer cells. However, its biological role in lung carcinogenesis is largely unknown. In this study, we found that S100A4 was frequently overexpressed in lung cancer cells, irrespective of histological subtype. Then we performed knockdown and forced expression of S100A4 in lung cancer cell lines and found that specific knockdown of S100A4 effectively suppressed cell proliferation only in lung cancer cells with S100A4-overexpression; forced expression of S100A4 accelerated cell motility only in S100A4 low-expressing lung cancer cells. PRDM2 and VASH1, identified as novel upregulated genes by microarray after specific knockdown of S100A4 in pancreatic cancer, were also analyzed, and we found that PRDM2 was significantly upregulated after S100A4-knockdown in one of two analyzed S100A4-overexpressing lung cancer cells. Our present results suggest that S100A4 plays an important role in lung carcinogenesis by means of cell proliferation and motility by a pathway similar to that in pancreatic cancer.

  7. AMPK activators suppress cervical cancer cell growth through inhibition of DVL3 mediated Wnt/β-catenin signaling activity.

    Directory of Open Access Journals (Sweden)

    H T Kwan

    Full Text Available Recent evidence has suggested that AMPK activators may be applied as therapeutic drugs in suppressing cancer cell growth. However, the molecular mechanism of their suppressive function in cancer cells is still unclear. Here we show that AMPK activators impair cervical cancer cell growth through the reduction of DVL3, a positive regulator in Wnt/β-catenin signaling and an oncogenic player in cervical cancer tumorigenesis. By western blot and immunohistochemical analyses, we demonstrated that DVL3 was frequently upregulated and significantly associated with elevated β-catenin (P = 0.009 and CyclinD1 (P = 0.009 expressions in cervical cancer. Enforced expression of DVL3 elevated β-catenin and augmented cervical cancer cell growth, verifying that DVL3-mediated Wnt/β-catenin activation is involved in cervical cancer oncogenesis. On the other aspect, we noted that the cervical cancer cell growth was remarkably suppressed by AMPK activators and such cell growth inhibition was in concomitant with the reduction of DVL3 protein level in dose- and time-dependent manners. Besides, impaired mTOR signaling activity also reduced DVL3 expression. In contrast, co-treatment with Compound C (AMPK inhibitor could significantly abrogate metformin induced DVL3 reduction. In addition, co-treatment with AM114 or MG132 (proteosomal inhibitors could partially restore DVL3 expression under the treatment of metformin. Further in vivo ubiquitination assay revealed that metformin could reduce DVL3 by ubiquitin/proteasomal degradation. To our knowledge, this is the first report showing the probable molecular mechanisms of that the AMPK activators suppress cervical cancer cell growth by impairing DVL3 protein synthesis via AMPK/mTOR signaling and/or partially promoting the proteasomal degradation of DVL3.

  8. Phellinus linteus extract induces autophagy and synergizes with 5-fluorouracil to inhibit breast cancer cell growth.

    Science.gov (United States)

    Lee, Wen-Ying; Hsu, Keng-Fu; Chiang, Tai-An; Chen, Chee-Jen

    2015-01-01

    Phellinus linteus (PL) is a medicinal mushroom due to its several biological properties, including anticancer activity. However, the mechanisms of its anticancer effect remain to be elucidated. We evaluated the inhibitory effects of the ethanolic extract from the PL combined with 5-FU on MDA-MB-231 breast cancer cell line and to determine the mechanism of cell death. Individually, PL extract and 5-FU significantly inhibited the proliferation of MDA-MB-231 cells in a dose-dependent manner. PL extract (30 mg/mL) in combination with 5-FU (10 μg/mL) synergistically inhibited MDA-MB-231 cells by 1.8-fold. PL did not induce apoptosis, as demonstrated by the DNA fragmentation assay, the sub-G1 population, and staining with annexin V-FITC and propidium iodide. The exposure of MDA-MB-231 cells to PL extracts resulted in several confirmed characteristics of autophagy, including the appearance of autophagic vacuoles revealed by monodansylcadaverine staining, the formation of acidic vesicular organelles, autophagosome membrane association of microtubule-associated protein light chain 3 (LC3) characterized by cleavage of LC3 and its punctuate redistribution, and ultrastructural observation of autophagic vacuoles by transmission electron microscopy. We concluded that PL extracts synergized with low doses of 5-FU to inhibit triple-negative breast cancer cell growth and demonstrated that PL extract can induce autophagy-related cell death. PMID:25622112

  9. PUTATIVE ROLE OF ADIPOSE TISSUE IN GROWTH AND METABOLISM OF COLON CANCER CELLS

    Directory of Open Access Journals (Sweden)

    BettySchwartz

    2014-06-01

    Given that adipocytes are a major source of adipokines and energy for the cancer cell, understanding the mechanisms of metabolic symbiosis between cancer cells and adipocytes should reveal new therapeutic possibilities.

  10. TSC22D2 interacts with PKM2 and inhibits cell growth in colorectal cancer.

    Science.gov (United States)

    Liang, Fang; Li, Qiao; Li, Xiayu; Li, Zheng; Gong, Zhaojian; Deng, Hao; Xiang, Bo; Zhou, Ming; Li, Xiaoling; Li, Guiyuan; Zeng, Zhaoyang; Xiong, Wei

    2016-09-01

    We previously identified TSC22D2 (transforming growth factor β-stimulated clone 22 domain family, member 2) as a novel cancer-associated gene in a rare multi-cancer family. However, its role in tumor development remains completely unknown. In this study, we found that TSC22D2 was significantly downregulated in colorectal cancer (CRC) and that TSC22D2 overexpression inhibited cell growth. Using a co-immunoprecipitation (co-IP) assay combined with mass spectrometry analysis to identify TSC22D2-interacting proteins, we demonstrated that TSC22D2 interacts with pyruvate kinase isoform M2 (PKM2). These findings were confirmed by the results of immunoprecipitation and immunofluorescence assays. Moreover, overexpression of TSC22D2 reduced the level of nuclear PKM2 and suppressed cyclin D1 expression. Collectively, our study reveals a growth suppressor function of TSC22D2 that is at least partially dependent on the TSC22D2-PKM2-cyclinD1 regulatory axis. In addition, our data provide important clues that might contribute to future studies evaluating the role of TSC22D2. PMID:27573352

  11. Suppression of cell growth and invasion by miR-205 in breast cancer

    Institute of Scientific and Technical Information of China (English)

    Hailong Wu; Shoumin Zhu; Yin-Yuan Mo

    2009-01-01

    MicroRNAs (miRNAs) are endogenous, small, non-coding RNAs, which are capable of silencing gene expression at the post-transcriptional level. In this study, we report that miR-205 is significantly underexpressed in breast tumor compared to the matched normal breast tissue. Similarly, breast cancer cell lines, including MCF-7 and MDA-MB-231, express a lower level miR-205 than the non-malignant MCF-10A cells. Of interest, ectopic expression of miR-205 significantly inhibits cell proliferation and anchorage independent growth, as well as cell invasion. Furthermore, miR-205 was shown to suppress lung metastasis in an animal model. Finally, western blot combined with the luciferase reporter assays demonstrate that ErbB3 and vascular endothelial growth factor A (VEGF-A) are direct targets for miR-205, and this miR-205-mediated suppression is likely through the direct interaction with the putative miR-205 binding site in the 3'-untranslated region (3'-UTR) of ErbB3 and VEGF-A. Together, these results suggest that miR-205 is a tumor suppressor in breast cancer.

  12. Effect of Sterols Isolated from Myrtillocactus geometrizans on Growth Inhibition of Colon and Breast Cancer Cells

    Directory of Open Access Journals (Sweden)

    Mario Augusto Bolaños-Carrillo

    2015-01-01

    Full Text Available Objective. To explore the effect of peniocerol and macdougallin on HCT-15 and MCF-7 cells proliferation, cell cycle, apoptosis, and PARP cleavage. Methods. HCT-15 and MCF-7 cells were treated with various concentrations of peniocerol and macdougallin (10–80 μM during 24 or 48 h. Crystal Violet Assay was used to evaluate the inhibition effect. Cell cycle regulation was examined by a propidium iodide method. Cell apoptosis was detected through both Annexin–V FLUOS/PI double-labeled cytometry assays and Western blot was applied to assess PARP cleavage. Results. Peniocerol and macdougallin induced growth inhibition and apoptosis in vitro in a time- and dose-dependent manner. Moreover, peniocerol and macdougallin induced arrest of cell cycle-dependent manner and increased the proportion of cells in G0/G1 phase. PARP cleavage in HCT-15 and MCF-7 cells was induced by treatment with peniocerol and macdougallin after 36 hours. Conclusions. Our results showed that the mechanism of cytotoxicity displayed by peniocerol and macdougallin is related to cell cycle arrest and apoptosis in both cell lines. This is a significant observation because it helps to understand the way some oxysterols isolated from Myrtillocactus geometrizans develop their biological activities against cancer cells.

  13. Transforming growth factor β-induced epithelial-mesenchymal transition increases cancer stem-like cells in the PANC-1 cell line

    OpenAIRE

    Wang, Hui; WU, JUNLI; Zhang, Ye; Xue, Xiaofeng; Tang, Dong; YUAN, ZHONGXU; Chen, Minyong; WEI, JISHU; Zhang, Jingjing; Miao, Yi

    2011-01-01

    The epithelial-mesenchymal transition plays a crucial role in the progression of pancreatic cancer. The aim of this study was to examine the possible association between the epithelial-mesenchymal transition and cancer stem-like cells in pancreatic cancer. We used transforming growth factor β to induce an epithelial-mesenchymal transition. The proportion of pancreatic cancer stem-like cells was measured and sorted by flow cytometry. The expression of markers was measured by quantitative PCR a...

  14. Biomimetic apatite-coated porous PVA scaffolds promote the growth of breast cancer cells

    International Nuclear Information System (INIS)

    Recapitulating the native environment of bone tissue is essential to develop in vitro models of breast cancer bone metastasis. The bone is a composite material consisting of organic matrix and inorganic mineral phase, primarily hydroxyapatite. In this study, we report the mineralization of porous poly vinyl alcohol (PVA) scaffolds upon incubation in modified Hanks' Balanced Salt Solution (HBSS) for 14 days. Scanning electron microscopy, energy dispersive X-ray analysis, and X-ray diffraction analysis revealed that the deposited minerals have composition similar to hydroxyapatite. The study demonstrated that the rate of nucleation and growth of minerals was faster on surfaces of less porous scaffolds. However, upon prolonged incubation, formation of mineral layer was observed on the surface of all the scaffolds. In addition, the study also demonstrated that 3D mineralization only occurred for scaffolds with highly interconnected porous networks. The mineralization of the scaffolds promoted the adsorption of serum proteins and consequently, the adhesion and proliferation of breast cancer cells. - Highlights: • Porous PVA scaffolds fabricated via mechanical agitation followed by freeze-drying. • Mineralization of the scaffold was carried out by utilizing biomimetic approach. • Mineralization resulted in increased protein adsorption on the scaffold. • Increased breast cancer cell growth was observed on mineralized scaffolds

  15. Biomimetic apatite-coated porous PVA scaffolds promote the growth of breast cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Ye, Mao; Mohanty, Pravansu; Ghosh, Gargi, E-mail: gargi@umich.edu

    2014-11-01

    Recapitulating the native environment of bone tissue is essential to develop in vitro models of breast cancer bone metastasis. The bone is a composite material consisting of organic matrix and inorganic mineral phase, primarily hydroxyapatite. In this study, we report the mineralization of porous poly vinyl alcohol (PVA) scaffolds upon incubation in modified Hanks' Balanced Salt Solution (HBSS) for 14 days. Scanning electron microscopy, energy dispersive X-ray analysis, and X-ray diffraction analysis revealed that the deposited minerals have composition similar to hydroxyapatite. The study demonstrated that the rate of nucleation and growth of minerals was faster on surfaces of less porous scaffolds. However, upon prolonged incubation, formation of mineral layer was observed on the surface of all the scaffolds. In addition, the study also demonstrated that 3D mineralization only occurred for scaffolds with highly interconnected porous networks. The mineralization of the scaffolds promoted the adsorption of serum proteins and consequently, the adhesion and proliferation of breast cancer cells. - Highlights: • Porous PVA scaffolds fabricated via mechanical agitation followed by freeze-drying. • Mineralization of the scaffold was carried out by utilizing biomimetic approach. • Mineralization resulted in increased protein adsorption on the scaffold. • Increased breast cancer cell growth was observed on mineralized scaffolds.

  16. Long-range Transcriptome Sequencing Reveals Cancer Cell Growth Regulatory Chimeric mRNA

    Directory of Open Access Journals (Sweden)

    Roberto Plebani

    2012-11-01

    Full Text Available mRNA chimeras from chromosomal translocations often play a role as transforming oncogenes. However, cancer transcriptomes also contain mRNA chimeras that may play a role in tumor development, which arise as transcriptional or post-transcriptional events. To identify such chimeras, we developed a deterministic screening strategy for long-range sequence analysis. High-throughput, long-read sequencing was then performed on cDNA libraries from major tumor histotypes and corresponding normal tissues. These analyses led to the identification of 378 chimeras, with an unexpectedly high frequency of expression (≈2 x 10-5 of all mRNA. Functional assays in breast and ovarian cancer cell lines showed that a large fraction of mRNA chimeras regulates cell replication. Strikingly, chimeras were shown to include both positive and negative regulators of cell growth, which functioned as such in a cell-type-specific manner. Replication-controlling chimeras were found to be expressed by most cancers from breast, ovary, colon, uterus, kidney, lung, and stomach, suggesting a widespread role in tumor development.

  17. EFEMP1 Suppresses Growth and Invasion of Lung Cancer Cells 
by Downregulating Matrix Metalloproteinase-7 Expression

    OpenAIRE

    Yuanyuan LANG; Meng, Jie; Song, Xiaomeng; Chen, Xiaojun

    2015-01-01

    Background and objective EFEMP1, a member of fibulin family proteins, is a very important extracellular matrix protein which is involved in cell metabolism and its role in tumor occurrence and progression is still poorly understood. The aim of this study is to investigate the functional effect and mechanism of EFEMP1 in lung cancer cell growth and invasion. Methods EFEMP1 expression in lung cancer cells was determined by Western blot. The promoter methylation status of EFEMP1 was detected by ...

  18. Withaferin-A suppress AKT induced tumor growth in colorectal cancer cells.

    Science.gov (United States)

    Suman, Suman; Das, Trinath P; Sirimulla, Suman; Alatassi, Houda; Ankem, Murali K; Damodaran, Chendil

    2016-03-22

    The oncogenic activation of AKT gene has emerged as a key determinant of the aggressiveness of colorectal cancer (CRC); hence, research has focused on targeting AKT signaling for the treatment of advanced stages of CRC. In this study, we explored the anti-tumorigenic effects of withaferin A (WA) on CRC cells overexpressing AKT in preclinical (in vitro and in vivo) models. Our results indicated that WA, a natural compound, resulted in significant inhibition of AKT activity and led to the inhibition of cell proliferation, migration and invasion by downregulating the epithelial to mesenchymal transition (EMT) markers in CRC cells overexpressing AKT. The oral administration of WA significantly suppressed AKT-induced aggressive tumor growth in a xenograft model. Molecular analysis revealed that the decreased expression of AKT and its downstream pro-survival signaling molecules may be responsible for tumor inhibition. Further, significant inhibition of some important EMT markers, i.e., Snail, Slug, β-catenin and vimentin, was observed in WA-treated human CRC cells overexpressing AKT. Significant inhibition of micro-vessel formation and the length of vessels were evident in WA-treated tumors, which correlated with a low expression of the angiogenic marker RETIC. In conclusion, the present study emphasizes the crucial role of AKT activation in inducing cell proliferation, angiogenesis and EMT in CRC cells and suggests that WA may overcome AKT-induced cell proliferation and tumor growth in CRC. PMID:26883103

  19. Detecting the epidermal growth factor receptors status in non-small cell lung cancer

    Institute of Scientific and Technical Information of China (English)

    MENG Xue; YU Jin-ming

    2011-01-01

    Non-small cell lung cancer is one of the leading causes of all cancer deaths,but despite years of research,it is still difficult to predict the response and clinical outcome of the disease.In recent years,new treatment strategies targeting the epidermal growth factor receptors (EGFR) have been developed.EGFR is one of the most frequently over expressed proteins in various cancers,including lung cancer,and signaling through this receptor has been known to cause tumor progression as well as resistance to different treatments.Therefore,EGFR has become an attractive target for various treatment strategies.However,it is important to note that not all patients with lung cancer are suitable for targeted treatment,and that patients should be selected for this treatment.Several studies have proven that the status of the EGFR can be both an indicator of suitability for treatment with,and predict the likelihood of response to EGFR targeted therapy.There are many standard techniques to be used for the detection of EGFR.This overview summarizes the ongoing and future investigations to determine the status of the EGFR.

  20. Overexpression of GAB2 in ovarian cancer cells promotes tumor growth and angiogenesis by upregulating chemokine expression

    Science.gov (United States)

    Duckworth, C; Zhang, L; Carroll, S L; Ethier, S P; Cheung, H W

    2016-01-01

    We previously found that the scaffold adapter GRB2-associated binding protein 2 (GAB2) is amplified and overexpressed in a subset of primary high-grade serous ovarian cancers and cell lines. Ovarian cancer cells overexpressing GAB2 are dependent on GAB2 for activation of the phosphatidylinositol 3-kinase (PI3K) pathway and are sensitive to PI3K inhibition. In this study, we show an important role of GAB2 overexpression in promoting tumor angiogenesis by upregulating expression of multiple chemokines. Specifically, we found that suppression of GAB2 by inducible small hairpin RNA in ovarian cancer cells inhibited tumor cell proliferation, angiogenesis and peritoneal tumor growth in immunodeficient mice. Overexpression of GAB2 upregulated the secretion of several chemokines from ovarian cancer cells, including CXCL1, CXCL2 and CXCL8. The secreted chemokines not only signal through endothelial CXCR2 receptor in a paracrine manner to promote endothelial tube formation, but also act as autocrine growth factors for GAB2-induced transformation of fallopian tube secretory epithelial cells and clonogenic growth of ovarian cancer cells overexpressing GAB2. Pharmacological inhibition of inhibitor of nuclear factor kappa-B kinase subunit β (IKKβ), but not PI3K, mechanistic target of rapamycin (mTOR) or mitogen-activated protein kinase (MEK), could effectively suppress GAB2-induced chemokine expression. Inhibition of IKKβ augmented the efficacy of PI3K/mTOR inhibition in suppressing clonogenic growth of ovarian cancer cells with GAB2 overexpression. Taken together, these findings suggest that overexpression of GAB2 in ovarian cancer cells promotes tumor growth and angiogenesis by upregulating expression of CXCL1, CXCL2 and CXCL8 that is IKKβ-dependent. Co-targeting IKKβ and PI3K pathways downstream of GAB2 might be a promising therapeutic strategy for ovarian cancer that overexpresses GAB2. PMID:26657155

  1. Mechanisms underlying the growth inhibitory effects of the cyclo-oxygenase-2 inhibitor celecoxib in human breast cancer cells

    International Nuclear Information System (INIS)

    Inhibitors of cyclo-oxygenase (COX)-2 are being extensively studied as anticancer agents. In the present study we evaluated the mechanisms by which a highly selective COX-2 inhibitor, celecoxib, affects tumor growth of two differentially invasive human breast cancer cell lines. MDA-MB-231 (highly invasive) and MDA-MB-468 (moderately invasive) cell lines were treated with varying concentrations of celecoxib in vitro, and the effects of this agent on cell growth and angiogenesis were monitored by evaluating cell proliferation, apoptosis, cell cycle arrest, and vasculogenic mimicry. The in vitro results of MDA-MB-231 cell line were further confirmed in vivo in a mouse xenograft model. The highly invasive MDA-MB-231 cells express higher levels of COX-2 than do the less invasive MDA-MB-468 cells. Celecoxib treatment inhibited COX-2 activity, indicated by prostaglandin E2 secretion, and caused significant growth arrest in both breast cancer cell lines. In the highly invasive MDA-MB-231 cells, the mechanism of celecoxib-induced growth arrest was by induction of apoptosis, associated with reduced activation of protein kinase B/Akt, and subsequent activation of caspases 3 and 7. In the less invasive MDA-MB-468 cells, growth arrest was a consequence of cell cycle arrest at the G0/G1 checkpoint. Celecoxib-induced growth inhibition was reversed by addition of exogenous prostaglandin E2 in MDA-MB-468 cells but not in MDA-MB-231 cells. Furthermore, MDA-MB-468 cells formed significantly fewer extracellular matrix associated microvascular channels in vitro than did the high COX-2 expressing MDA-MB-231 cells. Celecoxib treatment not only inhibited cell growth and vascular channel formation but also reduced vascular endothelial growth factor levels. The in vitro findings corroborated in vivo data from a mouse xenograft model in which daily administration of celecoxib significantly reduced tumor growth of MDA-MB-231 cells, which was associated with reduced vascularization and

  2. Hispolon inhibits the growth of estrogen receptor positive human breast cancer cells through modulation of estrogen receptor alpha.

    Science.gov (United States)

    Jang, Eun Hyang; Jang, Soon Young; Cho, In-Hye; Hong, Darong; Jung, Bom; Park, Min-Ju; Kim, Jong-Ho

    2015-08-01

    Human estrogen receptor α (ERα) is a nuclear transcription factor that is a major therapeutic target in breast cancer. The transcriptional activity of ERα is regulated by certain estrogen-receptor modulators. Hispolon, isolated from Phellinus linteus, a traditional medicinal mushroom called Sanghwang in Korea, has been used to treat various pathologies, such as inflammation, gastroenteric disorders, lymphatic diseases, and cancers. In this latter context, Hispolon has been reported to exhibit therapeutic efficacy against various cancer cells, including melanoma, leukemia, hepatocarcinoma, bladder cancer, and gastric cancer cells. However, ERα regulation by Hispolon has not been reported. In this study, we investigated the effects of Hispolon on the growth of breast cancer cells. We found that Hispolon decreased expression of ERα at both mRNA and the protein levels in MCF7 and T47D human breast cancer cells. Luciferase reporter assays showed that Hispolon decreased the transcriptional activity of ERα. Hispolon treatment also inhibited expression of the ERα target gene pS2. We propose that Hispolon, an anticancer drug extracted from natural sources, inhibits cell growth through modulation of ERα in estrogen-positive breast cancer cells and is a candidate for use in human breast cancer chemotherapy. PMID:26056942

  3. The growth inhibition of human pancreatic cancer cells by lipofectin mediated IGF-1R antisense oligonucleotides

    International Nuclear Information System (INIS)

    Objective: To study the enhancement of the growth inhibition by irradiation to human pancreatic cancer cells (PC-3) transfected by lipofectin-mediated insulin-like growth factor-1 receptor (IGF-1R) antisense oligonucleotides (ASON) and its tumorigenecity in nude mice. Methods: The curves of the survived PC-3 cells after 60Co γ radiation in varied dose were drawn and the optimal radiation dose was selected. Two transfection ways were utilized, transfected by IGF-1R lipo-ASON combined with or without ionizing radiation. Cells growth inhibition was shown by methyl thiazolium tetrazolium (MTT). The mRNA expression of IGF-1R was examined by reverse transcription-polymerase chain reaction (RT-PCR). Flow cytometry was used to demonstrate apoptotic changes in both groups. After the transplanted tumors have grown in nude mice, lipo-ASON was injected in both groups, then the effects of inhibition were compared. Results: The inhibitory effect of lipo-ASON was injected in both groups, then the effects of inhibition were compared. Results: The inhibitory effect of lipo-ASON (86.3%), the apoptotic rate (53.06%) and the decreasing of IGF-1R mRNA (79.2%) in irradiation group was higher than non-irradiation group. Also, the differences were significant in tumor volume in irradiation group comparing to the control group (P<0.01). Conclusion: The ASON of IGF-1R can effectively inhibit the growth of tumor, and its inhibition can be enhanced by irradiation. (authors)

  4. Clonogenic growth of human breast cancer cells co-cultured in direct contact with serum-activated fibroblasts

    International Nuclear Information System (INIS)

    Accumulating evidence suggests that fibroblasts play a pivotal role in promoting the growth of breast cancer cells. The objective of the present study was to characterize and validate an in vitro model of the interaction between small numbers of human breast cancer cells and human fibroblasts. We measured the clonogenic growth of small numbers of human breast cancer cells co-cultured in direct contact with serum-activated, normal human fibroblasts. Using DNA microarrays, we also characterized the gene expression profile of the serum-activated fibroblasts. In order to validate the in vivo relevance of our experiments, we then analyzed clinical samples of metastatic breast cancer for the presence of myofibroblasts expressing α-smooth muscle actin. Clonogenic growth of human breast cancer cells obtained directly from in situ and invasive tumors was dramatically and consistently enhanced when the tumor cells were co-cultured in direct contact with serum-activated fibroblasts. This effect was abolished when the cells were co-cultured in transwells separated by permeable inserts. The fibroblasts in our experimental model exhibited a gene expression signature characteristic of 'serum response' (i.e. myofibroblasts). Immunostaining of human samples of metastatic breast cancer tissue confirmed that myofibroblasts are in direct contact with breast cancer cells. Serum-activated fibroblasts promote the clonogenic growth of human breast cancer cells in vitro through a mechanism that involves direct physical contact between the cells. This model shares many important molecular and phenotypic similarities with the fibroblasts that are naturally found in breast cancers

  5. Transforming growth factor-β1 regulates epithelial-mesenchymal transition in association with cancer stem-like cells in a breast cancer cell line.

    Science.gov (United States)

    Jia, Yongfeng; Wu, Di; Yun, Fen; Shi, Lin; Luo, Nianrong; Liu, Zhiyue; Shi, Yonghong; Sun, Qinnuan; Jiang, Lili; Wang, Shiqi; Du, Maolin

    2014-01-01

    Epithelial-mesenchymal transition (EMT) is associated with altered connection and junctions between cells and changes in abilities of invasion and migration. In this study, we investigated whether SK-BR-3 breast cancer cells induced to undergo EMT exhibit changes in morphological and invasion abilities after Transforming growth factor β1 (TGF-β1) treatment. Serum-deprived SK-BR-3 cells were treated with TGF-β1 (0, 10 ng/mL) for 24 h. The cells morphological changes were observed and imaged using inverted phase contrast microscope. Scratch experiment and invasion experiment were employed to detect changes of invasion ability, cell-flow experiment was used to assess cell cycle, immunohistochemistry technique was used to detect epithelial and mesenchymal markers after the crawling cells were fixed. Our research reveal that SK-BR-3 cells become larger and more messy, the elongated cells extend pseudopodia, the link of the cells became more loosely and cell gap widened after TGF-β1 treatment. SK-BR-3 cells showed faster growing and improved invasion abilities after TGF-β1 treatment, and reduced G1 phase cells proportion in the total number of cells after the conversion, in contrast the S phase cells accounted for the proportion of the total number of cells increased. These findings indicate that TGF-β1-induced EMT in breast cancer cells may be associated with major alterations in morphological and invasion abilities. PMID:24955155

  6. NEU3 inhibitory effect of naringin suppresses cancer cell growth by attenuation of EGFR signaling through GM3 ganglioside accumulation.

    Science.gov (United States)

    Yoshinaga, Ayana; Kajiya, Natsuki; Oishi, Kazuki; Kamada, Yuko; Ikeda, Asami; Chigwechokha, Petros Kingstone; Kibe, Toshiro; Kishida, Michiko; Kishida, Shosei; Komatsu, Masaharu; Shiozaki, Kazuhiro

    2016-07-01

    Naringin, which is one of the flavonoids contained in citrus fruits, is well known to possess various healthy functions to humans. It has been reported that naringin suppresses cancer cell growth in vitro and in vivo, although the underlying mechanisms are not fully understood. Recently, the roles of glycoconjugates, such as gangliosides, in cancer cells have been focused because of their regulatory effects of malignant phenotypes. Here, to clarify the roles of naringin in the negative-regulation of cancer cell growth, the alteration of glycoconjugates induced by naringin exposure and its significance on cell signaling were investigated. Human cancer cells, HeLa and A549, were exposed to various concentrations of naringin. Naringin treatment induced the suppression of cell growth toward HeLa and A549 cells accompanied with an increase of apoptotic cells. In naringin-exposed cells, GM3 ganglioside was drastically increased compared to the GM3 content prior to the treatment. Furthermore, naringin inhibited NEU3 sialidase, a GM3 degrading glycosidase. Similarly, NEU3 inhibition activities were also detected by other flavanone, such as hesperidin and neohesperidin dihydrocalcone, but their aglycones showed less inhibitions. Naringin-treated cancer cells showed suppressed EGFR and ERK phosphorylation levels. These results suggest a novel mechanism of naringin in the suppression of cancer cell growth through the alteration of glycolipids. NEU3 inhibitory effect of naringin induced GM3 accumulation in HeLa and A549 cells, leading the attenuation of EGFR/ERK signaling accompanied with a decrease in cell growth. PMID:27105818

  7. A novel muscarinic antagonist R2HBJJ inhibits non-small cell lung cancer cell growth and arrests the cell cycle in G0/G1.

    Directory of Open Access Journals (Sweden)

    Nan Hua

    Full Text Available Lung cancers express the cholinergic autocrine loop, which facilitates the progression of cancer cells. The antagonists of mAChRs have been demonstrated to depress the growth of small cell lung cancers (SCLCs. In this study we intended to investigate the growth inhibitory effect of R2HBJJ, a novel muscarinic antagonist, on non-small cell lung cancer (NSCLC cells and the possible mechanisms. The competitive binding assay revealed that R2HBJJ had a high affinity to M3 and M1 AChRs. R2HBJJ presented a strong anticholinergic activity on carbachol-induced contraction of guinea-pig trachea. R2HBJJ markedly suppressed the growth of NSCLC cells, such as H1299, H460 and H157. In H1299 cells, both R2HBJJ and its leading compound R2-PHC displayed significant anti-proliferative activity as M3 receptor antagonist darifenacin. Exogenous replenish of ACh could attenuate R2HBJJ-induced growth inhibition. Silencing M3 receptor or ChAT by specific-siRNAs resulted in a growth inhibition of 55.5% and 37.9% on H1299 cells 96 h post transfection, respectively. Further studies revealed that treatment with R2HBJJ arrested the cell cycle in G0/G1 by down-regulation of cyclin D1-CDK4/6-Rb. Therefore, the current study reveals that NSCLC cells express an autocrine and paracrine cholinergic system which stimulates the growth of NSCLC cells. R2HBJJ, as a novel mAChRs antagonist, can block the local cholinergic loop by antagonizing predominantly M3 receptors and inhibit NSCLC cell growth, which suggest that M3 receptor antagonist might be a potential chemotherapeutic regimen for NSCLC.

  8. A novel muscarinic antagonist R2HBJJ inhibits non-small cell lung cancer cell growth and arrests the cell cycle in G0/G1.

    Science.gov (United States)

    Hua, Nan; Wei, Xiaoli; Liu, Xiaoyan; Ma, Xiaoyun; He, Xinhua; Zhuo, Rengong; Zhao, Zhe; Wang, Liyun; Yan, Haitao; Zhong, Bohua; Zheng, Jianquan

    2012-01-01

    Lung cancers express the cholinergic autocrine loop, which facilitates the progression of cancer cells. The antagonists of mAChRs have been demonstrated to depress the growth of small cell lung cancers (SCLCs). In this study we intended to investigate the growth inhibitory effect of R2HBJJ, a novel muscarinic antagonist, on non-small cell lung cancer (NSCLC) cells and the possible mechanisms. The competitive binding assay revealed that R2HBJJ had a high affinity to M3 and M1 AChRs. R2HBJJ presented a strong anticholinergic activity on carbachol-induced contraction of guinea-pig trachea. R2HBJJ markedly suppressed the growth of NSCLC cells, such as H1299, H460 and H157. In H1299 cells, both R2HBJJ and its leading compound R2-PHC displayed significant anti-proliferative activity as M3 receptor antagonist darifenacin. Exogenous replenish of ACh could attenuate R2HBJJ-induced growth inhibition. Silencing M3 receptor or ChAT by specific-siRNAs resulted in a growth inhibition of 55.5% and 37.9% on H1299 cells 96 h post transfection, respectively. Further studies revealed that treatment with R2HBJJ arrested the cell cycle in G0/G1 by down-regulation of cyclin D1-CDK4/6-Rb. Therefore, the current study reveals that NSCLC cells express an autocrine and paracrine cholinergic system which stimulates the growth of NSCLC cells. R2HBJJ, as a novel mAChRs antagonist, can block the local cholinergic loop by antagonizing predominantly M3 receptors and inhibit NSCLC cell growth, which suggest that M3 receptor antagonist might be a potential chemotherapeutic regimen for NSCLC. PMID:23285263

  9. AZD9291 in epidermal growth factor receptor inhibitor—resistant non-small-cell lung cancer

    OpenAIRE

    Stinchcombe, Thomas E.

    2016-01-01

    Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in advanced EGFR mutant non-small cell lung cancer have an objective response rate (ORR) of approximately 60–70% and a median progression free-survival (PFS) of approximately 10-13 months. Studies of tumor biopsies performed after progression on EGFR TKI revealed that 50-60% of EGFR mutant NSCLC developed an EGFR exon 20 T790M mutation as a mechanism of acquired resistance. AZD9291 is a third generation irreversible EGF...

  10. CREB mediates ICAM-3: inducing radio-resistance, cell growth and migration/invasion of the human nonsmall cell lung cancer cell

    International Nuclear Information System (INIS)

    The ICAM family proteins comprises cell surface molecules that are homologous to NCAM and are members of the single passed type 1 immunoglobulin superfamily (IgSF) that are anchored at the cellular membrane. The ICAM family consists of five subfamilies (ICAM-1 to ICAM-5) of heavily glycosylated cell surface receptors with common functional or structural homology. The extracellular domains of ICAM protein have roles in immune response and inflammation through various cell-cell interactions. The cytoplasmic tail residues of ICAM-3 participate in intracellular signaling such as calcium mobilization and tyrosine phosphorylation. Interestingly, the ICAM proteins appear to have a dual role in cancer. ICAM molecules may target and block tumor progression by stimulation of an immune response such as leukocyte activation. Conversely, other investigations have shown that ICAM molecules are involved in cancer malignancy because their increased expressions are associated with a poor diagnosis, lower survival rates and invasion in several cancers including melanoma, breast cancer and leukemia. We have also reported that an increase of ICAM-3 expression in several cancer cells and specimens of cervical cancer patient induce enhanced radio-resistance by the activation of focal adhesion kinase (FAK) and promote cancer cell proliferation by the activation of Akt and p44/42 MAPK. Therefore, these previous reports imply that ICAM-3 has various undefined roles in cancer. In this study, we investigated whether ICAM-3 increase cell migration and invasion through CREB activation and CREB has a role of increase of radioresistance and cell growth

  11. CREB mediates ICAM-3: inducing radio-resistance, cell growth and migration/invasion of the human nonsmall cell lung cancer cell

    Energy Technology Data Exchange (ETDEWEB)

    Park, Jong Kuk; So, Kwang Sup; Bae, In Hwa; Um, Hong Duck [Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of)

    2009-05-15

    The ICAM family proteins comprises cell surface molecules that are homologous to NCAM and are members of the single passed type 1 immunoglobulin superfamily (IgSF) that are anchored at the cellular membrane. The ICAM family consists of five subfamilies (ICAM-1 to ICAM-5) of heavily glycosylated cell surface receptors with common functional or structural homology. The extracellular domains of ICAM protein have roles in immune response and inflammation through various cell-cell interactions. The cytoplasmic tail residues of ICAM-3 participate in intracellular signaling such as calcium mobilization and tyrosine phosphorylation. Interestingly, the ICAM proteins appear to have a dual role in cancer. ICAM molecules may target and block tumor progression by stimulation of an immune response such as leukocyte activation. Conversely, other investigations have shown that ICAM molecules are involved in cancer malignancy because their increased expressions are associated with a poor diagnosis, lower survival rates and invasion in several cancers including melanoma, breast cancer and leukemia. We have also reported that an increase of ICAM-3 expression in several cancer cells and specimens of cervical cancer patient induce enhanced radio-resistance by the activation of focal adhesion kinase (FAK) and promote cancer cell proliferation by the activation of Akt and p44/42 MAPK. Therefore, these previous reports imply that ICAM-3 has various undefined roles in cancer. In this study, we investigated whether ICAM-3 increase cell migration and invasion through CREB activation and CREB has a role of increase of radioresistance and cell growth.

  12. The influence of myeloid-derived suppressor cells on angiogenesis and tumor growth after cancer surgery.

    Science.gov (United States)

    Wang, Jun; Su, Xiaosan; Yang, Liu; Qiao, Fei; Fang, Yu; Yu, Lu; Yang, Qian; Wang, Yiyin; Yin, Yanfeng; Chen, Rui; Hong, Zhipeng

    2016-06-01

    While myeloid-derived suppressor cells (MDSCs) have been reported to participate in the promotion of angiogenesis and tumor growth, little is known about their presence and function during perioperative period. Here, we demonstrated that human MDSCs expressing CD11b(+) , CD33(+) and HLA-DR(-) significantly increased in lung cancer patients after thoracotomy. CD11b(+) CD33(+) HLA-DR(-) MDSCs isolated 24 hr after surgery from lung cancer patients were more efficient in promoting angiogenesis and tumor growth than MDSCs isolated before surgical operation in allograft tumor model. In addition, CD11b(+) CD33(+) HLA-DR(-) MDSCs produced high levels of MMP-9. Using an experimental lung metastasis mouse model, we demonstrated that the numbers of metastases on lung surface and Gr-1(+) CD11b(+) MDSCs at postoperative period were enhanced in proportion to the degree of surgical manipulation. We also examined that syngeneic bone marrow mesenchymal stem cells (BMSCs) significantly inhibited the induction and proliferation of Gr-1(+) CD11b(+) MDSCs and further prevented lung metastasis formation in the mice undergoing laparotomy. Taken together, our results suggest that postoperatively induced MDSCs were qualified with potent proangiogenic and tumor-promotive ability and this cell population should be considered as a target for preventing postoperative tumor metastasis. PMID:26756887

  13. Phellinus linteus suppresses growth, angiogenesis and invasive behaviour of breast cancer cells through the inhibition of AKT signalling

    OpenAIRE

    Sliva, D; Jedinak, A; Kawasaki, J.; Harvey, K; Slivova, V

    2008-01-01

    The antitumour activity of a medicinal mushroom Phellinus linteus (PL), through the stimulation of immune system or the induction of apoptosis, has been recently described. However, the molecular mechanisms responsible for the inhibition of invasive behaviour of cancer cells remain to be addressed. In the present study, we demonstrate that PL inhibits proliferation (anchorage-dependent growth) as well as colony formation (anchorage-independent growth) of highly invasive human breast cancer ce...

  14. Camptothecin disrupts androgen receptor signaling and suppresses prostate cancer cell growth

    International Nuclear Information System (INIS)

    The androgen receptor (AR) is the main therapeutic target for treatment of metastatic prostate cancers. The present study demonstrates that the topoisomerase I inhibitor camptothecin selectively inhibits androgen-responsive growth of prostate cancer cells. Camptothecin strikingly inhibited mutated and wild-type AR protein expression in LNCaP and PC-3/AR cells. This inhibition coincided with decreased androgen-mediated AR phosphorylation at Ser81 and reduced androgen-mediated AR transcriptional activity in a dose-dependent manner. Additionally, camptothecin disrupted the association between AR and heat shock protein 90 and impeded binding of the synthetic androgen [3H]R1881 to AR in LNCaP cells. Camptothecin also blocked androgen-induced AR nuclear translocation, leading to downregulation of the AR target gene PSA. In addition to decreasing the intracellular and secreted prostate-specific antigen (PSA) levels, camptothecin markedly inhibited androgen-stimulated PSA promoter activity. Collectively, our data reveal that camptothecin not only serves as a traditional genotoxic agent but, by virtue of its ability to target and disrupt AR, may also be a novel candidate for the treatment of prostate cancer.

  15. Camptothecin disrupts androgen receptor signaling and suppresses prostate cancer cell growth

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Shicheng, E-mail: liusc59@yahoo.co.jp [Research and Development Department, Nipro Patch Co., Ltd., 8-1, Minamisakae-cho, Kasukabe, Saitama 344-0057 (Japan); Yuan, Yiming [Department of Geriatrics, West China Hospital, Sichuan University, Chengdu 610041 (China); Okumura, Yutaka; Shinkai, Norihiro; Yamauchi, Hitoshi [Research and Development Department, Nipro Patch Co., Ltd., 8-1, Minamisakae-cho, Kasukabe, Saitama 344-0057 (Japan)

    2010-04-02

    The androgen receptor (AR) is the main therapeutic target for treatment of metastatic prostate cancers. The present study demonstrates that the topoisomerase I inhibitor camptothecin selectively inhibits androgen-responsive growth of prostate cancer cells. Camptothecin strikingly inhibited mutated and wild-type AR protein expression in LNCaP and PC-3/AR cells. This inhibition coincided with decreased androgen-mediated AR phosphorylation at Ser{sup 81} and reduced androgen-mediated AR transcriptional activity in a dose-dependent manner. Additionally, camptothecin disrupted the association between AR and heat shock protein 90 and impeded binding of the synthetic androgen [{sup 3}H]R1881 to AR in LNCaP cells. Camptothecin also blocked androgen-induced AR nuclear translocation, leading to downregulation of the AR target gene PSA. In addition to decreasing the intracellular and secreted prostate-specific antigen (PSA) levels, camptothecin markedly inhibited androgen-stimulated PSA promoter activity. Collectively, our data reveal that camptothecin not only serves as a traditional genotoxic agent but, by virtue of its ability to target and disrupt AR, may also be a novel candidate for the treatment of prostate cancer.

  16. Mechanisms underlying the growth inhibitory effects of the cyclo-oxygenase-2 inhibitor celecoxib in human breast cancer cells

    OpenAIRE

    Basu, Gargi D; Pathangey, Latha B; Tinder, Teresa L; Gendler, Sandra J.; Mukherjee, Pinku

    2005-01-01

    Introduction Inhibitors of cyclo-oxygenase (COX)-2 are being extensively studied as anticancer agents. In the present study we evaluated the mechanisms by which a highly selective COX-2 inhibitor, celecoxib, affects tumor growth of two differentially invasive human breast cancer cell lines. Methods MDA-MB-231 (highly invasive) and MDA-MB-468 (moderately invasive) cell lines were treated with varying concentrations of celecoxib in vitro, and the effects of this agent on cell growth and angioge...

  17. The inhibition of lung cancer cell growth by intracellular immunization with LC-1 ScFv

    Institute of Scientific and Technical Information of China (English)

    2002-01-01

    A monoclonal antibody, LC-l, recognizing lung cancer associated common antigens was obtained in authors' laboratory. Its single chain Fv fragment (ScFv) named LC-1 ScFv was constructed based on recombinant phage displayed techniques. For expression on cell membrane, LC-1 ScFv was cloned into pDisplay vector, which directed the cloned gene to express as cell membrane bound protein. The resulting plasmid was sequenced and then introduced by the lipofectin method into a lung adenocarcinoma cell line SPC-A-1. G418 resistant cells were obtained by G418 selection. After transfection, LC-1 ScFv expression was observed by Western blot analysis and the expression of cognate antigens was down-regulated as shown in ELISA assay. SPC-A-1-pDisplay-ScFv cells grew in vitro at lower speed than the control intact cells and the cells transfected with vacant vector. Flow cytometry analysis detected a substantial increase in G1 phase and decrease in S phase in population of SPC-A-1-pDisplay-ScFv cells compared to SPC-A-1 and SPC-A1-pDisplay cells. Semi-quantitative RT-PCR analysis showed that c-myc expression was down-regulated in SPC-A-1-pDisplay-ScFv cells. It seems that the antigens recognized by LC-1 may be in some way involved in a growth stimulating pathway and the antibody blocking of the function of the antigens shut down the pathway and thus down-regulate the expression of c-myc and growth of the cells.

  18. Glycyrrhetinic Acid Inhibits Cell Growth and Induces Apoptosis in Ovarian Cancer A2780 Cells

    Directory of Open Access Journals (Sweden)

    Venus Haghshenas

    2014-10-01

    Full Text Available Purpose: Accumulating evidence indicates that glycyrrhizin (GZ and its hydrolyzed metabolite 18-β glycyrrhetinic acid (GA exhibit anti-inflammatory and anticancer activities. The objective of this study was to examine the in vitro cytotoxic activity of GA on human ovarian cancer A2780 cells. Methods: A2780 cells were cultured in RPMI1640 containing 10% fetal bovine serum. Cells were treated with different doses of GA and cell viability and proliferation were detected by dye exclusion and 3-bis-(2-methoxy-4-nitro-5-sulfophenyl-2H-tetrazolium-5-carboxanilide (XTT assays. Apoptosis induction and expression of Fas and Fas ligand (FasL were analyzed by flow cytometry. Results: We observed that GA decreases cell viability and suppressed cells proliferation in a dose-dependent manner as detected by dye-exclusion and XTT assayes. In addition, our flow cytometry data show that GA not only induces apoptosis in A2780 cells but also upregulates both Fas and FasL on these cells in a dose-dependent manner. Conclusion: we demonstrate that GA causes cell death in A2780 cells by inducing apoptosis.

  19. Cancer Cell Growth Inhibitory Effect of Bee Venom via Increase of Death Receptor 3 Expression and Inactivation of NF-kappa B in NSCLC Cells

    Directory of Open Access Journals (Sweden)

    Kyung Eun Choi

    2014-07-01

    Full Text Available Our previous findings have demonstrated that bee venom (BV has anti-cancer activity in several cancer cells. However, the effects of BV on lung cancer cell growth have not been reported. Cell viability was determined with trypan blue uptake, soft agar formation as well as DAPI and TUNEL assay. Cell death related protein expression was determined with Western blotting. An EMSA was used for nuclear factor kappaB (NF-κB activity assay. BV (1–5 μg/mL inhibited growth of lung cancer cells by induction of apoptosis in a dose dependent manner in lung cancer cell lines A549 and NCI-H460. Consistent with apoptotic cell death, expression of DR3 and DR6 was significantly increased. However, deletion of DRs by small interfering RNA significantly reversed BV induced cell growth inhibitory effects. Expression of pro-apoptotic proteins (caspase-3 and Bax was concomitantly increased, but the NF-κB activity and expression of Bcl-2 were inhibited. A combination treatment of tumor necrosis factor (TNF-like weak inducer of apoptosis, TNF-related apoptosis-inducing ligand, docetaxel and cisplatin, with BV synergistically inhibited both A549 and NCI-H460 lung cancer cell growth with further down regulation of NF-κB activity. These results show that BV induces apoptotic cell death in lung cancer cells through the enhancement of DR3 expression and inhibition of NF-κB pathway.

  20. Persistent STAT3 Activation in Colon Cancer Is Associated with Enhanced Cell Proliferation and Tumor Growth

    Directory of Open Access Journals (Sweden)

    Florian M. Corvinus

    2005-06-01

    Full Text Available Colorectal carcinoma (CRC is a major cause of morbidity and mortality in Western countries. It has so far been molecularly defined mainly by alterations of the Wnt pathway. We show here for the first time that aberrant activities of the signal transducer and activator of transcription STAT3 actively contribute to this malignancy and, thus, are a potential therapeutic target for CRC. Constitutive STAT3 activity was found to be abundant in dedifferentiated cancer cells and infiltrating lymphocytes of CRC samples, but not in non-neoplastic colon epithelium. Cell lines derived from malignant colorectal tumors lost persistent STAT3 activity in culture. However, implantation of colon carcinoma cells into nude mice resulted in restoration of STAT3 activity, suggesting a role of an extracellular stimulus within the tumor microenvironment as a trigger for STAT activation. STAT3 activity in CRC cells triggered through interleukin-6 or through a constitutively active STAT3 mutant promoted cancer cell multiplication, whereas STAT3 inhibition through a dominant-negative variant impaired IL-6-driven proliferation. Blockade of STAT3 activation in CRCderived xenograft tumors slowed down their development, arguing for a contribution of STAT3 to colorectal tumor growth.

  1. Relaxin reduces xenograft tumour growth of human MDA-MB-231 breast cancer cells

    OpenAIRE

    Radestock, Yvonne; Hoang-Vu, Cuong; Hombach-Klonisch, Sabine

    2008-01-01

    Introduction Relaxin levels are increased in cases of human breast cancer and has been shown to promote cancer cell migration in carcinoma cells of the breast, prostate gland and thyroid gland. In oestrogen receptor alpha-negative MDA-MB-231 human breast cancer cells, relaxin was shown to down-regulate the metastasis-promoting protein S100A4 (metastasin), a highly significant prognostic factor for poor survival in breast cancer patients. The cellular mechanisms of relaxin exposure in breast c...

  2. Epidermal Growth Factor Receptor Mutations and Radiotherapy 
in Non-small Cell Lung Cancer

    Directory of Open Access Journals (Sweden)

    Xing ZHONG

    2013-03-01

    Full Text Available Radiotherapy plays a pivotal role in the treatment for lung cancer. Epidermal growth factor receptor (EGFR mutation in non-small cell lung cancer (NSCLC which predicts tyrosine kinase inhibitor (TKI treatment response may also has effect on radiation response. NSCLC harboring kinase-domain mutations in EGFR exhibits enhanced radio-sensitivity due to dramatically diminished capacity to resolve radiation-induced DSBs (DNA double-strand breaks associating with the inefficiency of EGFR nuclear translocation. Recently, several preliminary clinical studies show certain efficacy of concurrent EGFR tyrosine kinase inhibitors and radiotherapy. However its further response in EGFR-mutated NSCLC is unclear. The correlation between EGFR mutation genotype and the radiotherapy response and clinical outcome is worthy of further study.

  3. Heat shock protein 70 antisense oligonucleotide inhibits cell growth and induces apoptosis in human gastric cancer cell line SGC-7901

    Institute of Scientific and Technical Information of China (English)

    Zhi-Gang Zhao; Wen-Lu Shen

    2005-01-01

    AIM: Heat shock protein (HSP)70 is over-expressed in human gastric cancer and plays an important role in the progression of this cancer. We investigated the effects of antisense HSP70 oligomer on human gastric cancer cell line SGC-7901, and its potential role in gene therapy for this cancer.METHODS: Human gastric cancer cell line SGC-7901 was treated in vitro with various concentrations of antisense HSP70 oligonucleotides at different intervals. Growth inhibition was determined as percentage by trypan blue dye exclusion test. Extracted DNA was electrophoresed on agarose gel, and distribution of cell cycle and kinetics of apoptosis induction were analyzed by propidium iodide DNA incorporation using flow cytometry, which was also used to detect the effects of antisense oligomer pretreatment on the subsequent apoptosis induced by heat shock in SGC-7901 cells. Proteins were extracted for simultaneous measurement of HSP70 expression level by SDS-PAGE Western blotting.RESULTS: The number of viable cells decreased in a doseand time-dependent manner, and ladder-like patterns of DNA fragments were observed in SGC-7901 cells treated with antisense HSP70 oligomers at a concentration of 10 μmol/L for 48 h or 8 μmol/L for 72 h, which were consistent with inter-nucleosomal DNA fragmentation. Flow cytometric analysis showed a dose- and time-dependent increase in apoptotic rate by HSP70 antisense oligomers. This response was accompanied with a decrease in the percentage of cells in the G1 and S phases of the cell cycle, suggesting inhibition of cell proliferation. In addition, flow cytometry also showed that pretreatment of SGC-7901 cells with HSP70 antisense oligomers enhanced the subsequent apoptosis induced by heat shock treatment. Western blotting demonstrated that HSP70 antisense oligomers inhibited HSP70 expression, which preceded apoptosis, and HSP70 was undetectable at the concentration of 10 μmol/L for 48 h or 8 μmol/L for 72 h.CONCLUSION: Antisense HSP70 oligomers

  4. Study of lung-metastasized prostate cancer cell line chemotaxis to epidermal growth factor with a BIOMEMS device

    International Nuclear Information System (INIS)

    Understanding the effects of different growth factors on cancer metastasis will enable researchers to develop effective post-surgery therapeutic strategies to stop the spread of cancer. Conventional Boyden chamber assays to evaluate cell motility in metastasis studies require high volumes of reagents and are impractical for high-throughput analysis. A microfluidic device was designed for arrayed assaying of prostate cancer cell migration towards different growth factors. The device was created with polydimethylsiloxane (PDMS) and featured two wells connected by 10 micro channels. One well was for cell seeding and the other well for specific growth factors. Each channel has a width of 20 μm, a length of 1 mm and a depth of 10 μm. The device was placed on a culture dish and primed with growth media. Lung-metastasized cells in suspension of RPMI 1640 media supplemented with 2% of fetal bovine serum (FBS) were seeded in the cell wells. Cell culture media with epidermal growth factor (EGF) of 25, 50, 75, 100 and 125 ng ml−1 concentrations were individually added in the respective growth factor wells. A 5-day time-lapsed study of cell migration towards the chemoattractant was performed. The average numbers of cells per device in the microchannels were obtained for each attractant condition. The results indicated migration of cells increased from 50 to 100 ng ml−1 of EGF and significantly decreased at 125 ng ml−1 of EGF, as compared to control. (paper)

  5. Growth inhibition and apoptosis in cancer cells induced by polyphenolic compounds of Acacia hydaspica: Involvement of multiple signal transduction pathways.

    Science.gov (United States)

    Afsar, Tayyaba; Trembley, Janeen H; Salomon, Christine E; Razak, Suhail; Khan, Muhammad Rashid; Ahmed, Khalil

    2016-01-01

    Acacia hydaspica R. Parker is known for its medicinal uses in multiple ailments. In this study, we performed bioassay-guided fractionation of cytotoxic compounds from A. hydaspica and investigated their effects on growth and signaling activity in prostate and breast cancer cell lines. Four active polyphenolic compounds were identified as 7-O-galloyl catechin (GC), catechin (C), methyl gallate (MG), and catechin-3-O-gallate (CG). The four compounds inhibited prostate cancer PC-3 cell growth in a dose-dependent manner, whereas CG and MG inhibited breast cancer MDA-MB-231 cell growth. All tested compounds inhibited cell survival and colony growth in both cell lines, and there was evidence of chromatin condensation, cell shrinkage and apoptotic bodies. Further, acridine orange, ethidium bromide, propidium iodide and DAPI staining demonstrated that cell death occurred partly via apoptosis in both PC-3 and MDA-MB-231 cells. In PC-3 cells treatment repressed the expression of anti-apoptotic molecules Bcl-2, Bcl-xL and survivin, coupled with down-regulation of signaling pathways AKT, NFκB, ERK1/2 and JAK/STAT. In MDA-MB-231 cells, treatment induced reduction of CK2α, Bcl-xL, survivin and xIAP protein expression along with suppression of NFκB, JAK/STAT and PI3K pathways. Our findings suggest that certain polyphenolic compounds derived from A. hydaspica may be promising chemopreventive/therapeutic candidates against cancer. PMID:26975752

  6. microRNA-218 inhibits prostate cancer cell growth and promotes apoptosis by repressing TPD52 expression

    International Nuclear Information System (INIS)

    Highlights: • miR-218 expression is downregulated in prostate cancer. • miR-218 inhibits prostate tumor cells proliferation partially through promoting apoptosis. • miR-218 targets TPD52 by binding to its 3′-UTR. • miR-218 suppresses prostate cancer cell growth through inhibiting TPD52 expression. - Abstract: The tumor protein D52 (TPD52) is an oncogene overexpressed in prostate cancer (PC) due to gene amplification. Although the oncogenic effect of TPD52 is well recognized, how its expression is regulated is still not clear. This study tried to explore the regulative role of miR-218, a tumor suppressing miRNA on TPD52 expression and prostate cancer cell proliferation. We found the expression of miR-218 was significantly lower in PC specimens. Based on gain and loss of function analysis, we found miR-218 significantly inhibit cancer cell proliferation by inducing apoptosis. These results strongly suggest that miR-218 plays a tumor suppressor role in PC cells. In addition, our data firstly demonstrated that miR-218 directly regulates oncogenic TPD52 in PC3 cells and the miR-218-TPD52 axis can regulate growth of this prostate cancer cell line. Knockdown of TPD52 resulted in significantly increased cancer cell apoptosis. Clearly understanding of oncogenic TPD52 pathways regulated by miR-218 might be helpful to reveal new therapeutic targets for PC

  7. Transforming growth factor-β1 regulates epithelial-mesenchymal transition in association with cancer stem-like cells in a breast cancer cell line

    OpenAIRE

    Jia, Yongfeng; Wu, Di; Yun, Fen; Shi, Lin; Luo, Nianrong; Liu, Zhiyue; Shi, Yonghong; Sun, Qinnuan; Jiang, Lili; Wang, Shiqi; Du, Maolin

    2014-01-01

    Epithelial-mesenchymal transition (EMT) is associated with altered connection and junctions between cells and changes in abilities of invasion and migration. In this study, we investigated whether SK-BR-3 breast cancer cells induced to undergo EMT exhibit changes in morphological and invasion abilities after Transforming growth factor β1 (TGF-β1) treatment. Serum-deprived SK-BR-3 cells were treated with TGF-β1 (0, 10 ng/mL) for 24 h. The cells morphological changes were observed and imaged us...

  8. Inhibitory effect of human telomerase antisense oligodeoxyribonucleotides on the growth of gastric cancer cell lines in variant tumor pathological subtype

    Institute of Scientific and Technical Information of China (English)

    Jing Ye; Yun-Lin Wu; Shu Zhang; Zi Chen; Li-Xia Guo; Ruo-Yu Zhou; Hong Xie

    2005-01-01

    AIM: To investigate the inhibitory effect of specialized human telomerase antisense oligodeoxyribonucleotides on the growth of well (MKN-28), moderately (SGC-7901)and poorly (MKN-45) differentiated gastric cancer cell lines under specific conditions and its inhibition mechanism,and to observe the correlation between the growth inhibition ratio and the tumor pathologic subtype of gastric cancer cells.METHODS: Telomerase activity in three gastric cancer cell lines of variant tumor pathologic subtype was determined by modified TRAP assay before and after the specialized human telomerase antisense oligodeoxyribonucleotides were dealt with under specific conditions. Effect of antisense oligomer under specific conditions of the growth and viability of gastric cancer cell lines was explored by using trypan blue dye exclusion assay, and cell apoptosis was detected by cell morphology observation, flow cytometry and TUNEL assay.RESULTS: Telomerase activity was detected in well,moderately and poorly differentiated gastric cancer cell lines (the quantification expression of telomerase activity was 43.7TPG, 56.5TPG, 76.7TPG, respectively).Telomerase activity was controlled to 30.2TPG, 36.3TPG and 35.2TPG for MKN-28, SGC-7901 and MKN-45 cell lines respectively after treatment with human telomerase antisense oligomers at the concentration of 5 μmol/L, and was entirely inhibited at 10 μmol/L, against the template region of telomerase RNA component, whereas no inhibition effect was detected in missense oligomers (P<0.05). After treatment with antisense oligomers at different concentrations under specific conditions for 96 h, significant growth inhibition effects were found in MKN-45 and SGC-7901gastric cancer cell lines (the inhibition ratio was 40.89%and 71.28%), but not in MKN-28 cell lines (15.86%). The ratio of inactive SGC-7901 cells increased according to the prolongation of treatment from 48 to 96 h. Missense oligomers could not lead to the same effect (P<0

  9. Peptide nucleic acids arrest the growth of gastric cancer cells SGC7901

    Institute of Scientific and Technical Information of China (English)

    王宽; 张岂凡; 王锡山; 薛英威; 庞达; 傅松滨

    2004-01-01

    Background Peptide nucleic acid (PNA) has many characteristics useful in molecular biology. This paper described an effective way to raise the cell ingestion rate of PNA so as to kill gastric cancer cells.Methods Heteroduplexes of PNAs and oligonucleotides, wrapped by Lipofectamine 2000, were used to infect SGC7901 cells. The inhibitive effect of heteroduplexes was evaluated by analyzing cell clone forming and cell growth rate. Telomerase activity of SGC7901 cells was detected by polymerase chain reaction enzyme-linked immunosorbent assay (PCR-ELISA) and silver staining assay.Results PNAs showed a dose-dependent inhibition of cell proliferation. The percentage of proliferation inhibition was 99.4% after 7 days; the rate of cloning inhibition was 98.2% after 8 days;whereas for oligonucleotide groups, at the same concentration, the percentages were 50. 1% and 67. 5% respectively. Antisense PNA-DNA-Lipofectamine 2000 group (AP-D-L group) exhibited significantly different percentages from the control groups (P<0.05). The test result indicated that telomerase activity of the AP-D-L group was inhibited (P<0.05). At the same time, the impact on cell morphology was observed.Conclusions The results showed that PNAs are potent antisense reagents. The telomeraseassociated therapies are very promising for the treatment of malignant tumours.

  10. Frondoside A inhibits human breast cancer cell survival, migration, invasion and the growth of breast tumor xenografts.

    Science.gov (United States)

    Al Marzouqi, Nadia; Iratni, Rabah; Nemmar, Abderrahim; Arafat, Kholoud; Ahmed Al Sultan, Mahmood; Yasin, Javed; Collin, Peter; Mester, Jan; Adrian, Thomas E; Attoub, Samir

    2011-10-01

    Breast cancer is a major challenge for pharmacologists to develop new drugs to improve the survival of cancer patients. Frondoside A is a triterpenoid glycoside isolated from the sea cucumber, Cucumaria frondosa. It has been demonstrated that Frondoside A inhibited the growth of pancreatic cancer cells in vitro and in vivo. We investigated the impact of Frondoside A on human breast cancer cell survival, migration and invasion in vitro, and on tumor growth in nude mice, using the human estrogen receptor-negative breast cancer cell line MDA-MB-231. The non-tumorigenic MCF10-A cell line derived from normal human mammary epithelium was used as control. Frondoside A (0.01-5 μM) decreased the viability of breast cancer cells in a concentration- and time-dependent manner, with 50%-effective concentration (EC50) of 2.5 μM at 24h. MCF10-A cells were more resistant to the cytotoxic effect of Frondoside A (EC50 superior to 5 μM at 24 h). In the MDA-MB-231 cells, Frondoside A effectively increased the sub-G1 (apoptotic) cell fraction through the activation of p53, and subsequently the caspases 9 and 3/7 cell death pathways. In addition, Frondoside A induced a concentration-dependent inhibition of MDA-MB-231 cell migration and invasion. In vivo, Frondoside A (100 μg/kg/dayi.p. for 24 days) strongly decreased the growth of MDA-MB-231 tumor xenografts in athymic mice, without manifest toxic side-effects. Moreover, we found that Frondoside A could enhance the killing of breast cancer cells induced by the chemotherapeutic agent paclitaxel. These findings identify Frondoside A as a promising novel therapeutic agent for breast cancer. PMID:21741966

  11. Docetaxel-loaded solid lipid nanoparticles suppress breast cancer cells growth with reduced myelosuppression toxicity

    Directory of Open Access Journals (Sweden)

    Yuan Q

    2014-10-01

    Full Text Available Qing Yuan,1 Jing Han,1,2 Wenshu Cong,1 Ying Ge,3 Dandan Ma,1,3,4 Zhaoxia Dai,3,4 Yaping Li,5 Xiaolin Bi1,3,4 1CAS Key Laboratory for Biological Effects of Nanomaterials and Nanosafety, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing, 2School of Life Sciences, Anhui University, Hefei, 3Cancer Center, Institute of Cancer Stem Cell, Dalian Medical University, Dalian, 4Graduate School, Dalian Medical University, Dalian, 5Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, People’s Republic of China Abstract: Docetaxel is an adjuvant chemotherapy drug widely used to treat multiple solid tumors; however, its toxicity and side effects limit its clinical efficacy. Herein, docetaxel-loaded solid lipid nanoparticles (DSNs were developed to reduce systemic toxicity of docetaxel while still keeping its anticancer activity. To evaluate its anticancer activity and toxicity, and to understand the molecular mechanisms of DSNs, different cellular, molecular, and whole genome transcription analysis approaches were utilized. The DSNs showed lower cytotoxicity compared with the commercial formulation of docetaxel (Taxotere® and induced more apoptosis at 24 hours after treatment in vitro. DSNs can cause the treated cancer cells to arrest in the G2/M phase in a dose-dependent manner similar to Taxotere. They can also suppress tumor growth very effectively in a mice model with human xenograft breast cancer. Systemic analysis of gene expression profiles by microarray and subsequent verification experiments suggested that both DSNs and Taxotere regulate gene expression and gene function, including DNA replication, DNA damage response, cell proliferation, apoptosis, and cell cycle regulation. Some of these genes expressed differentially at the protein level although their messenger RNA expression level was similar under Taxotere and DSN treatment. Moreover, DSNs improved the main side effect of Taxotere by greatly

  12. Cholesterol biosynthesis inhibitor RO 48-8071 suppresses growth of hormone-dependent and castration-resistant prostate cancer cells

    Directory of Open Access Journals (Sweden)

    Liang Y

    2016-05-01

    growth of aggressive castration-resistant human prostate cancer cell xenografts in vivo without any signs of toxicity to experimental animals. Importantly, RO did not reduce the viability of normal prostate cells in vitro. Our study is the first to demonstrate that the cholesterol biosynthesis inhibitor RO effectively suppresses growth of human prostate cancer cells. Our findings suggest that cholesterol biosynthesis inhibitors such as RO, when used in combination with commonly used chemotherapeutic drugs or ERβ specific ligands, could represent a novel therapeutic approach to prevent the growth of prostate cancer tumors. Keywords: prostate cancer, cholesterol biosynthesis inhibitor, cell viability, xenograft, castration resistant

  13. Expression of Robo protein in bladder cancer tissues and its effect on the growth of cancer cells by blocking Robo protein

    OpenAIRE

    Li, Yang; Cheng, Hepeng; Xu, Weibo; Tian, Xin; Li, Xiaodong; Zhu, Chaoyang

    2015-01-01

    This study aimed to detect the expression of Slit signaling protein ligand Robo protein in human bladder cancer and para-carcinoma tissue, and observe the tumor cell survival and growth by inoculating the bladder cancer cells with the blocked signaling protein into the subcutaneous tissue of nude mice. The expression of Robo protein was detected in T24 cells in human bladder uroepithelium carcinoma and cultivated human bladder uroepithelium carcinoma confirmed by pathological diagnosis. The c...

  14. Aurora kinase B is important for antiestrogen resistant cell growth and a potential biomarker for tamoxifen resistant breast cancer

    DEFF Research Database (Denmark)

    Larsen, Sarah L; Yde, Christina W; Laenkholm, Anne-Vibeke;

    2015-01-01

    endocrine resistance, immunohistochemistry was performed on archival primary tumor tissue from breast cancer patients who have received adjuvant endocrine treatment with tamoxifen. RESULTS: The selective Aurora kinase B inhibitor barasertib was identified to preferentially inhibit growth of fulvestrant...... and PARP cleavage in the fulvestrant resistant cells. Barasertib also exerted preferential growth inhibition of tamoxifen resistant T47D cell lines. Finally, high percentage of Aurora kinase B positive tumor cells was significantly associated with reduced disease-free and overall survival in 261 ER......-positive breast cancer patients, who have received tamoxifen as first-line adjuvant endocrine treatment. CONCLUSIONS: Our results indicate that Aurora kinase B is a driving factor for growth of antiestrogen resistant T47D breast cancer cell lines, and a biomarker for reduced benefit of tamoxifen treatment. Thus...

  15. Addition of 2-deoxyglucose enhances growth inhibition but reverses acidification in colon cancer cells treated with phenformin.

    Science.gov (United States)

    Lea, Michael A; Chacko, Jerel; Bolikal, Sandhya; Hong, Ji Y; Chung, Ryan; Ortega, Andres; desbordes, Charles

    2011-02-01

    A report that effects of butyrate on some cells may be mediated by activation of AMP-activated protein kinase (AMPK) prompted this study which examines if other AMPK activators can induce differentiation and inhibit proliferation of colon cancer cells in a manner similar to butyrate. Using induction of alkaline phosphatase as a marker, it was observed that compound C, an AMPK inhibitor, is able to reduce the differentiating effect of butyrate on SW1116 and Caco-2 colon cancer cells. Metformin was observed to be less effective than butyrate in the induction of alkaline phosphatase but was more effective as a growth inhibitor. Phenformin was found to be a more potent growth inhibitor than metformin and both compounds cause acidification of the medium when incubated with colon cancer cells. Combined incubation of 2-deoxyglucose with either of the biguanides prevented the acidification of the medium but enhanced the growth inhibitory effects. PMID:21378320

  16. Phenotype-dependent effects of EpCAM expression on growth and invasion of human breast cancer cell lines

    International Nuclear Information System (INIS)

    The epithelial cell adhesion molecule (EpCAM) has been shown to be overexpressed in breast cancer and stem cells and has emerged as an attractive target for immunotherapy of breast cancer patients. This study analyzes the effects of EpCAM on breast cancer cell lines with epithelial or mesenchymal phenotype. For this purpose, shRNA-mediated knockdown of EpCAM gene expression was performed in EpCAMhigh breast cancer cell lines with epithelial phenotype (MCF-7, T47D and SkBR3). Moreover, EpCAMlow breast carcinoma cell lines with mesenchymal phenotype (MDA-MB-231, Hs578t) and inducible overexpression of EpCAM were used to study effects on proliferation, migration and in vivo growth. In comparison to non-specific silencing controls (n/s-crtl) knockdown of EpCAM (E#2) in EpCAMhigh cell lines resulted in reduced cell proliferation under serum-reduced culture conditions. Moreover, DNA synthesis under 3D culture conditions in collagen was significantly reduced. Xenografts of MCF-7 and T47D cells with knockdown of EpCAM formed smaller tumors that were less invasive. EpCAMlow cell lines with tetracycline-inducible overexpression of EpCAM showed no increased cell proliferation or migration under serum-reduced growth conditions. MDA-MB-231 xenografts with EpCAM overexpression showed reduced invasion into host tissue and more infiltrates of chicken granulocytes. The role of EpCAM in breast cancer strongly depends on the epithelial or mesenchymal phenotype of tumor cells. Cancer cells with epithelial phenotype need EpCAM as a growth- and invasion-promoting factor, whereas tumor cells with a mesenchymal phenotype are independent of EpCAM in invasion processes and tumor progression. These findings might have clinical implications for EpCAM-based targeting strategies in patients with invasive breast cancer

  17. Neoadjuvant therapy affects tumor growth markers in early stage non-small-cell lung cancer

    Directory of Open Access Journals (Sweden)

    Chorostowska-Wynimko J

    2009-12-01

    Full Text Available Abstract Introduction While adjuvant therapy of early-stage non-small-cell lung cancer (NSCLC is widely accepted, literature data concerning neoadjuvant treatment provide contradictory results with both improved and unaffected survival rates. Also, data concerning potential effects of neo-adjuvant therapy on cellular level are scarce. Objective The aim of present study was to analyze the effect of chemotherapy followed by surgical resection on several key biological markers of tumor growth (TGF-β, VEGF, apoptosis (sAPO-1/Fas/CD95 and invasiveness (TIMP-1 assessed in the sera of NSCLC early-stage patients (IB-IIIA. Materials and methods Measurements were performed by ELISA method in blood serum from 24 NSCLC patients (I-IIIA collected prior therapy, one day before surgery and 3 days after. Results TGF-β serum concentrations were significantly lower after both chemotherapy (P Conclusion Neoadjuvant treatment of early-stage NSCLC affects mostly mechanisms responsible for tumor growth and vascularization. Its effect on cancer cells apoptotic activity needs further evaluation.

  18. Acetyl-CoA synthetase 2 promotes acetate utilization and maintains cancer cell growth under metabolic stress

    OpenAIRE

    Schug, Zachary T.; Peck, Barrie; Jones, Dylan T; Zhang, Qifeng; Grosskurth, Shaun; Alam, Israt S.; Goodwin, Louise M.; Smethurst, Elizabeth; Mason, Susan; Blyth, Karen; McGarry, Lynn; James, Daniel; Shanks, Emma; Kalna, Gabriela; Saunders, Rebecca E.

    2015-01-01

    Summary A functional genomics study revealed that the activity of acetyl-CoA synthetase 2 (ACSS2) contributes to cancer cell growth under low-oxygen and lipid-depleted conditions. Comparative metabolomics and lipidomics demonstrated that acetate is used as a nutritional source by cancer cells in an ACSS2-dependent manner, and supplied a significant fraction of the carbon within the fatty acid and phospholipid pools. ACSS2 expression is upregulated under metabolically stressed conditions and A...

  19. Triplex DNA-mediated downregulation of Ets2 expression results in growth inhibition and apoptosis in human prostate cancer cells

    OpenAIRE

    Giuseppina M. Carbone; Napoli, Sara; Valentini, Alessandra; Cavalli, Franco; Watson, Dennis K.; Catapano, Carlo V

    2004-01-01

    Ets2 is a member of the Ets family of transcription factors that in humans comprise 25 distinct members. Various Ets-domain transcription factors have been implicated in cancer development. Ets2 is expressed in prostate and breast cancer cells and is thought to have a role in promoting growth and survival in these cell types. However, a definitive role and the mechanisms whereby Ets2 acts in cancer cells are still unclear. Structural and functional similarities as well as overlapping DNA bind...

  20. Production of interleukin‑4 in CD133+ cervical cancer stem cells promotes resistance to apoptosis and initiates tumor growth.

    Science.gov (United States)

    Liu, Chun-Tao; Xin, Ying; Tong, Chun-Yan; Li, Bing; Bao, Hong-Li; Zhang, Cai-Yun; Wang, Xue-Hui

    2016-06-01

    The cancer stem cell (CSC) theory suggests that cancer growth and invasion is dictated by the small population of CSCs within the heterogenous tumor. The aim of the present study was to elucidate the cause for chemotherapy failure and the resistance of CSCs to apoptosis. A total of ~2.3% cluster of differentiation (CD)133+ cancer stem‑like side population (SP) cells were identified in cases of uterine cervical cancer. These CD133+ SP cells were found to potently initiate tumor growth and invasion, as they exhibit transcriptional upregulation of stemness genes, including octamer‑binding transcription factor‑4, B‑cell‑specific Moloney murine leukemia virus insertion site‑1, epithelial cell adhesion molecule, (sex determining region Y)‑box 2, Nestin and anti‑apoptotic B cell lymphoma‑2. In addition, the CD133+ SP cells showed resistance to multi‑drug treatment and apoptosis. The present study further showed that the secretion of interleukin‑4 (IL‑4) in CD133+ cervical cancer SP cells promoted cell proliferation and prevented the SP cells from apoptosis. Following the neutralization of IL‑4 with anti‑IL‑4 antibody, the CD133+ SP cells were more sensitive to drug treatment and apoptosis. Therefore, the data obtained in the present study suggested that the autocrine secretion of IL‑4 promotes increased survival and resistance to cell death in CSCs. PMID:27121303

  1. ST13, a proliferation regulator, inhibits growth and migration of colorectal cancer cell lines

    Institute of Scientific and Technical Information of China (English)

    Rui BAI; Zhong SHI; Jia-wei ZHANG; Dan LI; Yong-liang ZHU; Shu ZHENG

    2012-01-01

    Background and objective:ST13,is the gene encoding the HSP70 interacting protein (HIP).Previous research has shown that ST13 mRNA and protein levels are down-regulated in colorectal cancer (CRC) tissues compared with adjacent normal tissues.This study aims at the role of ST13 in the proliferation and migration of CRC cells.Methods:The transcript level of ST13 in different CRC cell lines was evaluated by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR).ST13-overexpressed and ST13-knockdown CRC cells were constructed respectively by lentiviral transduction,followed by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) assay,plate colony formation,cell-cycle analysis,and migration assays to evaluate the influence of ST13 on proliferation and migration in vitro.Moreover,a mouse xenograft study was performed to test in vivo tumorigenicity of ST13-knockdown CRC cells.Results:Lentivirus-mediated overexpression of ST13 in CRC cells inhibited cell proliferation,colony formation,and cell migration in vitro.In contrast,down-regulation of ST13 by lentiviralbased short hairpin RNA (shRNA) interference in CRC cells significantly increased cell proliferation and cloning efficiency in vitro.In addition,down-regulation of ST13 expression significantly increased the tumorigenicity of CRC cells in vivo.Conclusions:ST13 gene is a proliferation regulator that inhibits tumor growth in CRC and may affect cell migration.

  2. Decreased autocrine EGFR signaling in metastatic breast cancer cells inhibits tumor growth in bone and mammary fat pad.

    Science.gov (United States)

    Nickerson, Nicole K; Mohammad, Khalid S; Gilmore, Jennifer L; Crismore, Erin; Bruzzaniti, Angela; Guise, Theresa A; Foley, John

    2012-01-01

    Breast cancer metastasis to bone triggers a vicious cycle of tumor growth linked to osteolysis. Breast cancer cells and osteoblasts express the epidermal growth factor receptor (EGFR) and produce ErbB family ligands, suggesting participation of these growth factors in autocrine and paracrine signaling within the bone microenvironment. EGFR ligand expression was profiled in the bone metastatic MDA-MB-231 cells (MDA-231), and agonist-induced signaling was examined in both breast cancer and osteoblast-like cells. Both paracrine and autocrine EGFR signaling were inhibited with a neutralizing amphiregulin antibody, PAR34, whereas shRNA to the EGFR was used to specifically block autocrine signaling in MDA-231 cells. The impact of these was evaluated with proliferation, migration and gene expression assays. Breast cancer metastasis to bone was modeled in female athymic nude mice with intratibial inoculation of MDA-231 cells, and cancer cell-bone marrow co-cultures. EGFR knockdown, but not PAR34 treatment, decreased osteoclasts formed in vitro (p<0.01), reduced osteolytic lesion tumor volume (p<0.01), increased survivorship in vivo (p<0.001), and resulted in decreased MDA-231 growth in the fat pad (p<0.01). Fat pad shEGFR-MDA-231 tumors produced in nude mice had increased necrotic areas and decreased CD31-positive vasculature. shEGFR-MDA-231 cells also produced decreased levels of the proangiogenic molecules macrophage colony stimulating factor-1 (MCSF-1) and matrix metalloproteinase 9 (MMP9), both of which were decreased by EGFR inhibitors in a panel of EGFR-positive breast cancer cells. Thus, inhibiting autocrine EGFR signaling in breast cancer cells may provide a means for reducing paracrine factor production that facilitates microenvironment support in the bone and mammary gland. PMID:22276166

  3. Decreased autocrine EGFR signaling in metastatic breast cancer cells inhibits tumor growth in bone and mammary fat pad.

    Directory of Open Access Journals (Sweden)

    Nicole K Nickerson

    Full Text Available Breast cancer metastasis to bone triggers a vicious cycle of tumor growth linked to osteolysis. Breast cancer cells and osteoblasts express the epidermal growth factor receptor (EGFR and produce ErbB family ligands, suggesting participation of these growth factors in autocrine and paracrine signaling within the bone microenvironment. EGFR ligand expression was profiled in the bone metastatic MDA-MB-231 cells (MDA-231, and agonist-induced signaling was examined in both breast cancer and osteoblast-like cells. Both paracrine and autocrine EGFR signaling were inhibited with a neutralizing amphiregulin antibody, PAR34, whereas shRNA to the EGFR was used to specifically block autocrine signaling in MDA-231 cells. The impact of these was evaluated with proliferation, migration and gene expression assays. Breast cancer metastasis to bone was modeled in female athymic nude mice with intratibial inoculation of MDA-231 cells, and cancer cell-bone marrow co-cultures. EGFR knockdown, but not PAR34 treatment, decreased osteoclasts formed in vitro (p<0.01, reduced osteolytic lesion tumor volume (p<0.01, increased survivorship in vivo (p<0.001, and resulted in decreased MDA-231 growth in the fat pad (p<0.01. Fat pad shEGFR-MDA-231 tumors produced in nude mice had increased necrotic areas and decreased CD31-positive vasculature. shEGFR-MDA-231 cells also produced decreased levels of the proangiogenic molecules macrophage colony stimulating factor-1 (MCSF-1 and matrix metalloproteinase 9 (MMP9, both of which were decreased by EGFR inhibitors in a panel of EGFR-positive breast cancer cells. Thus, inhibiting autocrine EGFR signaling in breast cancer cells may provide a means for reducing paracrine factor production that facilitates microenvironment support in the bone and mammary gland.

  4. Gain of glucose-independent growth upon metastasis of breast cancer cells to the brain

    OpenAIRE

    Chen, Jinyu; Lee, Ho-Jeong; Wu, Xuefeng; Huo, Lei; Kim, Sun-Jin; Xu, Lei; Wang, Yan; He, Junqing; Bollu, Lakshmi Reddy; Gao, Guang; Su, Fei; Briggs, James; Liu, Xiaojing; Melman, Tamar; Asara, John M.

    2014-01-01

    Breast cancer brain metastasis is resistant to therapy and a particularly poor prognostic feature in patient survival. Altered metabolism is a common feature of cancer cells but little is known as to what metabolic changes benefit breast cancer brain metastases. We found that brain-metastatic breast cancer cells evolved the ability to survive and proliferate independent of glucose due to enhanced gluconeogenesis and oxidations of glutamine and branched chain amino acids, which together sustai...

  5. Protein Kinase C alpha (PKCα) dependent signaling mediates endometrial cancer cell growth and tumorigenesis

    Science.gov (United States)

    Haughian, James M.; Reno, Elaine M.; Thorne, Alicia M.; Bradford, Andrew P.

    2009-01-01

    Endometrial cancer is the most common invasive gynecologic malignancy, yet molecular mechanisms and signaling pathways underlying its etiology and pathophysiology remain poorly characterized. We sought to define a functional role for the protein kinase C (PKC) isoform, PKCα, in an established cell model of endometrial adenocarcinoma. Ishikawa cells depleted of PKCα protein grew slower, formed fewer colonies in anchorage-independent growth assays and exhibited impaired xenograft tumor formation in nude mice. Consistent with impaired growth, PKCα knockdown increased levels of the cyclin dependent kinase (CDK) inhibitors p21Cip1/WAF1 (p21) and p27Kip1 (p27). Despite the absence of functional phosphatase and tensin homologue (PTEN) protein in Ishikawa cells, PKCα knockdown reduced Akt phosphorylation at serine 473 and concomitantly inhibited phosphorylation of the Akt target, glycogen synthase kinase-3β (GSK-3β). PKCα knockdown also resulted in decreased basal ERK phosphorylation and attenuated ERK activation following EGF stimulation. p21 and p27 expression was not increased by treatment of Ishikawa cells with ERK and Akt inhibitors, suggesting PKCα regulates CDK expression independently of Akt and ERK. Immunohistochemical analysis of grade 1 endometrioid adenocarcinoma revealed aberrant PKCα expression, with foci of elevated PKCα staining, not observed in normal endometrium. These studies demonstrate a critical role for PKCα signaling in endometrial tumorigenesis by regulating expression of CDK inhibitors p21 and p27 and activation of Akt and ERK dependent proliferative pathways. Thus, targeting PKCα may provide novel therapeutic options in endometrial tumors. PMID:19672862

  6. 1-o-acetylbritannilactone (ABL) inhibits angiogenesis and lung cancer cell growth through regulating VEGF-Src-FAK signaling.

    Science.gov (United States)

    Zhengfu, He; Hu, Zhang; Huiwen, Miao; Zhijun, Li; Jiaojie, Zhou; Xiaoyi, Yan; Xiujun, Cai

    2015-08-21

    The search for safe, effective and affordable therapeutics against non-small cell lung cancer (NSCLC) and other lung cancers is important. Here we explored the potential effect of 1-o-acetylbritannilactone (ABL), a novel extract from Inula britannica-F, on angiogenesis and lung cancer cell growth. We demonstrated that ABL dose-dependently inhibited vascular endothelial growth factor (VEGF)-induced proliferation, migration, and capillary structure formation of cultured human umbilical vascular endothelial cells (HUVECs). In vivo, ABL administration suppressed VEGF-induced new vasculature formation in Matrigel plugs. For the mechanism investigations, we found that ABL largely inhibited VEGF-mediated activation of Src kinase and focal adhesion kinase (FAK) in HUVECs. Furthermore, treatment of A549 NSCLC cells with ABL resulted in cell growth inhibition and Src-FAK in-activation. Significantly, administration of a single dose of ABL (12 mg/kg/day) remarkably suppressed growth of A549 xenografts in nude mice. In vivo microvessels formation and Src activation were also significantly inhibited in ABL-treated xenograft tumors. Taken together, our findings suggest that ABL suppresses angiogenesis and lung cancer cell growth possibly via regulating the VEGFR-Src-FAK signaling. PMID:26102035

  7. Inhibition of system L (LAT1/CD98hc) reduces the growth of cultured human breast cancer cells.

    Science.gov (United States)

    Shennan, David B; Thomson, Jean

    2008-10-01

    It has been suggested that system L (LAT1/CD98hc) is up-regulated in cancer cells, including breast tumour cells, and is therefore a promising molecular target to inhibit or limit tumour cell growth. In view of this, we have examined the effect of BCH and other inhibitors of system L on the growth of MCF-7, ZR-75-1 and MDA-MB-231 cells. Treating cells with BCH markedly inhibited the metabolism of WST-1 in a dose-dependent fashion. Similarly, melphalan and D-leucine inhibited the growth of cultured breast cancer cells whereas MeAIB, an inhibitor of system A, was without effect. The effects of BCH and melphalan on cell growth were non-additive suggesting that both compounds were acting at a single locus. The results indicate that system L is required to maintain MCF-7, ZR-75-1 and MDA-MB-231 cell growth and support the notion that LAT1/CD98hc may be a suitable target to inhibit breast cancer progression. PMID:18813831

  8. Decreased expression of the mannose 6- phosphate/insulin-like growth factor-II receptor promotes growth of human breast cancer cells

    International Nuclear Information System (INIS)

    Loss or mutation of the mannose 6-phosphate/insulin-like growth factor-II receptor (M6P/IGF2R) has been found in breast cancer. However, whether or not decreased levels of functional M6P/IGF2R directly contribute to the process of carcinogenesis needs to be further verified by functional studies. In this study, using viral and ribozyme strategies we reduced the expression of M6P/IGF2R in human breast cancer cells and then examined the effect on growth and apoptosis of these cells. Our results showed that infection of MCF-7 cells with the adenovirus carrying a ribozyme targeted against the M6P/IGF2R mRNA dramatically reduced the level of transcripts and the functional activity of M6P/IGF2R in these cells. Accordingly, cells treated with the ribozyme exhibited a higher growth rate and a lower apoptotic index than control cells (infected with a control vector). Furthermore, decreased expression of M6P/IGF2R enhanced IGF-II-induced proliferation and reduced cell susceptibility to TNF-induced apoptosis. These results suggest that M6P/IGF2R functions as a growth suppressor and its loss or mutation may contribute to development and progression of cancer. This study also demonstrates that adenoviral delivery of the ribozyme provides a useful tool for investigating the role of M6P/IGF2R in regulation of cell growth

  9. Cancer Stem Cells, Cancer Cell Plasticity and Radiation Therapy

    OpenAIRE

    Vlashi, Erina; Pajonk, Frank

    2014-01-01

    Since the first prospective identification of cancer stem cells in solid cancers the cancer stem cell hypothesis has reemerged as a research topic of increasing interest. It postulates that solid cancers are organized hierarchically with a small number of cancer stem cells driving tumor growth, repopulation after injury and metastasis. They give rise to differentiated progeny, which lack these features. The model predicts that for any therapy to provide cure, all cancer stem cells have to be ...

  10. TRPM7 is required for ovarian cancer cell growth, migration and invasion

    International Nuclear Information System (INIS)

    Highlights: • Silence of TRPM7 in ovarian cancer cells inhibits cell proliferation, migration and invasion. • Silence of TRPM7 decreases phosphorylation levels of Akt, Src and p38 in ovarian cancer cells. • Silence of TRPM7 increases expression of filamentous actin and number of focal adhesions in ovarian cancer cells. - Abstract: Our previous study demonstrated that the melastatin-related transient receptor potential channel 7 (TRPM7) was highly expressed in ovarian carcinomas and its overexpression was significantly associated with poor prognosis in ovarian cancer patients. However, the function of TRPM7 in ovarian cancer is mostly unknown. In this study, we examined the roles of TRPM7 in ovarian cancer cell proliferation, migration and invasion. We found that short hairpin RNA interference-mediated silence of TRPM7 significantly inhibited cell proliferation, colony formation, migration and invasion in multiple ovarian cancer cell lines. Mechanistic investigation revealed that silence of TRPM7 decreased phosphorylation levels of Akt, Src and p38 and increased filamentous actin and focal adhesion number in ovarian cancer cells. Thus, our results suggest that TRPM7 is required for proliferation, migration and invasion of ovarian cancer cells through regulating multiple signaling transduction pathways and the formation of focal adhesions

  11. TRPM7 is required for ovarian cancer cell growth, migration and invasion

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Jing; Liao, Qian-jin [The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013 (China); Zhang, Yi [Department of Obstetrics and Gynaecology, Xiangya Hospital, Central South University, Changsha 410078 (China); Zhou, Hui; Luo, Chen-hui; Tang, Jie; Wang, Ying; Tang, Yan; Zhao, Min; Zhao, Xue-heng [The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013 (China); Zhang, Qiong-yu [Department of Basic Medical Science, Yongzhou Vocational Technical College, Yong Zhou 425100 (China); Xiao, Ling, E-mail: lingxiaocsu@126.com [Department of Histology and Embryology, School of Basic Medical Sciences, Central South University, Changsha 410013 (China); Institute of Clinical Pharmacology, Central South University, Changsha 410018 (China)

    2014-11-28

    Highlights: • Silence of TRPM7 in ovarian cancer cells inhibits cell proliferation, migration and invasion. • Silence of TRPM7 decreases phosphorylation levels of Akt, Src and p38 in ovarian cancer cells. • Silence of TRPM7 increases expression of filamentous actin and number of focal adhesions in ovarian cancer cells. - Abstract: Our previous study demonstrated that the melastatin-related transient receptor potential channel 7 (TRPM7) was highly expressed in ovarian carcinomas and its overexpression was significantly associated with poor prognosis in ovarian cancer patients. However, the function of TRPM7 in ovarian cancer is mostly unknown. In this study, we examined the roles of TRPM7 in ovarian cancer cell proliferation, migration and invasion. We found that short hairpin RNA interference-mediated silence of TRPM7 significantly inhibited cell proliferation, colony formation, migration and invasion in multiple ovarian cancer cell lines. Mechanistic investigation revealed that silence of TRPM7 decreased phosphorylation levels of Akt, Src and p38 and increased filamentous actin and focal adhesion number in ovarian cancer cells. Thus, our results suggest that TRPM7 is required for proliferation, migration and invasion of ovarian cancer cells through regulating multiple signaling transduction pathways and the formation of focal adhesions.

  12. PPAR{gamma} ligands induce growth inhibition and apoptosis through p63 and p73 in human ovarian cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Soyeon [Cancer Research Institute, Seoul National University College of Medicine and Hospital, Seoul (Korea, Republic of); Innovative Research Institute for Cell Therapy, Seoul National University College of Medicine and Hospital, Seoul (Korea, Republic of); Lee, Jae-Jung [Cancer Research Institute, Seoul National University College of Medicine and Hospital, Seoul (Korea, Republic of); Heo, Dae Seog, E-mail: heo1013@snu.ac.kr [Cancer Research Institute, Seoul National University College of Medicine and Hospital, Seoul (Korea, Republic of); Department of Internal Medicine, Seoul National University College of Medicine and Hospital, Seoul (Korea, Republic of); Innovative Research Institute for Cell Therapy, Seoul National University College of Medicine and Hospital, Seoul (Korea, Republic of)

    2011-03-18

    Research highlights: {yields} PPAR{gamma} ligands increased the rate of apoptosis and inhibition of proliferation in ovarian cancer cells. {yields} PPAR{gamma} ligands induced p63 and p73 expression, but not p53. {yields} p63 and p73 leads to an increase in p21 expression and apoptosis in ovarian cancer cells with treatment PPAR{gamma} ligands. {yields} These findings suggest that PPAR{gamma} ligands suppressed growth of ovarian cancer cells through upregulation of p63 and p73. -- Abstract: Peroxisome proliferator-activated receptor gamma (PPAR{gamma}) agonists, including thiazolidinediones (TZDs), can induce anti-proliferation, differentiation, and apoptosis in various cancer cell types. This study investigated the mechanism of the anticancer effect of TZDs on human ovarian cancer. Six human ovarian cancer cell lines (NIH:OVCAR3, SKOV3, SNU-251, SNU-8, SNU-840, and 2774) were treated with the TZD, which induced dose-dependent inhibition of cell growth. Additionally, these cell lines exhibited various expression levels of PPAR{gamma} protein as revealed by Western blotting. Flow cytometry showed that the cell cycle was arrested at the G1 phase, as demonstrated by the appearance of a sub-G1 peak. This observation was corroborated by the finding of increased levels of Bax, p21, PARP, and cleaved caspase 3 in TGZ-treated cells. Interestingly, when we determined the effect of p53-induced growth inhibition in these three human ovarian cancer cells, we found that they either lacked p53 or contained a mutant form of p53. Furthermore, TGZ induced the expression of endogenous or exogenous p63 and p73 proteins and p63- or p73-directed short hairpin (si) RNAs inhibited the ability of TGZ to regulate expression of p21 in these cells. Thus, our results suggest that PPAR{gamma} ligands can induce growth suppression of ovarian cancer cells and mediate p63 and p73 expression, leading to enhanced growth inhibition and apoptosis. The tumor suppressive effects of PPAR{gamma} ligands

  13. PPARγ ligands induce growth inhibition and apoptosis through p63 and p73 in human ovarian cancer cells

    International Nuclear Information System (INIS)

    Research highlights: → PPARγ ligands increased the rate of apoptosis and inhibition of proliferation in ovarian cancer cells. → PPARγ ligands induced p63 and p73 expression, but not p53. → p63 and p73 leads to an increase in p21 expression and apoptosis in ovarian cancer cells with treatment PPARγ ligands. → These findings suggest that PPARγ ligands suppressed growth of ovarian cancer cells through upregulation of p63 and p73. -- Abstract: Peroxisome proliferator-activated receptor gamma (PPARγ) agonists, including thiazolidinediones (TZDs), can induce anti-proliferation, differentiation, and apoptosis in various cancer cell types. This study investigated the mechanism of the anticancer effect of TZDs on human ovarian cancer. Six human ovarian cancer cell lines (NIH:OVCAR3, SKOV3, SNU-251, SNU-8, SNU-840, and 2774) were treated with the TZD, which induced dose-dependent inhibition of cell growth. Additionally, these cell lines exhibited various expression levels of PPARγ protein as revealed by Western blotting. Flow cytometry showed that the cell cycle was arrested at the G1 phase, as demonstrated by the appearance of a sub-G1 peak. This observation was corroborated by the finding of increased levels of Bax, p21, PARP, and cleaved caspase 3 in TGZ-treated cells. Interestingly, when we determined the effect of p53-induced growth inhibition in these three human ovarian cancer cells, we found that they either lacked p53 or contained a mutant form of p53. Furthermore, TGZ induced the expression of endogenous or exogenous p63 and p73 proteins and p63- or p73-directed short hairpin (si) RNAs inhibited the ability of TGZ to regulate expression of p21 in these cells. Thus, our results suggest that PPARγ ligands can induce growth suppression of ovarian cancer cells and mediate p63 and p73 expression, leading to enhanced growth inhibition and apoptosis. The tumor suppressive effects of PPARγ ligands may have applications for the treatment of ovarian cancer.

  14. The chalcone butein from Rhus verniciflua Stokes inhibits clonogenic growth of human breast cancer cells co-cultured with fibroblasts

    Directory of Open Access Journals (Sweden)

    Tan Jenny

    2005-03-01

    Full Text Available Abstract Background Butein (3,4,2',4'-tetrahydroxychalone, a plant polyphenol, is a major biologically active component of the stems of Rhus verniciflua Stokes. It has long been used as a food additive in Korea and as an herbal medicine throughout Asia. Recently, butein has been shown to suppress the functions of fibroblasts. Because fibroblasts are believed to play an important role in promoting the growth of breast cancer cells, we investigated the ability of butein to inhibit the clonogenic growth of small numbers of breast cancer cells co-cultured with fibroblasts in vitro. Methods We first measured the clonogenic growth of small numbers of the UACC-812 human breast cancer cell line co-cultured on monolayers of serum-activated, human fibroblasts in the presence of butein (2 μg/mL or various other modulators of fibroblast function (troglitazone-1 μg/mL; GW9662-1 μM; meloxican-1 μM; and 3,4 dehydroproline-10 μg/mL. In a subsequent experiment, we measured the dose-response effect on the clonogenic growth of UACC-812 breast cancer cells by pre-incubating the fibroblasts with varying concentrations of butein (10 μg/ml-1.25 μg/mL. Finally, we measured the clonogenic growth of primary breast cancer cells obtained from 5 clinical specimens with normal fibroblasts and with fibroblasts that had been pre-treated with a fixed dose of butein (2.5 μg/mL. Results Of the five modulators of fibroblast function that we tested, butein was by far the most potent inhibitor of clonogenic growth of UACC-812 breast cancer cells co-cultured with fibroblasts. Pre-treatment of fibroblasts with concentrations of butein as low as 2.5 μg/mL nearly abolished subsequent clonogenic growth of UACC-812 breast cancer cells co-cultured with the fibroblasts. A similar dose of butein had no effect on the clonogenic growth of breast cancer cells cultured in the absence of fibroblasts. Significantly, clonogenic growth of the primary breast cancer cells was also

  15. Squalamine and cisplatin block angiogenesis and growth of human ovarian cancer cells with or without HER-2 gene overexpression.

    Science.gov (United States)

    Li, Dan; Williams, Jon I; Pietras, Richard J

    2002-04-25

    Angiogenesis is important for growth and progression of ovarian cancers. Squalamine is a natural antiangiogenic sterol, and its potential role in treatment of ovarian cancers with or without standard cisplatin chemotherapy was assessed. Since HER-2 gene overexpression is associated with cisplatin resistance in vitro and promotion of tumor angiogenesis in vivo, the response of ovarian cancer cells with or without HER-2 gene overexpression to squalamine and cisplatin was evaluated both in tumor xenograft models and in tissue culture. Ovarian cancer cells with or without HER-2 overexpression were grown as subcutaneous xenografts in nude mice. Animals were treated by intraperitoneal injection with control vehicle, cisplatin, squalamine or cisplatin combined with squalamine. At the end of the experiment, tumors were assessed for tumor growth inhibition and for changes in microvessel density and apoptosis. Additional in vitro studies evaluated effects of squalamine on tumor and endothelial cell growth and on signaling pathways in human endothelial cells. Profound growth inhibition was elicited by squalamine alone and by combined treatment with squalamine and cisplatin for both parental and HER-2-overexpressing ovarian tumor xenografts. Immunohistochemical evaluation of tumors revealed decreased microvessel density and increased apoptosis. Although HER-2-overexpressing tumors had more angiogenic and less apoptotic activity than parental cancers, growth of both tumor types was similarly suppressed by treatment with squalamine combined with cisplatin. In in vitro studies, we found that squalamine does not directly affect proliferation of ovarian cells. However, squalamine significantly blocked VEGF-induced activation of MAP kinase and cell proliferation in human vascular endothelial cells. The results suggest that squalamine is anti-angiogenic for ovarian cancer xenografts and appears to enhance cytotoxic effects of cisplatin chemotherapy independent of HER-2 tumor status

  16. Repression of the Integrated Papillomavirus E6/E7 Promoter Is Required for Growth Suppression of Cervical Cancer Cells

    OpenAIRE

    Francis, Delicia A.; Schmid, Susanne I.; Howley, Peter M.

    2000-01-01

    The human papillomavirus (HPV) E2 protein is an important regulator of viral E6 and E7 gene expression. E2 can repress the viral promoter for E6 and E7 expression as well as block progression of the cell cycle in cancer cells harboring the DNA of “high-risk” HPV types. Although the phenomenon of E2-mediated growth arrest of HeLa cells and other HPV-positive cancer cells has been well documented, the specific mechanism by which E2 affects cellular proliferation has not yet been elucidated. Her...

  17. Gastric Cancer Stem Cells

    OpenAIRE

    Takaishi, Shigeo; Okumura, Tomoyuki; Timothy C Wang

    2008-01-01

    Cancer stem cells are defined as the unique subpopulation in the tumors that possess the ability to initiate tumor growth and sustain self-renewal as well as metastatic potential. Accumulating evidence in recent years strongly indicate the existence of cancer stem cells in solid tumors of a wide variety of organs. In this review, we will discuss the possible existence of a gastric cancer stem cell. Our recent data suggest that a subpopulation with a defined marker shows spheroid colony format...

  18. Vascular endothelial growth factor A, secreted in response to transforming growth factor-β1 under hypoxic conditions, induces autocrine effects on migration of prostate cancer cells

    Institute of Scientific and Technical Information of China (English)

    Eric Darrington; Miao Zhong; Bao-Han Vo; Shafiq A Khan

    2012-01-01

    Hypoxia and transforming growth factor-β1 (TGF-β1) increase vascular endothelial growth factor A (VEGFA) expression in a number of malignancies.This effect of hypoxia and TGF-β1 might be responsible for tumor progression and metastasis of advanced prostate cancer.In the present study,TGF-β1 was shown to induce VEGFA165 secretion from both normal cell lines (HPV7 and RWPE1) and prostate cancer cell lines (DU 145 and PC3).Conversely,hypoxia-stimulated VEGFA165 secretion was observed only in prostate cancer cell lines.Hypoxia induced TGF-β1 expression in PC3 prostate cancer cells,and the TGF-β type Ⅰ receptor (ALK5) kinase inhibitor partially blocked hypoxia-mediated VEGFA165 secretion.This effect of hypoxia provides a novel mechanism to increase VEGFA expression in prostate cancer cells.Although autocrine signaling of VEGFA has been implicated in prostate cancer progression and metastasis,the associated mechanism is poorly characterized.VEGFA activity is mediated via VEGF receptor (VEGFR) 1 (Fit-1 ) and 2 (Flk-1/KDR).Whereas VEGFR-1 mRNA was detected in normal prostate epithelial cells,VEGFR-2 mRNA and VEGFR protein were expressed only in PC3 cells.VEGFA165 treatment induced phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) in PC3 cells but not in HPV7 cells,suggesting that the autocrine function of VEGFA may be uniquely associated with prostate cancer.Activation of VEGFR-2 by VEGFA165 was shown to enhance migration of PC3 cells.A similar effect was also observed with endogenous VEGFA induced by TGF-β1 and hypoxia.These findings illustrate that an autocrine loop of VEGFA via VEGFR-2 is critical for the tumorigertic effects of TGF-β1 and hypoxia on metastatic prostate cancers.

  19. Roles of Mir-144-ZFX pathway in growth regulation of non-small-cell lung cancer.

    Directory of Open Access Journals (Sweden)

    Wangjian Zha

    Full Text Available BACKGROUND: Lung cancer is the leading cause of cancer-related death worldwide. Non-small cell lung carcinoma (NSCLC accounts for most of the lung cancer cases and the prognosis of this disease remains poor despite decades of intensive investigation. Thus new insights into underlying mechanisms by which NSCLC develops are avidly needed as the basis for development of new lines of therapeutic strategies. The past decade has witnessed a growing interest on the regulatory roles of micro RNAs on various categories of malignancies. Related data has been well documented in carcinogenesis and pathophysiology of a variety of malignancies. Even so, there is a relative lack of data on roles of mir-144 in tumor biology and there has been no report showing the involvement of mir-144 in NSCLC development. METHODS/PRINCIPAL FINDING: From human NSCLC tumor tissue samples and cell culture samples, we found that the expression of mir-144 is associated with malignant phenotype of NSCLC. Further investigations showed that ectopic mir-144 expression dramatically inhibits NSCLC tumor cell growth and induces apoptosis as manifested by elevated apoptotic protein markers and flowcytometry change. Moreover, we also found that ZFX protein expression is also associated with malignant phenotype of NSCLC and knockdown of ZFX protein results in a similar effect as of ectopic mir-144 expression. Finally, we found that ZFX expression is highly adjustable upon presence of mir-144 and ectopic expression of ZFX dramatically dampens mir-144 action of tumor inhibition. CONCLUSIONS: Our results for the first time showed mir-144-ZFX pathway is involved in the development of NSCLC, which sheds a light for further investigations on underlying mechanisms toward better understanding and management of NSCLC.

  20. Effects of phosphorothioate anti-sense oligodeoxynucleotides on colorectal cancer cell growth and telomerase activity

    Institute of Scientific and Technical Information of China (English)

    Xi-Shan Wang; Kuan Wang; Xue Li; Song-Bin Fu

    2004-01-01

    AIM: To investigate the inhibitory effect of phosphorothioate anti-sense oligodeoxynucleotides (PASODN) on colorectal cancer LS-174T cells in vitro and the mechanism of inhibition of telomerase activity in these cells.METHODS: PASODN were used to infect LS-174T cells and block human telomerase RNA (hTR) through anti-sense technology. The inhibitory effect of PASODN was evaluated by colony-forming inhibition assay and growth curve. Changes of telomerase activity in LS-174T cells were detected by polymerase chain reaction-enzyme-linked immunosorbent assay (PCR-ELISA), and the level of apoptosis was analyzed by flow cytometry (FCM) assay.RESULTS: PASODN showed a dose and time-dependent inhibition of cell proliferation. The optimal dosage of PASODN was 10 μmol/L. The colony-forming efficiency was 10.3% in PASODN group after 10 d, whereas that in phosphorothioate mis-sense oligodeoxynucleotides (PMSODN) group with the same concentration and in PBS group (blank control) was 49.1% and 50.7%, respectively. PCR-ELISA results indicated that telomerase activity in the PASODN group was obviously inhibited in comparison with in the control groups (P<0.01,t = 3.317 and 3.241, t0.01 (20) = 2.845). Meanwhile, before the number of cells was decreased, the morphological changes were observed in the cells of PASODN group. The cells in PASODN group showed the apoptotic peak at 72 h after infection, whereas the control group did not show.CONCLUSION: Specific sequence oligonucleotides can inhibit telomerase activity and lead to cell apoptosis,suggesting a novel treatment strategy for malignant tumors induced by telomerase.

  1. Pentastatin-1, a collagen IV derived 20-mer peptide, suppresses tumor growth in a small cell lung cancer xenograft model

    International Nuclear Information System (INIS)

    Angiogenesis is the formation of neovasculature from a pre-existing vascular network. Progression of solid tumors including lung cancer is angiogenesis-dependent. We previously introduced a bioinformatics-based methodology to identify endogenous anti-angiogenic peptide sequences, and validated these predictions in vitro in human umbilical vein endothelial cell (HUVEC) proliferation and migration assays. One family of peptides with high activity is derived from the α-fibrils of type IV collagen. Based on the results from the in vitro screening, we have evaluated the ability of a 20 amino acid peptide derived from the α5 fibril of type IV collagen, pentastatin-1, to suppress vessel growth in an angioreactor-based directed in vivo angiogenesis assay (DIVAA). In addition, pentastatin-1 suppressed tumor growth with intraperitoneal peptide administration in a small cell lung cancer (SCLC) xenograft model in nude mice using the NCI-H82 human cancer cell line. Pentastatin-1 decreased the invasion of vessels into angioreactors in vivo in a dose dependent manner. The peptide also decreased the rate of tumor growth and microvascular density in vivo in a small cell lung cancer xenograft model. The peptide treatment significantly decreased the invasion of microvessels in angioreactors and the rate of tumor growth in the xenograft model, indicating potential treatment for angiogenesis-dependent disease, and for translational development as a therapeutic agent for lung cancer

  2. The insulin-like growth factor 1 receptor causes acquired resistance to erlotinib in lung cancer cells with the wild-type epidermal growth factor receptor.

    Science.gov (United States)

    Suda, Kenichi; Mizuuchi, Hiroshi; Sato, Katsuaki; Takemoto, Toshiki; Iwasaki, Takuya; Mitsudomi, Tetsuya

    2014-08-15

    Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) therapy often provides a dramatic response in lung cancer patients with EGFR mutations. In addition, moderate clinical efficacy of the EGFR-TKI, erlotinib, has been shown in lung cancer patients with the wild-type EGFR. Numerous molecular mechanisms that cause acquired resistance to EGFR-TKIs have been identified in lung cancers with the EGFR mutations; however, few have been reported in lung cancers with the wild-type EGFR. We used H358 lung adenocarcinoma cells lacking EGFR mutations that showed modest sensitivity to erlotinib. The H358 cells acquired resistance to erlotinib via chronic exposure to the drug. The H358 erlotinib-resistant (ER) cells do not have a secondary EGFR mutation, neither MET gene amplification nor PTEN downregulation; these have been identified in lung cancers with the EGFR mutations. From comprehensive screening of receptor tyrosine kinase phosphorylation, we observed increased phosphorylation of insulin-like growth factor 1 receptor (IGF1R) in H358ER cells compared with parental H358 cells. H358ER cells responded to combined therapy with erlotinib and NVP-AEW541, an IGF1R-TKI. Our results indicate that IGF1R activation is a molecular mechanism that confers acquired resistance to erlotinib in lung cancers with the wild-type EGFR. PMID:24458568

  3. Peganum harmala L.’s anti-growth effect on a breast cancer cell line

    Directory of Open Access Journals (Sweden)

    Somayeh Hashemi Sheikh Shabani

    2015-12-01

    Full Text Available This research was done to evaluate the induction of apoptosis in MDA-MB-231 breast cancer cell line by Peganum harmala’s extract, in which a significant amount of ß-carbolines is included. The apoptosis incidence was assessed through Annexin-V-Flous kit. The expressions of genes through which intrinsic apoptosis pathway are involved, Bax, Bcl-2, Bid, and Puma, over the genes the expressions of which are linked to extrinsic apoptosis pathway, TRAIL, Caspase8, p21, and p53, were examined by RT-PCR and Real-time PCR. The results demonstrate that the extract decreases the growth rate of the cancer cell line through inducing apoptosis mechanism. As long as the expression of anti-apoptosis Bcl-2 gen reduced dramatically, an over-expression in Bax and Puma genes was monitored indicating activation of intrinsic apoptosis pathway. A notable over-expression observed with TRAIL and Caspase8 genes as well as Bid gene. The latter is an intermediate for both intrinsic and extrinsic pathways of apoptosis.

  4. Histone Deacetylase Inhibitors Activate Tristetraprolin Expression through Induction of Early Growth Response Protein 1 (EGR1 in Colorectal Cancer Cells

    Directory of Open Access Journals (Sweden)

    Cyril Sobolewski

    2015-08-01

    Full Text Available The RNA-binding protein tristetraprolin (TTP promotes rapid decay of mRNAs bearing 3' UTR AU-rich elements (ARE. In many cancer types, loss of TTP expression is observed allowing for stabilization of ARE-mRNAs and their pathologic overexpression. Here we demonstrate that histone deacetylase (HDAC inhibitors (Trichostatin A, SAHA and sodium butyrate promote TTP expression in colorectal cancer cells (HCA-7, HCT-116, Moser and SW480 cells and cervix carcinoma cells (HeLa. We found that HDAC inhibitors-induced TTP expression, promote the decay of COX-2 mRNA, and inhibit cancer cell proliferation. HDAC inhibitors were found to promote TTP transcription through activation of the transcription factor Early Growth Response protein 1 (EGR1. Altogether, our findings indicate that loss of TTP in tumors occurs through silencing of EGR1 and suggests a therapeutic approach to rescue TTP expression in colorectal cancer.

  5. 1-o-acetylbritannilactone (ABL) inhibits angiogenesis and lung cancer cell growth through regulating VEGF-Src-FAK signaling

    International Nuclear Information System (INIS)

    The search for safe, effective and affordable therapeutics against non-small cell lung cancer (NSCLC) and other lung cancers is important. Here we explored the potential effect of 1-o-acetylbritannilactone (ABL), a novel extract from Inula britannica-F, on angiogenesis and lung cancer cell growth. We demonstrated that ABL dose-dependently inhibited vascular endothelial growth factor (VEGF)-induced proliferation, migration, and capillary structure formation of cultured human umbilical vascular endothelial cells (HUVECs). In vivo, ABL administration suppressed VEGF-induced new vasculature formation in Matrigel plugs. For the mechanism investigations, we found that ABL largely inhibited VEGF-mediated activation of Src kinase and focal adhesion kinase (FAK) in HUVECs. Furthermore, treatment of A549 NSCLC cells with ABL resulted in cell growth inhibition and Src-FAK in-activation. Significantly, administration of a single dose of ABL (12 mg/kg/day) remarkably suppressed growth of A549 xenografts in nude mice. In vivo microvessels formation and Src activation were also significantly inhibited in ABL-treated xenograft tumors. Taken together, our findings suggest that ABL suppresses angiogenesis and lung cancer cell growth possibly via regulating the VEGFR-Src-FAK signaling. - Highlights: • 1-o-acetylbritannilactone (ABL) inhibits VEGF-induced angiogenesis in vivo. • ABL inhibits VEGF-induced HUVEC migration, proliferation, capillary tube formation. • ABL inhibits VEGF-mediated activation of Src and FAK in HUVECs. • ABL inhibits growth and Src-FAK activation in A549 cells. • ABL administration inhibits A549 tumor angiogenesis and growth in nude mice

  6. 1-o-acetylbritannilactone (ABL) inhibits angiogenesis and lung cancer cell growth through regulating VEGF-Src-FAK signaling

    Energy Technology Data Exchange (ETDEWEB)

    Zhengfu, He; Hu, Zhang; Huiwen, Miao; Zhijun, Li [Department of Thoracic Surgery, Sir Run Run Shaw Hospital of Zhejiang University School of Medicine, Hangzhou (China); Jiaojie, Zhou [Zhejiang University School of Medicine, Hangzhou (China); Xiaoyi, Yan, E-mail: xiaoyiyan163@163.com [Zhejiang University School of Medicine, Hangzhou (China); Xiujun, Cai, E-mail: xiujuncaomaj@163.com [Sir Run Run Shaw Hospital of Zhejiang University School of Medicine, Hangzhou (China)

    2015-08-21

    The search for safe, effective and affordable therapeutics against non-small cell lung cancer (NSCLC) and other lung cancers is important. Here we explored the potential effect of 1-o-acetylbritannilactone (ABL), a novel extract from Inula britannica-F, on angiogenesis and lung cancer cell growth. We demonstrated that ABL dose-dependently inhibited vascular endothelial growth factor (VEGF)-induced proliferation, migration, and capillary structure formation of cultured human umbilical vascular endothelial cells (HUVECs). In vivo, ABL administration suppressed VEGF-induced new vasculature formation in Matrigel plugs. For the mechanism investigations, we found that ABL largely inhibited VEGF-mediated activation of Src kinase and focal adhesion kinase (FAK) in HUVECs. Furthermore, treatment of A549 NSCLC cells with ABL resulted in cell growth inhibition and Src-FAK in-activation. Significantly, administration of a single dose of ABL (12 mg/kg/day) remarkably suppressed growth of A549 xenografts in nude mice. In vivo microvessels formation and Src activation were also significantly inhibited in ABL-treated xenograft tumors. Taken together, our findings suggest that ABL suppresses angiogenesis and lung cancer cell growth possibly via regulating the VEGFR-Src-FAK signaling. - Highlights: • 1-o-acetylbritannilactone (ABL) inhibits VEGF-induced angiogenesis in vivo. • ABL inhibits VEGF-induced HUVEC migration, proliferation, capillary tube formation. • ABL inhibits VEGF-mediated activation of Src and FAK in HUVECs. • ABL inhibits growth and Src-FAK activation in A549 cells. • ABL administration inhibits A549 tumor angiogenesis and growth in nude mice.

  7. Inhibition of nuclear factor-kappa B differentially affects thyroid cancer cell growth, apoptosis, and invasion

    OpenAIRE

    Schweppe Rebecca E; Bauerle Kevin T; Haugen Bryan R

    2010-01-01

    Abstract Background Nuclear factor-κB (NF-κB) is constitutively activated in many cancers and plays a key role in promoting cell proliferation, survival, and invasion. Our understanding of NF-κB signaling in thyroid cancer, however, is limited. In this study, we have investigated the role of NF-κB signaling in thyroid cancer cell proliferation, invasion, and apoptosis using selective genetic inhibition of NF-κB in advanced thyroid cancer cell lines. Results Three pharmacologic inhibitors of N...

  8. Role of Insulin-Like Growth Factor-1 Signaling Pathway in Cisplatin-Resistant Lung Cancer Cells

    Energy Technology Data Exchange (ETDEWEB)

    Sun Yunguang [Department of Radiation Oncology, Vanderbilt University Medical Center, Nashville, TN (United States); Zheng Siyuan [Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN (United States); Torossian, Artour; Speirs, Christina K.; Schleicher, Stephen; Giacalone, Nicholas J. [Department of Radiation Oncology, Vanderbilt University Medical Center, Nashville, TN (United States); Carbone, David P. [Department of Hematology and Oncology, Vanderbilt University Medical Center, Nashville, TN (United States); Zhao Zhongming, E-mail: zhongming.zhao@vanderbilt.edu [Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN (United States); Lu Bo, E-mail: bo.lu@vanderbilt.edu [Department of Radiation Oncology, Vanderbilt University Medical Center, Nashville, TN (United States)

    2012-03-01

    Purpose: The development of drug-resistant phenotypes has been a major obstacle to cisplatin use in non-small-cell lung cancer. We aimed to identify some of the molecular mechanisms that underlie cisplatin resistance using microarray expression analysis. Methods and Materials: H460 cells were treated with cisplatin. The differences between cisplatin-resistant lung cancer cells and parental H460 cells were studied using Western blot, MTS, and clonogenic assays, in vivo tumor implantation, and microarray analysis. The cisplatin-R cells were treated with human recombinant insulin-like growth factor (IGF) binding protein-3 and siRNA targeting IGF-1 receptor. Results: Cisplatin-R cells illustrated greater expression of the markers CD133 and aldehyde dehydrogenase, more rapid in vivo tumor growth, more resistance to cisplatin- and etoposide-induced apoptosis, and greater survival after treatment with cisplatin or radiation than the parental H460 cells. Also, cisplatin-R demonstrated decreased expression of insulin-like growth factor binding protein-3 and increased activation of IGF-1 receptor signaling compared with parental H460 cells in the presence of IGF-1. Human recombinant IGF binding protein-3 reversed cisplatin resistance in cisplatin-R cells and targeting of IGF-1 receptor using siRNA resulted in sensitization of cisplatin-R-cells to cisplatin and radiation. Conclusions: The IGF-1 signaling pathway contributes to cisplatin-R to cisplatin and radiation. Thus, this pathway represents a potential target for improved lung cancer response to treatment.

  9. Role of Insulin-Like Growth Factor-1 Signaling Pathway in Cisplatin-Resistant Lung Cancer Cells

    International Nuclear Information System (INIS)

    Purpose: The development of drug-resistant phenotypes has been a major obstacle to cisplatin use in non–small-cell lung cancer. We aimed to identify some of the molecular mechanisms that underlie cisplatin resistance using microarray expression analysis. Methods and Materials: H460 cells were treated with cisplatin. The differences between cisplatin-resistant lung cancer cells and parental H460 cells were studied using Western blot, MTS, and clonogenic assays, in vivo tumor implantation, and microarray analysis. The cisplatin-R cells were treated with human recombinant insulin-like growth factor (IGF) binding protein-3 and siRNA targeting IGF-1 receptor. Results: Cisplatin-R cells illustrated greater expression of the markers CD133 and aldehyde dehydrogenase, more rapid in vivo tumor growth, more resistance to cisplatin- and etoposide-induced apoptosis, and greater survival after treatment with cisplatin or radiation than the parental H460 cells. Also, cisplatin-R demonstrated decreased expression of insulin-like growth factor binding protein-3 and increased activation of IGF-1 receptor signaling compared with parental H460 cells in the presence of IGF-1. Human recombinant IGF binding protein-3 reversed cisplatin resistance in cisplatin-R cells and targeting of IGF-1 receptor using siRNA resulted in sensitization of cisplatin-R-cells to cisplatin and radiation. Conclusions: The IGF-1 signaling pathway contributes to cisplatin-R to cisplatin and radiation. Thus, this pathway represents a potential target for improved lung cancer response to treatment.

  10. MiR-92b regulates the cell growth, cisplatin chemosensitivity of A549 non small cell lung cancer cell line and target PTEN.

    Science.gov (United States)

    Li, Yan; Li, Li; Guan, Yan; Liu, Xiuju; Meng, Qingyong; Guo, Qisen

    2013-11-01

    MicroRNAs (miRNAs) have emerged to play important roles in tumorigenesis and drug resistance of human cancer. Fewer studies were explored the roles of miR-92b on human lung cancer cell growth and resistance to cisplatin (CDDP). In this paper, we utilized real-time PCR to verify miR-92b was significantly up-regulated in non-small cell lung cancer (NSCLC) tissues compared to matched adjacent normal tissues. In vitro assay demonstrated that knock-down of miR-92b inhabits cell growth and sensitized the A549/CDDP cells to CDDP. Furthermore, we found miR-92b could directly target PTEN, a unique tumor suppressor gene, which was downregulated in lung cancer tissues compared to the matched adjacent normal tissues. These data indicate that the miR-92b play an oncogene roles by regulates cell growth, cisplatin chemosensitivity phenotype, and could serve as a novel potential maker for NSCLC therapy. PMID:24099768

  11. Transforming growth factor-β synthesized by stromal cells and cancer cells participates in bone resorption induced by oral squamous cell carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Nakamura, Ryosuke [Department of Oral Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo (Japan); Department of Maxillofacial Surgery, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo (Japan); Kayamori, Kou [Department of Oral Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo (Japan); Oue, Erika [Department of Oral Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo (Japan); Department of Maxillofacial Surgery, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo (Japan); Sakamoto, Kei [Department of Oral Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo (Japan); Harada, Kiyoshi [Department of Maxillofacial Surgery, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo (Japan); Yamaguchi, Akira, E-mail: akira.mpa@tmd.ac.jp [Department of Oral Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo (Japan)

    2015-03-20

    Transforming growth factor beta (TGF-β) plays a significant role in the regulation of the tumor microenvironment. To explore the role of TGF-β in oral cancer-induced bone destruction, we investigated the immunohistochemical localization of TGF-β and phosphorylated Smad2 (p-Smad2) in 12 surgical specimens of oral squamous cell carcinoma (OSCC). These studies revealed TGF-β and p-Smad2 expression in cancer cells in all tested cases. Several fibroblasts located between cancer nests and resorbing bone expressed TGF-β in 10 out of 12 cases and p-Smad2 in 11 out of 12 cases. Some osteoclasts also exhibited p ∼ Smad2 expression. The OSCC cell line, HSC3, and the bone marrow-derived fibroblastic cell line, ST2, synthesized substantial levels of TGF-β. Culture media derived from HSC3 cells could stimulate Tgf-β1 mRNA expression in ST2 cells. Recombinant TGF-β1 could stimulate osteoclast formation induced by receptor activator of nuclear factor kappa-B ligand (RANKL) in RAW264 cells. TGF-β1 could upregulate the expression of p-Smad2 in RAW264 cells, and this action was suppressed by the addition of a neutralizing antibody against TGF-β or by SB431542. Transplantation of HSC3 cells onto the calvarial region of athymic mice caused bone destruction, associated with the expression of TGF-β and p-Smad2 in both cancer cells and stromal cells. The bone destruction was substantially inhibited by the administration of SB431542. The present study demonstrated that TGF-β synthesized by both cancer cells and stromal cells participates in the OSCC-induced bone destruction. - Highlights: • Cancer cell, fibroblastic cells, and osteoclasts at bone resorbing area by oral cancer exhibited TGF-β and p-Smad2. • TGF-β1 stimulated osteoclastogenesis induced by RAKL in RAW264 cell. • Xenograft model of oral cancer-induced bone resorption was substantially inhibited by SB431542. • TGF-β synthesized by both cancer cells and stromal cells participates in the OSCC

  12. Transforming growth factor-β synthesized by stromal cells and cancer cells participates in bone resorption induced by oral squamous cell carcinoma

    International Nuclear Information System (INIS)

    Transforming growth factor beta (TGF-β) plays a significant role in the regulation of the tumor microenvironment. To explore the role of TGF-β in oral cancer-induced bone destruction, we investigated the immunohistochemical localization of TGF-β and phosphorylated Smad2 (p-Smad2) in 12 surgical specimens of oral squamous cell carcinoma (OSCC). These studies revealed TGF-β and p-Smad2 expression in cancer cells in all tested cases. Several fibroblasts located between cancer nests and resorbing bone expressed TGF-β in 10 out of 12 cases and p-Smad2 in 11 out of 12 cases. Some osteoclasts also exhibited p ∼ Smad2 expression. The OSCC cell line, HSC3, and the bone marrow-derived fibroblastic cell line, ST2, synthesized substantial levels of TGF-β. Culture media derived from HSC3 cells could stimulate Tgf-β1 mRNA expression in ST2 cells. Recombinant TGF-β1 could stimulate osteoclast formation induced by receptor activator of nuclear factor kappa-B ligand (RANKL) in RAW264 cells. TGF-β1 could upregulate the expression of p-Smad2 in RAW264 cells, and this action was suppressed by the addition of a neutralizing antibody against TGF-β or by SB431542. Transplantation of HSC3 cells onto the calvarial region of athymic mice caused bone destruction, associated with the expression of TGF-β and p-Smad2 in both cancer cells and stromal cells. The bone destruction was substantially inhibited by the administration of SB431542. The present study demonstrated that TGF-β synthesized by both cancer cells and stromal cells participates in the OSCC-induced bone destruction. - Highlights: • Cancer cell, fibroblastic cells, and osteoclasts at bone resorbing area by oral cancer exhibited TGF-β and p-Smad2. • TGF-β1 stimulated osteoclastogenesis induced by RAKL in RAW264 cell. • Xenograft model of oral cancer-induced bone resorption was substantially inhibited by SB431542. • TGF-β synthesized by both cancer cells and stromal cells participates in the OSCC

  13. Changes in epidermal growth factor receptor expression during chemotherapy in non-small cell lung cancer

    DEFF Research Database (Denmark)

    Jakobsen, Jan Nyrop; Santoni-Rugiu, Eric; Sørensen, Jens Benn

    2014-01-01

    BACKGROUND: Antibodies targeting epidermal growth factor receptor (EGFR), such as cetuximab, may potentially improve outcome in non-small cell lung cancer (NSCLC) patients with high EGFR expression. The EGFR expression may be heterogeneously distributed within tumors, and small biopsies may thus...... not accurately reveal the EGFR expression. In addition, EGFR expression may also change during chemotherapy. The current study investigates the magnitude of these two issues. MATERIALS AND METHODS: EGFR expression in diagnostic biopsies and resection specimen was compared in 53 NSCLC patients stage T1......-4N0-1M0 treated with surgery without preceding chemotherapy (OP group), and 65 NSCLC patients stage T1-3N0-2M0 (NAC group) treated with preoperative carboplatin and paclitaxel in order to evaluate the discordance of EGFR expression between samples. RESULTS: Discordance between tumors dichotomized...

  14. p53 is required for metformin-induced growth inhibition, senescence and apoptosis in breast cancer cells.

    Science.gov (United States)

    Li, Puyu; Zhao, Ming; Parris, Amanda B; Feng, Xiaoshan; Yang, Xiaohe

    2015-09-01

    The p53 tumor repressor gene is commonly mutated in human cancers. The tumor inhibitory effect of metformin on p53-mutated breast cancer cells remains unclear. Data from the present study demonstrated that p53 knockdown or mutation has a negative effect on metformin or phenformin-induced growth inhibition, senescence and apoptosis in breast cancer cells. We also found that p53 reactivating agent nutlin-3α and CP/31398 promoted metformin-induced growth inhibition, senescence and apoptosis in MCF-7 (wt p53) and MDA-MB-231 (mt p53) cells, respectively. Treatment of MCF-7 cells with metformin or phenformin induced increase in p53 protein levels and the transcription of its downstream target genes, Bax and p21, in a dose-dependent manner. Moreover, we demonstrated that AMPK-mTOR signaling played a role in metformin-induced p53 up-regulation. The present study showed that p53 is required for metformin or phenformin-induced growth inhibition, senescence and apoptosis in breast cancer cells. The combination of metformin with p53 reactivating agents, like nutlin-3α and CP/31398, is a promising strategy for improving metformin-mediated anti-cancer therapy, especially for tumors with p53 mutations. PMID:26225749

  15. Splenectomy inhibits non-small cell lung cancer growth by modulating anti-tumor adaptive and innate immune response

    OpenAIRE

    Levy, Liran; Mishalian, Inbal; Bayuch, Rachel; Zolotarov, Lida; Michaeli, Janna; Fridlender, Zvi G.

    2015-01-01

    It has been shown that inhibitors of the immune system reside in the spleen and inhibit the endogenous antitumor effects of the immune system. We hypothesized that splenectomy would inhibit the growth of relatively large non-small lung cancer (NSCLC) tumors by modulating the systemic inhibition of the immune system, and in particular Myeloid Derived Suppressor Cells (MDSC). The effect of splenectomy was evaluated in several murine lung cancer models. We found that splenectomy reduces tumor gr...

  16. Combination of α-Tomatine and Curcumin Inhibits Growth and Induces Apoptosis in Human Prostate Cancer Cells.

    Directory of Open Access Journals (Sweden)

    Huarong Huang

    Full Text Available α-Tomatine is a glycoalkaloid found in tomatoes and curcumin is a major yellow pigment of turmeric. In the present study, the combined effect of these two compounds on prostate cancer cells was studied. Treatment of different prostate cancer cells with curcumin or α-tomatine alone resulted in growth inhibition and apoptosis in a concentration-dependent manner. Combinations of α-tomatine and curcumin synergistically inhibited the growth and induced apoptosis in prostate cancer PC-3 cells. Effects of the α-tomatine and curcumin combination were associated with synergistic inhibition of NF-κB activity and a potent decrease in the expression of its downstream gene Bcl-2 in the cells. Moreover, strong decreases in the levels of phospho-Akt and phosphor-ERK1/2 were found in PC-3 cells treated with α-tomatine and curcumin in combination. In animal experiment, SCID mice with PC-3 xenograft tumors were treated with α-tomatine and curcumin. Combination of α-tomatine and curcumin more potently inhibited the growth of PC-3 tumors than either agent alone. Results from the present study indicate that α-tomatine in combination with curcumin may be an effective strategy for inhibiting the growth of prostate cancer.

  17. Positional Isomers of Aspirin Are Equally Potent in Inhibiting Colon Cancer Cell Growth: Differences in Mode of Cyclooxygenase Inhibition

    OpenAIRE

    Kodela, Ravinder; Chattopadhyay, Mitali; Goswami, Satindra; Gan, Zong Yuan; Rao, Praveen P.N.; Nia, Kamran V.; Velázquez-Martínez, Carlos A.; Kashfi, Khosrow

    2013-01-01

    We compared the differential effects of positional isomers of acetylsalicylic acid (o-ASA, m-ASA, and p-ASA) on cyclooxygenase (COX) inhibition, gastric prostaglandin E2 (PGE2), malondialdehyde, tumor necrosis factor-alpha (TNF-α) levels, superoxide dismutase (SOD) activity, human adenocarcinoma colon cancer cell growth inhibition, cell proliferation, apoptosis, and cell-cycle progression. We also evaluated the gastric toxicity exerted by ASA isomers. All ASA isomers inhibit COX enzymes, but ...

  18. MiR-378 is an independent prognostic factor and inhibits cell growth and invasion in colorectal cancer

    International Nuclear Information System (INIS)

    MicroRNAs(miRNAs) are small non-coding RNAs that participate in a variety of biologic processes, and dysregulation of miRNA is always associated with cancer development and progression. Aberrant expression of miR-378 has been found in some types of cancer. However, effects and potential mechanisms of miR-378 in colorectal cancer (CRC) have not been explored. Quantitative RT-PCR was performed to evaluate miR-378 levels in CRC cell lines and 84 pairs of CRC cancer and normal adjacent mucosa. Kaplan–Meier and Cox proportional regression analyses were utilized to determine the association of miR-378 expression with survival of patients. MTT and invasion assays were used to determine the role of miR-378 in regulation of CRC cancer cell growth and invasion, respectively. Tumor growth was assessed by subcutaneous inoculation of cells into BALB/c nude mice. Luciferase assay was performed to assess miR-378 binding to vimentin gene. In this study, we confirmed that miR-378 significantly down-regulated in CRC cancer tissues and cell lines. Moreover, patients with low miR-378 expression had significantly poorer overall survival, and miR-378 expression was an independent prognostic factor in CRC. Over-expression of miR-378 inhibited SW620 cell growth and invasion, and resulted in down-regulation of vimentin expression. However, miR-378 knock-down promoted these processes and enhanced the expression of vimentin. In addition, we further identified vimentin as the functional downstream target of miR-378 by directly targeting the 3′-UTR of vimentin. In conclusion, miR-378 may function as a tumor suppressor and plays an important role in inhibiting tumor growth and invasion. Our present results implicate the potential effects of miR-378 on prognosis and treatment of CRC cancer

  19. Control of the growth of human breast cancer cells in culture by manipulation of arachidonate metabolism

    International Nuclear Information System (INIS)

    Arachidonate metabolites are important regulators of human breast cancer cells. Production of bioactive lipids are frequently initiated by the enzyme phospholipase A2 which releases arachidonic acid (AA) that is rapidly metabolized by cyclooxygenases (COX) or lipoxygenases (LO) to other highly potent lipids. In this study we screened a number of inhibitors which blocked specific pathways of AA metabolism for their antiproliferative activity on MCF-7 wild type and MCF-7 ADR drug resistant breast cancer cells. The toxicity of these inhibitors was further tested on human bone marrow cell proliferation. Inhibitors of LO pathways (specifically the 5-LO pathway) were most effective in blocking proliferation. Inhibitors of platelet activating factor, a byproduct of arachidonate release, were also effective antiproliferative agents. Curcumin, an inhibitor of both COX and LO pathways of eicosanoid metabolism, was 12-fold more effective in blocking proliferation of the MCF-7 ADRs cells compared to MCF-7 wild type (WT) cells. These inhibitors that effectively blocked the proliferation of breast cancer cells showed varying degrees of toxicity to cultures of human bone marrow cells. We observed greater toxicity to bone marrow cells with inhibitors that interfere with the utilization of AA in contrast to those which block utilization of its downstream metabolites. MK-591, MK-886, PCA-4248, and AA-861 blocked proliferation of breast cancer cells but showed no toxicity to bone marrow cells. These inhibitors were effective in blocking the proliferation of breast cancer cells and may be potentially useful in human breast cancer therapy

  20. Differences in growth properties of endometrial cancer in three dimensional (3D) culture and 2D cell monolayer

    Energy Technology Data Exchange (ETDEWEB)

    Chitcholtan, Kenny, E-mail: kenny.chitcholtan@otago.ac.nz [Department of Obstetrics and Gynaecology, University of Otago, Christchurch, 2 Riccarton Avenue, Christchurch 8011 (New Zealand); Asselin, Eric, E-mail: Eric.Asselin@uqtr.ca [Department of Chemistry and Biology, University of Quebec, at Trois-Rivières, C.P. 500, Trois-Rivières, Quebec, Canada G9A 5H7 (Canada); Parent, Sophie, E-mail: Sophie.Parent@uqtr.ca [Department of Chemistry and Biology, University of Quebec, at Trois-Rivières, C.P. 500, Trois-Rivières, Quebec, Canada G9A 5H7 (Canada); Sykes, Peter H., E-mail: peter.sykes@otago.ac.nz [Department of Obstetrics and Gynaecology, University of Otago, Christchurch, 2 Riccarton Avenue, Christchurch 8011 (New Zealand); Evans, John J., E-mail: john.evans@otago.ac.nz [Department of Obstetrics and Gynaecology, University of Otago, Christchurch, 2 Riccarton Avenue, Christchurch 8011 (New Zealand); Centre of Neuroendocrinology and The MacDiarmid Institute of Advanced Materials and Nanotechnology, University of Otago, Christchurch, 2 Riccarton Avenue, Christchurch 8011 (New Zealand)

    2013-01-01

    Three-dimensional (3D) in vitro models have an invaluable role in understanding the behaviour of tumour cells in a well defined microenvironment. This is because some aspects of tumour characteristics cannot be fully recapitulated in a cell monolayer (2D). In the present study, we compared growth patterns, expression of signalling molecules, and metabolism-associated proteins of endometrial cancer cell lines in 3D and 2D cell cultures. Cancer cells formed spherical structures in 3D reconstituted basement membrane (3D rBM), and the morphological appearance was cell line dependent. Cell differentiation was observed after 8 days in the 3D rBM. There was reduced proliferation, detected by less expression of PCNA in 3D rBM than in 2D cell monolayers. The addition of exogenous epidermal growth factor (EGF) to cancer cells induced phosphorylation of EGFR and Akt in both cell culture conditions. The uptake of glucose was selectively altered in the 3D rBM, but there was a lack of association with Glut-1 expression. The secretion of vascular endothelial growth factor (VEGF) and prostaglandin E{sub 2} (PGE{sub 2}) was selectively altered in 3D rBM, and it was cell line dependent. Our data demonstrated that 3D rBM as an in vitro model can influence proliferation and metabolism of endometrial cancer cell behaviour compared to 2D cell monolayer. Changes are specific to individual cell types. The use of 3D rBM is, therefore, important in the in vitro study of targeted anticancer therapies.

  1. Differences in growth properties of endometrial cancer in three dimensional (3D) culture and 2D cell monolayer

    International Nuclear Information System (INIS)

    Three-dimensional (3D) in vitro models have an invaluable role in understanding the behaviour of tumour cells in a well defined microenvironment. This is because some aspects of tumour characteristics cannot be fully recapitulated in a cell monolayer (2D). In the present study, we compared growth patterns, expression of signalling molecules, and metabolism-associated proteins of endometrial cancer cell lines in 3D and 2D cell cultures. Cancer cells formed spherical structures in 3D reconstituted basement membrane (3D rBM), and the morphological appearance was cell line dependent. Cell differentiation was observed after 8 days in the 3D rBM. There was reduced proliferation, detected by less expression of PCNA in 3D rBM than in 2D cell monolayers. The addition of exogenous epidermal growth factor (EGF) to cancer cells induced phosphorylation of EGFR and Akt in both cell culture conditions. The uptake of glucose was selectively altered in the 3D rBM, but there was a lack of association with Glut-1 expression. The secretion of vascular endothelial growth factor (VEGF) and prostaglandin E2 (PGE2) was selectively altered in 3D rBM, and it was cell line dependent. Our data demonstrated that 3D rBM as an in vitro model can influence proliferation and metabolism of endometrial cancer cell behaviour compared to 2D cell monolayer. Changes are specific to individual cell types. The use of 3D rBM is, therefore, important in the in vitro study of targeted anticancer therapies.

  2. beta-TrCP inhibition reduces prostate cancer cell growth via upregulation of the aryl hydrocarbon receptor.

    Directory of Open Access Journals (Sweden)

    Udi Gluschnaider

    Full Text Available BACKGROUND: Prostate cancer is a common and heterogeneous disease, where androgen receptor (AR signaling plays a pivotal role in development and progression. The initial treatment for advanced prostate cancer is suppression of androgen signaling. Later on, essentially all patients develop an androgen independent stage which does not respond to anti hormonal treatment. Thus, alternative strategies targeting novel molecular mechanisms are required. beta-TrCP is an E3 ligase that targets various substrates essential for many aspects of tumorigenesis. METHODOLOGY/PRINCIPAL FINDINGS: Here we show that beta-TrCP depletion suppresses prostate cancer and identify a relevant growth control mechanism. shRNA targeted against beta-TrCP reduced prostate cancer cell growth and cooperated with androgen ablation in vitro and in vivo. We found that beta-TrCP inhibition leads to upregulation of the aryl hydrocarbon receptor (AhR mediating the therapeutic effect. This phenomenon could be ligand independent, as the AhR ligand 2,3,7,8-Tetrachlorodibenzo-p-Dioxin (TCDD did not alter prostate cancer cell growth. We detected high AhR expression and activation in basal cells and atrophic epithelial cells of human cancer bearing prostates. AhR expression and activation is also significantly higher in tumor cells compared to benign glandular epithelium. CONCLUSIONS/SIGNIFICANCE: Together these observations suggest that AhR activation may be a cancer counteracting mechanism in the prostate. We maintain that combining beta-TrCP inhibition with androgen ablation could benefit advanced prostate cancer patients.

  3. Radical Decisions in Cancer: Redox Control of Cell Growth and Death

    Energy Technology Data Exchange (ETDEWEB)

    Sainz, Rosa M., E-mail: sainzrosa@uniovi.es [Cellular Biology and Morphology Department, School of Medicine, University of Oviedo, Oviedo 33006 (Spain); University Institute of Oncology of Asturias (IUOPA), University of Oviedo, Oviedo 33006 (Spain); Lombo, Felipe [University Institute of Oncology of Asturias (IUOPA), University of Oviedo, Oviedo 33006 (Spain); Functional Biology Department, Area of Microbiology, School of Medicine, University of Oviedo, Oviedo 33006 (Spain); Mayo, Juan C. [Cellular Biology and Morphology Department, School of Medicine, University of Oviedo, Oviedo 33006 (Spain); University Institute of Oncology of Asturias (IUOPA), University of Oviedo, Oviedo 33006 (Spain)

    2012-04-25

    Free radicals play a key role in many physiological decisions in cells. Since free radicals are toxic to cellular components, it is known that they cause DNA damage, contribute to DNA instability and mutation and thus favor carcinogenesis. However, nowadays it is assumed that free radicals play a further complex role in cancer. Low levels of free radicals and steady state levels of antioxidant enzymes are responsible for the fine tuning of redox status inside cells. A change in redox state is a way to modify the physiological status of the cell, in fact, a more reduced status is found in resting cells while a more oxidative status is associated with proliferative cells. The mechanisms by which redox status can change the proliferative activity of cancer cells are related to transcriptional and posttranscriptional modifications of proteins that play a critical role in cell cycle control. Since cancer cells show higher levels of free radicals compared with their normal counterparts, it is believed that the anti-oxidative stress mechanism is also increased in cancer cells. In fact, the levels of some of the most important antioxidant enzymes are elevated in advanced status of some types of tumors. Anti-cancer treatment is compromised by survival mechanisms in cancer cells and collateral damage in normal non-pathological tissues. Though some resistance mechanisms have been described, they do not yet explain why treatment of cancer fails in several tumors. Given that some antitumoral treatments are based on the generation of free radicals, we will discuss in this review the possible role of antioxidant enzymes in the survival mechanism in cancer cells and then, its participation in the failure of cancer treatments.

  4. Radical Decisions in Cancer: Redox Control of Cell Growth and Death

    International Nuclear Information System (INIS)

    Free radicals play a key role in many physiological decisions in cells. Since free radicals are toxic to cellular components, it is known that they cause DNA damage, contribute to DNA instability and mutation and thus favor carcinogenesis. However, nowadays it is assumed that free radicals play a further complex role in cancer. Low levels of free radicals and steady state levels of antioxidant enzymes are responsible for the fine tuning of redox status inside cells. A change in redox state is a way to modify the physiological status of the cell, in fact, a more reduced status is found in resting cells while a more oxidative status is associated with proliferative cells. The mechanisms by which redox status can change the proliferative activity of cancer cells are related to transcriptional and posttranscriptional modifications of proteins that play a critical role in cell cycle control. Since cancer cells show higher levels of free radicals compared with their normal counterparts, it is believed that the anti-oxidative stress mechanism is also increased in cancer cells. In fact, the levels of some of the most important antioxidant enzymes are elevated in advanced status of some types of tumors. Anti-cancer treatment is compromised by survival mechanisms in cancer cells and collateral damage in normal non-pathological tissues. Though some resistance mechanisms have been described, they do not yet explain why treatment of cancer fails in several tumors. Given that some antitumoral treatments are based on the generation of free radicals, we will discuss in this review the possible role of antioxidant enzymes in the survival mechanism in cancer cells and then, its participation in the failure of cancer treatments

  5. The human mineral dust-induced gene, mdig, is a cell growth regulating gene associated with lung cancer

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Y.D.; Lu, Y.J.; Yuan, B.Z.; Castranova, V.; Shi, X.L.; Stauffer, J.L.; Demers, L.M.; Chen, F. [NIOSH, Morgantown, WV (US). Health Effects Laboratory Division

    2005-07-21

    Environmental or occupational exposure to mineral dusts, mainly silica and asbestos, is associated with an increased incidence of lung inflammation, fibrosis, and/or cancer. To better understand the molecular events associated with these pulmonary diseases, we attempted to identify genes that are regulated by mineral dusts. Using a differential display reverse transcription polymerase chain reaction technique and mRNAs of alveolar macrophages from both normal individuals and coal miners, we identified a novel mineral dust-induced gene named mdig, which had not been fully characterized. The expression of mdig mRNA was detected in alveolar macrophages from coal miners but not from normal subjects. The inducible expression of mdig could be observed in A549 cells exposed to silica particles in a time-dependent manner. The full-length mdig mRNA was expressed in human lung cancer tissues but was barely detectable in the adjacent normal tissues. In addition, a number of lung cancer cell lines constitutively express mdig. Alternative spliced transcripts of mdig were detected in some lung cancer cell lines. Silencing mdig mRNA expression in A549 lung cancer cells by siRNA-mediated RNA interference inhibits cell proliferation and sensitizes the cells to silica-induced cytotoxicity. These results suggest that the mdig gene may be involved in the regulation of cell growth and possibly the development of cancer.

  6. EFEMP1 Suppresses Growth and Invasion of Lung Cancer Cells 
by Downregulating Matrix Metalloproteinase-7 Expression

    Directory of Open Access Journals (Sweden)

    Yuanyuan LANG

    2015-02-01

    Full Text Available Background and objective EFEMP1, a member of fibulin family proteins, is a very important extracellular matrix protein which is involved in cell metabolism and its role in tumor occurrence and progression is still poorly understood. The aim of this study is to investigate the functional effect and mechanism of EFEMP1 in lung cancer cell growth and invasion. Methods EFEMP1 expression in lung cancer cells was determined by Western blot. The promoter methylation status of EFEMP1 was detected by methylation-specific PCR (MSP. After transfection of control or EFEMP1 vector in lung cancer cells, the ability of colony formation and invasion was detected by colony formation experiment and matrigel invasion method. Western blot and real-time PCR were used to detect matrix metalloproteinase-7 (MMP-7 expression. Luciferase assay was used to detect expression of MMP-7 reporter construct transfected with or without EFEMP1 in lung cancer cells. Results Western blot result showed EFEMP1 expression was downregulated in lung cancer cells. The promoter region of EFEMP1 was methylated in A549 and H1299 and after treatment with 5-aza-2’-deoxycytidine, the EFEMP1 expression was upregulated. The growth and invasion of A549 and H1299 were all significantly suppressed by transfecting with EFEMP1 and the MMP-7 expression was dowanregulated by EFEMP1 as well. Expression activity of MMP-7 reporter construct was decreased by cotransfecting with EFEMP1. Conclusion Collectively, these results suggest that EFEMP1 functions as a suppressor of lung cancer growth and invasion. Epigenetic silencing of EFEMP1 promotes lung cancer invasion and metastasis by activating MMP-7 expression.

  7. Notch Signaling Activation in Cervical Cancer Cells Induces Cell Growth Arrest with the Involvement of the Nuclear Receptor NR4A2

    Science.gov (United States)

    Sun, Lichun; Liu, Mingqiu; Sun, Guang-Chun; Yang, Xu; Qian, Qingqing; Feng, Shuyu; Mackey, L. Vienna; Coy, David H.

    2016-01-01

    Cervical cancer is a second leading cancer death in women world-wide, with most cases in less developed countries. Notch signaling is highly conserved with its involvement in many cancers. In the present study, we established stable cervical cell lines with Notch activation and inactivation and found that Notch activation played a suppressive role in cervical cancer cells. Meanwhile, the transient overexpression of the active intracellular domain of all four Notch receptors (ICN1, 2, 3, and 4) also induced the suppression of cervical cancer Hela cell growth. ICN1 also induced cell cycle arrest at phase G1. Notch1 signaling activation affected the expression of serial genes, especially the genes associated with cAMP signaling, with an increase of genes like THBS1, VCL, p63, c-Myc and SCG2, a decrease of genes like NR4A2, PCK2 and BCL-2. Particularly, The nuclear receptor NR4A2 was observed to induce cell proliferation via MTT assay and reduce cell apoptosis via FACS assay. Furthermore, NR4A2's activation could reverse ICN1-induced suppression of cell growth while erasing ICN1-induced increase of tumor suppressor p63. These findings support that Notch signaling mediates cervical cancer cell growth suppression with the involvement of nuclear receptor NR4A2. Notably, Notch/NR4A2/p63 signaling cascade possibly is a new signling pathway undisclosed. PMID:27471554

  8. Thioredoxin-like 2 regulates human cancer cell growth and metastasis via redox homeostasis and NF-kB signaling

    Science.gov (United States)

    Cancer cells have an efficient antioxidant system to counteract their increased generation of ROS. However, whether this ability to survive high levels of ROS has an important role in the growth and metastasis of tumors is not well understood. Here, we demonstrate that the redox protein thioredoxin-...

  9. Arsenic Trioxide Inhibits Cell Growth and Induces Apoptosis through Inactivation of Notch Signaling Pathway in Breast Cancer

    Directory of Open Access Journals (Sweden)

    Zhiwei Wang

    2012-08-01

    Full Text Available Arsenic trioxide has been reported to inhibit cell growth and induce apoptotic cell death in many human cancer cells including breast cancer. However, the precise molecular mechanisms underlying the anti-tumor activity of arsenic trioxide are still largely unknown. In the present study, we assessed the effects of arsenic trioxide on cell viability and apoptosis in breast cancer cells. For mechanistic studies, we used multiple cellular and molecular approaches such as MTT assay, apoptosis ELISA assay, gene transfection, RT-PCR, Western blotting, and invasion assays. For the first time, we found a significant reduction in cell viability in arsenic trioxide-treated cells in a dose-dependent manner, which was consistent with induction of apoptosis and also associated with down-regulation of Notch-1 and its target genes. Taken together, our findings provide evidence showing that the down-regulation of Notch-1 by arsenic trioxide could be an effective approach, to cause down-regulation of Bcl-2, and NF-κB, resulting in the inhibition of cell growth and invasion as well as induction of apoptosis. These results suggest that the anti-tumor activity of arsenic trioxide is in part mediated through a novel mechanism involving inactivation of Notch-1 and its target genes. We also suggest that arsenic trioxide could be further developed as a potential therapeutic agent for the treatment of breast cancer.

  10. Curcumin induces apoptosis in breast cancer cells and inhibits tumor growth in vitro and in vivo

    OpenAIRE

    Lv, Zhi-Dong; Liu, Xiang-Ping; Zhao, Wei-Jun; Dong, Qian; Li, Fu-Nian; Wang, Hai-Bo; Kong, Bin

    2014-01-01

    Curcumin has shown therapeutic and/or adjuvant therapeutic effects on the treatment of some patients with breast cancer. However, its mechanisms of action are largely unknown. This study was designed to investigate its antitumor effect and underlying mechanisms in human breast cancer MDA-MB-231 and MCF-7 cells. The MTT assay was used to evaluate cell viability, and flow cytometry, acridine orange staining and transmission electron microscopy were used to detect apoptosis for cultured cells. T...

  11. Antisense oligonucleotide to insulin—like growth factor Ⅱ induces apotosis in human ovarian cancer AO cell line

    Institute of Scientific and Technical Information of China (English)

    YINDELING; LUPU; 等

    1998-01-01

    The effects of antisense oligonucleotide to insulin0like growth factor -Ⅱ(IGFⅡ)to induce apotosis in human ovarian cancer cells were evaluated.Antiproliferation effects of antisense to IGFⅡin ovarian cancer AO cells were determined by 3H-thymidine incorporation.Apoptosis of the IGFⅡ antisense-treated cells was quantitated by both nuclear condensation and flow cytometry after cells were stained with propidium iodide,IGFⅡ antisense(4.5μM) treatment of 48h maximally inhibited proliferation of AO cells,More than 25% of IGFⅡantisense-treated cells(4.5μM for 24h) had undergone apoptosis,whereas less than 3% of the cells were apoptotic in either IGFⅡ sense-treated cells or untreated cells.Antisense oligonucleotide to IGFⅡ significantly inhibited cell proliferation and induced apoptosis in human ovarian cancer AO cell.These data suggest that IGFII may be a potential target in treatment of ovarian cancer and antisense oligonucleotide to IGFⅡ may serve as a therapeutic approach.

  12. Bombesin receptor subtype-3 agonists stimulate the growth of lung cancer cells and increase EGF receptor tyrosine phosphorylation

    OpenAIRE

    Moody, Terry W.; Sancho, Veronica; Florio, Alessia di; Nuche-Berenguer, Bernardo; Mantey, Samuel; Jensen, Robert T.

    2011-01-01

    The effects of bombesin receptor subtype-3 (BRS-3) agonists were investigated on lung cancer cells. The BRS-3 agonist (DTyr6, βAla11, Phe13, Nle14)bombesin6-14 (BA1), but not gastrin releasing peptide (GRP) or neuromedin B (NMB) increased significantly the clonal growth of NCI-H1299 cells stably transfected with BRS-3 (NCI-H1299-BRS-3). Also, BA1 addition to NCI-H727 or NCI-H1299-BRS-3 cells caused Tyr1068 phosphorylation of the epidermal growth factor receptor (EGFR). Similarly, (DTyr6, R-Ap...

  13. Belinostat-induced apoptosis and growth inhibition in pancreatic cancer cells involve activation of TAK1-AMPK signaling axis

    International Nuclear Information System (INIS)

    Highlights: •Belinostat activates AMPK in cultured pancreatic cancer cells. •Activation of AMPK is important for belinostat-induced cytotoxic effects. •ROS and TAK1 are involved in belinostat-induced AMPK activation. •AMPK activation mediates mTOR inhibition by belinostat. -- Abstract: Pancreatic cancer accounts for more than 250,000 deaths worldwide each year. Recent studies have shown that belinostat, a novel pan histone deacetylases inhibitor (HDACi) induces apoptosis and growth inhibition in pancreatic cancer cells. However, the underlying mechanisms are not fully understood. In the current study, we found that AMP-activated protein kinase (AMPK) activation was required for belinostat-induced apoptosis and anti-proliferation in PANC-1 pancreatic cancer cells. A significant AMPK activation was induced by belinostat in PANC-1 cells. Inhibition of AMPK by RNAi knockdown or dominant negative (DN) mutation significantly inhibited belinostat-induced apoptosis in PANC-1 cells. Reversely, AMPK activator AICAR and A-769662 exerted strong cytotoxicity in PANC-1 cells. Belinostat promoted reactive oxygen species (ROS) production in PANC-1 cells, increased ROS induced transforming growth factor-β-activating kinase 1 (TAK1)/AMPK association to activate AMPK. Meanwhile, anti-oxidants N-Acetyl-Cysteine (NAC) and MnTBAP as well as TAK1 shRNA knockdown suppressed belinostat-induced AMPK activation and PANC-1 cell apoptosis. In conclusion, we propose that belinostat-induced apoptosis and growth inhibition require the activation of ROS-TAK1-AMPK signaling axis in cultured pancreatic cancer cells

  14. Belinostat-induced apoptosis and growth inhibition in pancreatic cancer cells involve activation of TAK1-AMPK signaling axis

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Bing, E-mail: wangbin69@yahoo.com; Wang, Xin-bao; Chen, Li-yu; Huang, Ling; Dong, Rui-zen

    2013-07-19

    Highlights: •Belinostat activates AMPK in cultured pancreatic cancer cells. •Activation of AMPK is important for belinostat-induced cytotoxic effects. •ROS and TAK1 are involved in belinostat-induced AMPK activation. •AMPK activation mediates mTOR inhibition by belinostat. -- Abstract: Pancreatic cancer accounts for more than 250,000 deaths worldwide each year. Recent studies have shown that belinostat, a novel pan histone deacetylases inhibitor (HDACi) induces apoptosis and growth inhibition in pancreatic cancer cells. However, the underlying mechanisms are not fully understood. In the current study, we found that AMP-activated protein kinase (AMPK) activation was required for belinostat-induced apoptosis and anti-proliferation in PANC-1 pancreatic cancer cells. A significant AMPK activation was induced by belinostat in PANC-1 cells. Inhibition of AMPK by RNAi knockdown or dominant negative (DN) mutation significantly inhibited belinostat-induced apoptosis in PANC-1 cells. Reversely, AMPK activator AICAR and A-769662 exerted strong cytotoxicity in PANC-1 cells. Belinostat promoted reactive oxygen species (ROS) production in PANC-1 cells, increased ROS induced transforming growth factor-β-activating kinase 1 (TAK1)/AMPK association to activate AMPK. Meanwhile, anti-oxidants N-Acetyl-Cysteine (NAC) and MnTBAP as well as TAK1 shRNA knockdown suppressed belinostat-induced AMPK activation and PANC-1 cell apoptosis. In conclusion, we propose that belinostat-induced apoptosis and growth inhibition require the activation of ROS-TAK1-AMPK signaling axis in cultured pancreatic cancer cells.

  15. Inhibitory effects of small molecular peptides from Spirulina (Arthrospira) platensis on cancer cell growth.

    Science.gov (United States)

    Wang, Zhujun; Zhang, Xuewu

    2016-02-01

    In this study, the whole proteins of Spirulina (Arthrospira) platensis were extracted, hydrolysis with three proteases (trypsin, alcalase and papain) was performed, and gel filtration chromatography was employed to separate hydrolysates. Totally, 15 polypeptides were isolated, which showed anti-proliferation activities on five cancer cells (HepG-2, MCF-7, SGC-7901, A549 and HT-29), with the IC50 values between <31.25 and 336.57 μg mL(-1). Moreover, a new peptide YGFVMPRSGLWFR was identified from papain-digested hydrolysates. It also exhibited inhibitory activities on cancer cells, and the best activity was observed on A549 cancer cells (IC50 values 104.05 μg mL(-1)). In other words, these polypeptides exhibited anti-proliferation activities on cancer cells, and low toxicity or stimulatory activity on normal cells, suggesting that they are promising ingredients in food and pharmaceutical applications. PMID:26584028

  16. Activation of AMPK inhibits cervical cancer cell growth through AKT/FOXO3a/FOXM1 signaling cascade

    International Nuclear Information System (INIS)

    Although advanced-stage cervical cancer can benefit from current treatments, approximately 30% patients may fail after definitive treatment eventually. Therefore, exploring alternative molecular therapeutic approaches is imperatively needed for this disease. We have recently shown that activation of AMP-activated protein kinase (AMPK), a metabolic sensor, hampers cervical cancer cell growth through blocking the Wnt/β-catenin signaling activity. Here, we report that activated AMPK (p-AMPK) also inhibits cervical cancer cell growth by counteracting FOXM1 function. Effect of the activation of AMPK on FOXM1 expression was examined by hypoxia and glucose deprivation, as well as pharmacological AMPK activators such as A23187, AICAR and metformin. RT Q-PCR and Western blot analysis were employed to investigate the activities of AMPK, FOXM1 and AKT/FOXO3a signaling. Consistent with our previous findings, the activation of AMPK by either AMPK activators such as AICAR, A23187, metformin, glucose deprivation or hypoxia significantly inhibited the cervical cancer cell growth. Importantly, we found that activated AMPK activity was concomitantly associated with the reduction of both the mRNA and protein levels of FOXM1. Mechanistically, we showed that activated AMPK was able to reduce AKT mediated phosphorylation of p-FOXO3a (Ser253). Interestingly, activated AMPK could not cause any significant changes in FOXM1 in cervical cancer cells in which endogenous FOXO3a levels were knocked down using siRNAs, suggesting that FOXO3a is involved in the suppression of FOXM1. Taken together, our results suggest the activated AMPK impedes cervical cancer cell growth through reducing the expression of FOXM1

  17. The Epidermal Growth Factor Receptor Responsive miR-125a Represses Mesenchymal Morphology in Ovarian Cancer Cells

    Directory of Open Access Journals (Sweden)

    Karen D. Cowden Dahl

    2009-11-01

    Full Text Available The epithelial-to-mesenchymal transition (EMT that occurs during embryonic development is recapitulated during tumor metastasis. Important regulators of this process include growth factors, transcription factors, and adhesion molecules. New evidence suggests that microRNA (miRNA activity contributes to metastatic progression and EMT; however, the mechanisms leading to altered miRNA expression during cancer progression remain poorly understood. Importantly, overexpression of the epidermal growth factor receptor (EGFR in ovarian cancer correlates with poor disease outcome and induces EMT in ovarian cancer cells. We report that EGFR signaling leads to transcriptional repression of the miRNA miR-125a through the ETS family transcription factor PEA3. Overexpression of miR-125a induces conversion of highly invasive ovarian cancer cells from a mesenchymal to an epithelial morphology, suggesting miR-125a is a negative regulator of EMT. We identify AT-rich interactive domain 3B (ARID3B as a target of miR-125a and demonstrate that ARID3B is overexpressed in human ovarian cancer. Repression of miR-125a through growth factor signaling represents a novel mechanism for regulating ovarian cancer invasive behavior.

  18. Roles of Mir-144-ZFX Pathway in Growth Regulation of Non-Small-Cell Lung Cancer

    OpenAIRE

    Zha, Wangjian; Cao, Liu; Shen, Ying; Mao HUANG

    2013-01-01

    Background Lung cancer is the leading cause of cancer-related death worldwide. Non-small cell lung carcinoma (NSCLC) accounts for most of the lung cancer cases and the prognosis of this disease remains poor despite decades of intensive investigation. Thus new insights into underlying mechanisms by which NSCLC develops are avidly needed as the basis for development of new lines of therapeutic strategies. The past decade has witnessed a growing interest on the regulatory roles of micro RNAs on ...

  19. EZH2 knockdown suppresses the growth and invasion of human inflammatory breast cancer cells

    OpenAIRE

    Mu, Zhaomei; Li, Hua; Fernandez, Sandra V.; Alpaugh, Katherine R; Zhang, Rugang; Cristofanilli, Massimo

    2013-01-01

    Introduction Inflammatory breast cancer (IBC) is the most metastatic variant of breast cancer with the poorest survival in all types of breast cancer patients and presently therapeutic targets for IBC are very limited. Enhancer of zeste homolog 2 (EZH2) is frequently expressed in human IBC and its expression positively correlates with worse clinical outcome. However, the molecular basis for EZH2 promoting IBC has not been explored. Here, we investigated the functional role of EZH2 in IBC cell...

  20. Gambogic acid inhibits growth, induces apoptosis, and overcomes drug resistance in human colorectal cancer cells.

    Science.gov (United States)

    Wen, Chuangyu; Huang, Lanlan; Chen, Junxiong; Lin, Mengmeng; Li, Wen; Lu, Biyan; Rutnam, Zina Jeyapalan; Iwamoto, Aikichi; Wang, Zhongyang; Yang, Xiangling; Liu, Huanliang

    2015-11-01

    The emergence of chemoresistance is a major limitation of colorectal cancer (CRC) therapies and novel biologically based therapies are urgently needed. Natural products represent a novel potential anticancer therapy. Gambogic acid (GA), a small molecule derived from Garcinia hanburyi Hook. f., has been demonstrated to be highly cytotoxic to several types of cancer cells and have low toxicity to the hematopoietic system. However, the potential role of GA in colorectal cancer and its ability to overcome the chemotherapeutic resistance in CRC cells have not been well studied. In the present study, we showed that GA directly inhibited proliferation and induced apoptosis in both 5-fluorouracil (5-FU) sensitive and 5-FU resistant colorectal cancer cells; induced apoptosis via activating JNK signaling pathway. The data, therefore, suggested an alternative strategy to overcome 5-FU resistance in CRC and that GA could be a promising medicinal compound for colorectal cancer therapy. PMID:26397804

  1. HSulf-1 suppresses cell growth and down-regulates Hedgehog signaling in human gastric cancer cells

    OpenAIRE

    MA, HUI-YAN; Zhang, Fang; Li, Jie; Mo, Min-Li; Chen, Zhao; Liu, Lili; Zhou, Hai-Meng; Sheng, Qing

    2011-01-01

    Gastric cancer is the second most lethal cancer worldwide. Despite the current surgical and adjuvant therapies, 5-year survival remains less than 20–25% in the US, Europe and China. Therefore, there is an urgent need to identify new therapeutic targets for treating this malignant disease. Accumulating evidence has supported that aberrant activation of the Hedgehog signaling pathway plays a crucial role in tumorigenesis and progression of gastric cancer. Human sulfatase-1 (HSulf-1) is a recent...

  2. Modulation of estrogen and epidermal growth factor receptors by rosemary extract in breast cancer cells.

    Science.gov (United States)

    González-Vallinas, Margarita; Molina, Susana; Vicente, Gonzalo; Sánchez-Martínez, Ruth; Vargas, Teodoro; García-Risco, Mónica R; Fornari, Tiziana; Reglero, Guillermo; Ramírez de Molina, Ana

    2014-06-01

    Breast cancer is the leading cause of cancer-related mortality among females worldwide, and therefore the development of new therapeutic approaches is still needed. Rosemary (Rosmarinus officinalis L.) extract possesses antitumor properties against tumor cells from several organs, including breast. However, in order to apply it as a complementary therapeutic agent in breast cancer, more information is needed regarding the sensitivity of the different breast tumor subtypes and its effect in combination with the currently used chemotherapy. Here, we analyzed the antitumor activities of a supercritical fluid rosemary extract (SFRE) in different breast cancer cells, and used a genomic approach to explore its effect on the modulation of ER-α and HER2 signaling pathways, the most important mitogen pathways related to breast cancer progression. We found that SFRE exerts antitumor activity against breast cancer cells from different tumor subtypes and the downregulation of ER-α and HER2 receptors by SFRE might be involved in its antitumor effect against estrogen-dependent (ER+) and HER2 overexpressing (HER2+) breast cancer subtypes. Moreover, SFRE significantly enhanced the effect of breast cancer chemotherapy (tamoxifen, trastuzumab, and paclitaxel). Overall, our results support the potential utility of SFRE as a complementary approach in breast cancer therapy. PMID:24615943

  3. INHIBITORY EFFECTS OF MIFEPRISTONE ON THE GROWTH OF HUMAN GASTRIC CANCER CELL LINE MKN-45 IN VITRO AND IN VIVO

    Institute of Scientific and Technical Information of China (English)

    Da-qiang Li; Li-hua Pan; Zhi-min Shao

    2004-01-01

    Objective To explore the effects of mifepristone on the growth of human gastric cancer cell line MKN-45 and its possible mechanisms.Methods In situ hybridization was used to detect the expression of progesterone receptor (PR) mRNA in MKN-45cells. Proliferation, cell cycle distribution, and the expression of Bcl-xL and vascular endothelial growth factor (VEGF) of MKN-45 cells incubated with various concentrations of mifepristone (1, 5, 10, and 20 μmol/L) were analyzed using MTT reduction assay, flow cytometry, reverse transcription-polymerase chain reaction (RT-PCR), and enzyme-linked immunoabsorbent assay (ELISA), respectively. After transplantation of MKN-45 cells underneath the skin of athymic mice, mifepristone proliferating cell nuclear antigen (PCNA) in xenografted tumors were detected using transmission electron microscopy and immunohistochemical staining, respectively.Results PR mRNA was highly expressed in cultured MKN-45 cell. Mifepristone dose-dependently inhibited the proliferation of MKN-45 cells, and the inhibitory rate was dramatically increased from 7.21% to 47.23%. The inhibitory effect was accompanied by a dose-dependent increase in the percentage of cells in G0/G1 phase, and with a concurrent decrease in the proportion of S- and G2/M-phase cells and the proliferative index from 57.65% to 24.54%. Meanwhile,mifepristone dom-regulated the expression of Bcl-xL and VEGF in a dose-dependent manner. In vivo, mifepristone effectively inhibited the growth of xenografted tumors in nude mice (55.14% for inhibitory rate), induced apoptosis, and down-regulated PCNA expression in gastric cancer.Conclusion Mifepristone exerts significant growth inhibitory effects on PR-positive human MKN-45 gastric cancer cells via multiple mechanisms, and may be a beneficial agent against the tumor.

  4. Herbal Extract SH003 Suppresses Tumor Growth and Metastasis of MDA-MB-231 Breast Cancer Cells by Inhibiting STAT3-IL-6 Signaling

    OpenAIRE

    Youn Kyung Choi; Sung-Gook Cho; Sang-Mi Woo; Yee Jin Yun; Sunju Park; Yong Cheol Shin; Seong-Gyu Ko

    2014-01-01

    Cancer inflammation promotes cancer progression, resulting in a high risk of cancer. Here, we demonstrate that our new herbal extract, SH003, suppresses both tumor growth and metastasis of MDA-MB-231 breast cancer cells via inhibiting STAT3-IL-6 signaling path. Our new herbal formula, SH003, mixed extract from Astragalus membranaceus, Angelica gigas, and Trichosanthes kirilowii Maximowicz, suppressed MDA-MB-231 tumor growth and lung metastasis in vivo and reduced the viability and metastatic ...

  5. 15-Lipoxygenase-1 Production is Lost in Pancreatic Cancer and Overexpression of the Gene Inhibits Tumor Cell Growth

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    René Hennig

    2007-11-01

    Full Text Available Pancreatic cancer patients have an abysmal prognosis because of late diagnosis and lack of therapeutic options. Pancreatic intraepithelial neoplasias (PaniNs, the precursor lesions, are a potential target for chemoprevention. Targeting eicosanoid pathways is an obvious choice because 5-lipoxygenase (5-LOX has been suggested as a tumor promoter in pancreatic carcinogenesis. Here we provide evidence that 15-lipoxygenase-1 (15-LOX-1 expression and activity may exert antitumorigenic effects in pancreatic cancer. Reverse transcription- polymerase chain reaction (RTPCR and Western blot analysis showed absence or very weak expression of 15-LOX-1 in all pancreatic cancer cell lines tested. 15-LOX-1 was strongly stained in normal ductal cells, tubular complexes, and centroacinar cells, but no staining was seen in islets, cancer cells, PanlN lesions, or in tumor cells in lymph node metastases, indicating that 15-LOX-1 expression is lost during tumor development in human pancreas. Overexpression of 15-LOX-1 in pancreatic tumor cells or treatment with its arachidonic acid-derived metabolite resulted in decreased cell growth. These findings provide evidence that loss of 15-LOX-1 may play an important role in pancreatic carcinogenesis, possibly as a tumor suppressor gene. Thus, induction of 15-LOX-1 expression may be an attractive option for the prevention and treatment of pancreatic cancer.

  6. Epidermal growth factor suppresses induction by progestin of the adhesion protein desmoplakin in T47D breast cancer cells

    International Nuclear Information System (INIS)

    Although the effects of progesterone on cell cycle progression are well known, its role in spreading and adhesion of breast cancer cells has not attracted much attention until recently. Indeed, by controlling cell adhesion proteins, progesterone may play a direct role in breast cancer invasion and metastasis. Progesterone has also been shown to modulate epidermal growth factor (EGF) effects in neoplasia, although EGF effects on progesterone pathways and targets are less well understood. In the present study we identify an effect of EGF on a progesterone target, namely desmoplakin. Initially flow cytometry was used to establish the growing conditions and demonstrate that the T47D breast cancer cell line was responding to progesterone and EGF in a classical manner. Differential display RT-PCR was employed to identify differentially expressed genes affected by progesterone and EGF. Western and Northern blotting were used to verify interactions between EGF and progesterone in three breast cancer cell lines: T47D, MCF-7, and ZR-75. We found the cell adhesion protein desmoplakin to be upregulated by progesterone – a process that was suppressed by EGF. This appears to be a general but not universal effect in breast cancer cell lines. Our findings suggest that progesterone and EGF may play opposing roles in metastasis. They also suggest that desmoplakin may be a useful biomarker for mechanistic studies designed to analyze the crosstalk between EGF and progesterone dependent events. Our work may help to bridge the fields of metastasis and differentiation, and the mechanisms of steroid action

  7. Non-steroidal anti-inflammatory drugs decrease E2F1 expression and inhibit cell growth in ovarian cancer cells.

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    Blanca L Valle

    Full Text Available Epidemiological studies have shown that the regular use of non-steroidal anti-inflammatory (NSAIDs drugs is associated with a reduced risk of various cancers. In addition, in vitro and experiments in mouse models have demonstrated that NSAIDs decrease tumor initiation and/or progression of several cancers. However, there are limited preclinical studies investigating the effects of NSAIDs in ovarian cancer. Here, we have studied the effects of two NSAIDs, diclofenac and indomethacin, in ovarian cancer cell lines and in a xenograft mouse model. Diclofenac and indomethacin treatment decreased cell growth by inducing cell cycle arrest and apoptosis. In addition, diclofenac and indomethacin reduced tumor volume in a xenograft model of ovarian cancer. To identify possible molecular pathways mediating the effects of NSAID treatment in ovarian cancer, we performed microarray analysis of ovarian cancer cells treated with indomethacin or diclofenac. Interestingly, several of the genes found downregulated following diclofenac or indomethacin treatment are transcriptional target genes of E2F1. E2F1 was downregulated at the mRNA and protein level upon treatment with diclofenac and indomethacin, and overexpression of E2F1 rescued cells from the growth inhibitory effects of diclofenac and indomethacin. In conclusion, NSAIDs diclofenac and indomethacin exert an anti-proliferative effect in ovarian cancer in vitro and in vivo and the effects of NSAIDs may be mediated, in part, by downregulation of E2F1.

  8. ZIP4 Regulates Pancreatic Cancer Cell Growth by Activating IL-6/STAT3 Pathway via Zinc Finger Transcription Factor CREB

    Science.gov (United States)

    Zhang, Yuqing; Bharadwaj, Uddalak; Logsdon, Craig D.; Chen, Changyi; Yao, Qizhi; Li, Min

    2010-01-01

    Purpose Recent studies indicate a strong correlation of zinc transporter ZIP4 and pancreatic cancer progression; however, the underlying mechanisms are unclear. We have recently found that ZIP4 is overexpressed in pancreatic cancer. In this study, we investigated the signaling pathway through which ZIP4 regulates pancreatic cancer growth. Experimental Design The expression of cyclin D1, IL-6, and STAT3 in pancreatic cancer xenografts and cells were examined by real time PCR, Bio-Plex cytokine assay, and Western blot, respectively. The activity of CREB is examined by a promoter activity assay. Results Cyclin D1 was significantly increased in the ZIP4 overexpressing MIA PaCa-2 cells (MIA-ZIP4)-injected orthotopic xenografts and was downregulated in the ZIP4 silenced ASPC-1 (ASPC-shZIP4) group. The phosphorylation of signal transducer and activator of transcription 3 (STAT3), an upstream activator of cyclin D1, was increased in MIA-ZIP4 cells, and decreased in ASPC-shZIP4 cells. IL-6, a known upstream activator for STAT3, was also found to be significantly increased in the MIA-ZIP4 cells and xenografts, and decreased in the ASPC-shZIP4 group. Overexpression of ZIP4 led to a 75% increase of IL-6 promoter activity, and caused increased phosphorylation of cAMP response element binding protein (CREB). Conclusions Our study suggest that ZIP4 overexpression causes increased IL-6 transcription via CREB, which in turn activates STAT3, and leads to increased cyclin D1 expression, resulting in increased cell proliferation and tumor progression in pancreatic cancer. These results elucidated a novel pathway in ZIP4-mediated pancreatic cancer growth, and suggest new therapeutic targets including ZIP4, IL-6, and STAT3 in pancreatic cancer treatment. PMID:20160059

  9. Production of transforming growth factor α in human pancreatic cancer cells: evidence for a superagonist autocrine cycle

    International Nuclear Information System (INIS)

    Previous work showed that cultured human pancreatic cancer cells overexpress the epidermal growth factor (EGF) receptor. In the present study, the authors sought to determine whether some of these cell lines produce transforming growth factor α (TGF-α). Utilizing a radiolabeled TGF-α cDNA in hybridization experiments, they determined that ASPC-1, T3M4, PANC-1, COLO-357, and MIA PaCa-2 cell lines expressed TGF-α mRNA. Serum-free medium conditioned by T3M4 and ASPC-1 cells contained significant amounts of TGF-α protein. Although unlabeled TGF-α readily competed with 125I-labeled EGF for binding, each cell line exhibited lower surface binding and internalization of 125I-labeled TGF-α as compared to 125I-labeled EGF. Both TGF-α and EGF significantly enhanced the anchorage-independent growth of PANC-1, T3M4, and ASPC-1 cells. However, TGF-α was 10- to 100-fold more potent than EGF. These findings suggest that the concomitant overexpression of EGF receptors and production of TGF-α may represent an efficient mechanism for certain cancer cells to obtain a growth advantage

  10. Repression of the integrated papillomavirus E6/E7 promoter is required for growth suppression of cervical cancer cells.

    Science.gov (United States)

    Francis, D A; Schmid, S I; Howley, P M

    2000-03-01

    The human papillomavirus (HPV) E2 protein is an important regulator of viral E6 and E7 gene expression. E2 can repress the viral promoter for E6 and E7 expression as well as block progression of the cell cycle in cancer cells harboring the DNA of "high-risk" HPV types. Although the phenomenon of E2-mediated growth arrest of HeLa cells and other HPV-positive cancer cells has been well documented, the specific mechanism by which E2 affects cellular proliferation has not yet been elucidated. Here, we show that bovine papillomavirus (BPV) E2-induced growth arrest of HeLa cells requires the repression of the E6 and E7 promoter. This repression is specific for E2TA and not E2TR, a BPV E2 variant that lacks the N-terminal transactivation domain. We demonstrate that expression of HPV16 E6 and E7 from a heterologous promoter that is not regulated by E2 rescues HeLa cells from E2-mediated growth arrest. Our data indicate that the pathway of E2-mediated growth arrest of HeLa cells requires repression of E6 and E7 expression through an activity specified by the transactivation domain of E2TA. PMID:10684283

  11. Cell motility and ECM proteolysis regulate tumor growth and tumor relapse by altering the fraction of cancer stem cells and their spatial scattering

    Science.gov (United States)

    Kumar, Sandeep; Kulkarni, Rahul; Sen, Shamik

    2016-06-01

    Tumors consist of multiple cell sub-populations including cancer stem cells (CSCs), transiently amplifying cells and terminally differentiated cells (TDCs), with the CSC fraction dictating the aggressiveness of the tumor and drug sensitivity. In epithelial cancers, tumor growth is influenced greatly by properties of the extracellular matrix (ECM), with cancer progression associated with an increase in ECM density. However, the extent to which increased ECM confinement induced by an increase in ECM density influences tumor growth and post treatment relapse dynamics remains incompletely understood. In this study, we use a cellular automata-based discrete modeling approach to study the collective influence of ECM density, cell motility and ECM proteolysis on tumor growth, tumor heterogeneity, and tumor relapse after drug treatment. We show that while increased confinement suppresses tumor growth and the spatial scattering of CSCs, this effect can be reversed when cells become more motile and proteolytically active. Our results further suggest that, in addition to the absolute number of CSCs, their spatial positioning also plays an important role in driving tumor growth. In a nutshell, our study suggests that, in confined environments, cell motility and ECM proteolysis are two key factors that regulate tumor growth and tumor relapse dynamics by altering the number and spatial distribution of CSCs.

  12. Mead acid inhibits the growth of KPL-1 human breast cancer cells in vitro and in vivo.

    Science.gov (United States)

    Kinoshita, Yuichi; Yoshizawa, Katsuhiko; Hamazaki, Kei; Emoto, Yuko; Yuri, Takashi; Yuki, Michiko; Shikata, Nobuaki; Kawashima, Hiroshi; Tsubura, Airo

    2014-10-01

    The effects of mead acid (MA; 5,8,11-eicosatrienoic acid) on the suppression of breast cancer cell growth and metastasis were examined in vitro and in vivo by using the KPL-1 human breast cancer cell line. MA suppressed KPL-1 cell growth in culture with an IC50 value of 214.2 µM (65.7 µg/ml) for 72 h, and MA significantly suppressed transplanted KPL-1 tumor growth (tumor volume and tumor weight: 872±103 mm3 and 1,000±116 mg vs. 376±66 mm3 and 517±84 mg) and regional (axillary) lymph node metastasis (67%, 10/15 vs. 10%, 1/10) in female athymic mice fed an MA-rich diet for 8 weeks. Tumor suppression was due to the suppression of cell proliferation. In ELISA, although vascular endothelial growth factor (VEGF) levels were unchanged, VEGF receptor (VEGFR)1 and VEGFR2 levels were significantly decreased after treatment with a 214.2-µM dose of MA for 72 h; E-cadherin levels were unchanged. As VEGF, VEGFR1 and VEGFR2 expression was co-localized in KPL-1 cells, the mechanism leading to cell growth suppression was VEGF signaling directly to KPL-1 cells by an autocrine process. In contrast, MA did not influence angiogenesis. The mechanisms of action were through VEGF signaling directly to cancer cells. PMID:25109488

  13. A novel method, digital genome scanning detects KRAS gene amplification in gastric cancers: involvement of overexpressed wild-type KRAS in downstream signaling and cancer cell growth

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    Yanagihara Kazuyoshi

    2009-06-01

    Full Text Available Abstract Background Gastric cancer is the third most common malignancy affecting the general population worldwide. Aberrant activation of KRAS is a key factor in the development of many types of tumor, however, oncogenic mutations of KRAS are infrequent in gastric cancer. We have developed a novel quantitative method of analysis of DNA copy number, termed digital genome scanning (DGS, which is based on the enumeration of short restriction fragments, and does not involve PCR or hybridization. In the current study, we used DGS to survey copy-number alterations in gastric cancer cells. Methods DGS of gastric cancer cell lines was performed using the sequences of 5000 to 15000 restriction fragments. We screened 20 gastric cancer cell lines and 86 primary gastric tumors for KRAS amplification by quantitative PCR, and investigated KRAS amplification at the DNA, mRNA and protein levels by mutational analysis, real-time PCR, immunoblot analysis, GTP-RAS pull-down assay and immunohistochemical analysis. The effect of KRAS knock-down on the activation of p44/42 MAP kinase and AKT and on cell growth were examined by immunoblot and colorimetric assay, respectively. Results DGS analysis of the HSC45 gastric cancer cell line revealed the amplification of a 500-kb region on chromosome 12p12.1, which contains the KRAS gene locus. Amplification of the KRAS locus was detected in 15% (3/20 of gastric cancer cell lines (8–18-fold amplification and 4.7% (4/86 of primary gastric tumors (8–50-fold amplification. KRAS mutations were identified in two of the three cell lines in which KRAS was amplified, but were not detected in any of the primary tumors. Overexpression of KRAS protein correlated directly with increased KRAS copy number. The level of GTP-bound KRAS was elevated following serum stimulation in cells with amplified wild-type KRAS, but not in cells with amplified mutant KRAS. Knock-down of KRAS in gastric cancer cells that carried amplified wild

  14. A novel method, digital genome scanning detects KRAS gene amplification in gastric cancers: involvement of overexpressed wild-type KRAS in downstream signaling and cancer cell growth

    International Nuclear Information System (INIS)

    Gastric cancer is the third most common malignancy affecting the general population worldwide. Aberrant activation of KRAS is a key factor in the development of many types of tumor, however, oncogenic mutations of KRAS are infrequent in gastric cancer. We have developed a novel quantitative method of analysis of DNA copy number, termed digital genome scanning (DGS), which is based on the enumeration of short restriction fragments, and does not involve PCR or hybridization. In the current study, we used DGS to survey copy-number alterations in gastric cancer cells. DGS of gastric cancer cell lines was performed using the sequences of 5000 to 15000 restriction fragments. We screened 20 gastric cancer cell lines and 86 primary gastric tumors for KRAS amplification by quantitative PCR, and investigated KRAS amplification at the DNA, mRNA and protein levels by mutational analysis, real-time PCR, immunoblot analysis, GTP-RAS pull-down assay and immunohistochemical analysis. The effect of KRAS knock-down on the activation of p44/42 MAP kinase and AKT and on cell growth were examined by immunoblot and colorimetric assay, respectively. DGS analysis of the HSC45 gastric cancer cell line revealed the amplification of a 500-kb region on chromosome 12p12.1, which contains the KRAS gene locus. Amplification of the KRAS locus was detected in 15% (3/20) of gastric cancer cell lines (8–18-fold amplification) and 4.7% (4/86) of primary gastric tumors (8–50-fold amplification). KRAS mutations were identified in two of the three cell lines in which KRAS was amplified, but were not detected in any of the primary tumors. Overexpression of KRAS protein correlated directly with increased KRAS copy number. The level of GTP-bound KRAS was elevated following serum stimulation in cells with amplified wild-type KRAS, but not in cells with amplified mutant KRAS. Knock-down of KRAS in gastric cancer cells that carried amplified wild-type KRAS resulted in the inhibition of cell growth and

  15. Decreased expression of the mannose 6- phosphate/insulin-like growth factor-II receptor promotes growth of human breast cancer cells

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    Landman Natalie

    2002-07-01

    Full Text Available Abstract Background Loss or mutation of the mannose 6-phosphate/insulin-like growth factor-II receptor (M6P/IGF2R has been found in breast cancer. However, whether or not decreased levels of functional M6P/IGF2R directly contribute to the process of carcinogenesis needs to be further verified by functional studies. Methods In this study, using viral and ribozyme strategies we reduced the expression of M6P/IGF2R in human breast cancer cells and then examined the effect on growth and apoptosis of these cells. Results Our results showed that infection of MCF-7 cells with the adenovirus carrying a ribozyme targeted against the M6P/IGF2R mRNA dramatically reduced the level of transcripts and the functional activity of M6P/IGF2R in these cells. Accordingly, cells treated with the ribozyme exhibited a higher growth rate and a lower apoptotic index than control cells (infected with a control vector. Furthermore, decreased expression of M6P/IGF2R enhanced IGF-II-induced proliferation and reduced cell susceptibility to TNF-induced apoptosis. Conclusions These results suggest that M6P/IGF2R functions as a growth suppressor and its loss or mutation may contribute to development and progression of cancer. This study also demonstrates that adenoviral delivery of the ribozyme provides a useful tool for investigating the role of M6P/IGF2R in regulation of cell growth.

  16. Effects of Coptis extract combined with chemotherapeutic agents on ROS production, multidrug resistance, and cell growth in A549 human lung cancer cells

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    He Chengwei

    2012-04-01

    Full Text Available Abstract Background Non–small cell lung cancer is associated with high expression of multidrug resistance (MDR proteins and low production of reactive oxygen species (ROS. Coptis extract (COP, a Chinese medicinal herb, and its major constituent, berberine (BER, have anticancer properties. This study aims to investigate the effects of COP and BER combined with chemotherapeutic agents, including fluorouracil (5-FU, camptothecin (CPT, and paclitaxel (TAX, on cell proliferation, ROS production, and MDR in A549 human non-small cell lung cancer cells. Methods A549 cells were treated with different doses of COP and BER, combined with 5-FU, CPT, and TAX. Cell viability was measured by an XTT (2,3-bis-(2-methoxy-4- nitro-5-sulfophenyl-2 H-tetrazolium-5-carboxanilide assay. Intracellular ROS levels were determined by measuring the oxidative conversion of cell permeable 2′,7′-dichlorofluorescein diacetate to fluorescent dichlorofluorescein. MDR of A549 cells was assessed by rhodamine 123 retention assay. Results Both COP and BER significantly inhibited A549 cell growth in a dose-dependent manner. Combinations of COP or BER with chemotherapeutic agents (5-FU, CPT, and TAX exhibited a stronger inhibitory effect on A549 cell growth. In addition, COP and BER increased ROS production and reduced MDR in A549 cells. Conclusion As potential adjuvants to chemotherapy for non–small cell lung cancer, COP and BER increase ROS production, reduce MDR, and enhance the inhibitory effects of chemotherapeutic agents on A549 cell growth.

  17. Embelin suppresses growth of human pancreatic cancer xenografts, and pancreatic cancer cells isolated from KrasG12D mice by inhibiting Akt and Sonic hedgehog pathways.

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    Minzhao Huang

    Full Text Available Pancreatic cancer is a deadly disease, and therefore effective treatment and/or prevention strategies are urgently needed. The objectives of this study were to examine the molecular mechanisms by which embelin inhibited human pancreatic cancer cell growth in vitro, and xenografts in Balb C nude mice, and pancreatic cancer cell growth isolated from KrasG12D transgenic mice. XTT assays were performed to measure cell viability. AsPC-1 cells were injected subcutaneously into Balb c nude mice and treated with embelin. Cell proliferation and apoptosis were measured by Ki67 and TUNEL staining, respectively. The expression of Akt, and Sonic Hedgehog (Shh and their target gene products were measured by the immunohistochemistry, and Western blot analysis. The effects of embelin on pancreatic cancer cells isolated from 10-months old KrasG12D mice were also examined. Embelin inhibited cell viability in pancreatic cancer AsPC-1, PANC-1, MIA PaCa-2 and Hs 766T cell lines, and these inhibitory effects were blocked either by constitutively active Akt or Shh protein. Embelin-treated mice showed significant inhibition in tumor growth which was associated with reduced expression of markers of cell proliferation (Ki67, PCNA and Bcl-2 and cell cycle (cyclin D1, CDK2, and CDK6, and induction of apoptosis (activation of caspase-3 and cleavage of PARP, and increased expression of Bax. In addition, embelin inhibited the expression of markers of angiogenesis (COX-2, VEGF, VEGFR, and IL-8, and metastasis (MMP-2 and MMP-9 in tumor tissues. Antitumor activity of embelin was associated with inhibition of Akt and Shh pathways in xenografts, and pancreatic cancer cells isolated from KrasG12D mice. Furthermore, embelin also inhibited epithelial-to-mesenchymal transition (EMT by up-regulating E-cadherin and inhibiting the expression of Snail, Slug, and ZEB1. These data suggest that embelin can inhibit pancreatic cancer growth, angiogenesis and metastasis by suppressing Akt and

  18. S14 protein in breast cancer cells: Direct evidence of regulation by SREBP-1c, superinduction with progestin, and effects on cell growth

    International Nuclear Information System (INIS)

    Most breast cancers exhibit brisk lipogenesis, and require it for growth. S14 is a lipogenesis-related nuclear protein that is overexpressed in most breast cancers. Sterol response element-binding protein-1c (SREBP-1c) is required for induction of lipogenesis-related genes, including S14 and fatty acid synthase (FAS), in hepatocytes, and correlation of SREBP-1c and FAS expression suggested that SREBP-1c drives lipogenesis in tumors as well. We directly tested the hypothesis that SREBP-1c drives S14 expression and mediates lipogenic effects of progestin in T47D breast cancer cells. Dominant-negative SREBP-1c inhibited induction of S14 and FAS mRNAs by progestin, while active SREBP-1c induced without hormone and superinduced in its presence. Changes in S14 mRNA were reflected in protein levels. A lag time and lack of progestin response elements indicated that S14 and FAS gene activation by progestin is indirect. Knockdown of S14 reduced, whereas overexpression stimulated, T47D cell growth, while nonlipogenic MCF10a mammary epithelial cells were not growth-inhibited. These data directly demonstrate that SREBP-1c drives S14 gene expression in breast cancer cells, and progestin magnifies that effect via an indirect mechanism. This supports the prediction, based on S14 gene amplification and overexpression in breast tumors, that S14 augments breast cancer cell growth and survival

  19. microRNA 21-mediated suppression of Sprouty1 by Pokemon affects liver cancer cell growth and proliferation.

    Science.gov (United States)

    Jin, Xiu-Li; Sun, Qin-Sheng; Liu, Feng; Yang, Hong-Wei; Liu, Min; Liu, Hong-Xia; Xu, Wei; Jiang, Yu-Yang

    2013-07-01

    Transcriptional repressor Pokemon is a critical factor in embryogenesis, development, cell proliferation, differentiation, and oncogenesis, thus behaving as an oncogene. Oncomine database suggests a potential correlation between the expressions of Pokemon and Sprouty1. This study investigated the regulatory role of Pokemon in Sprouty1 expression and the effect on liver cancer cell growth and proliferation, revealing a novel miR-21-mediated regulatory circuit. In normal (HL-7702) and cancer (QGY-7703) liver cell lines, Sprouty1 expression is inversely correlated with Pokemon levels. Targeted expression or siRNA-mediated silencing showed that Pokemon is a repressor of Sprouty1 expression at both mRNA and protein levels, but Pokemon cannot affect the promoter activity of Sprouty1. Sprouty1 is a target of miR-21 and interestingly, we found that miR-21 is up-regulated by Pokemon in liver cancer cells. Luciferase reporter assays showed that Pokemon up-regulated miR-21 transcription in a dose-dependent manner, and ChIP assay exhibited a direct binding of Pokemon to the miR-21 promoter at -747 to -399 bp. Site-directed mutagenesis of the GC boxes at -684 to -679 bp and -652 to -647 bp of miR-21 promoter abolished the regulatory activity by Pokemon. Furthermore, we found that the modulation of Pokemon and miR-21 expression affected the growth and proliferation of liver cancer cells QGY-7703. In summary, our findings demonstrate that Pokemon suppresses Sprouty1 expression through a miR-21-mediated mechanism, affecting the growth and proliferation of liver cancer cells. This study recognized miR-21 and Sprouty1 as novel targets of the Pokemon regulatory network. PMID:23355454

  20. 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

  1. Fibroblast growth factor signaling and inhibition in non-small cell lung cancer and their role in squamous cell tumors

    International Nuclear Information System (INIS)

    With the introduction of targeted agents primarily applicable to non-small cell lung cancer (NSCLC) of adenocarcinoma histology, there is a heightened unmet need in the squamous cell carcinoma population. Targeting the angiogenic fibroblast growth factor (FGF)/FGF receptor (FGFR) signaling pathway is among the strategies being explored in squamous NSCLC; these efforts are supported by growth-promoting effects of FGF signaling in preclinical studies (including interactions with other pathways) and observations suggesting that FGF/FGFR-related aberrations may be more common in squamous versus adenocarcinoma and other histologies. A number of different anti-FGF/FGFR approaches have shown promise in preclinical studies. Clinical trials of two multitargeted tyrosine kinase inhibitors are restricting enrollment to patients with squamous NSCLC: a phase I/II trial of nintedanib added to first-line gemcitabine/cisplatin and a phase II trial of ponatinib for previously treated advanced disease, with the latter requiring not only squamous disease but also a confirmed FGFR kinase amplification or mutation. There are several ongoing clinical trials of multitargeted agents in general NSCLC populations, including but not limited to patients with squamous disease. Other FGF/FGFR-targeted agents are in earlier clinical development. While results are awaited from these clinical investigations in squamous NSCLC and other disease settings, additional research is needed to elucidate the role of FGF/FGFR signaling in the biology of NSCLC of different histologies

  2. Up-regulation of SRPK1 in non-small cell lung cancer promotes the growth and migration of cancer cells.

    Science.gov (United States)

    Liu, Hongcheng; Hu, Xuefei; Zhu, Yuming; Jiang, Gening; Chen, Sheng

    2016-06-01

    Dys-regulation of serine-arginine protein kinase 1 (SRPK1) has been reported in non-small cell lung cancer (NSCLC). However, its functions in the progression of NSCLC remain poorly understood. In this study, the expression of SRPK1 in NSCLC tissues was determined using real-time PCR, and the roles of SRPK1 in the progression of NSCLC were investigated. It was found that both the mRNA level and the protein level of SRPK1 were up-regulated in NSCLC tissues. Forced expression of SRPK1 promoted the growth and migration of NSCLC cells, while knocking down the expression of SRPK1 inhibited the growth, migration, and tumorigenicity of NSCLC cells. Mechanism studies showed that SRPK1 activated the transcriptional activity of beta-catenin/T-cell factor (TCF) complex, and knocking down the expression of SRPK1 attenuated the expression of target genes of beta-catenin/T-cell factor (TCF) complex. In addition, silencing the expression of SRPK1 down-regulated the phosphorylation of GSK3beta. Taken together, SRPK1 might play an oncogenic role in NSCLC, and SRPK1 might be a therapeutic target for NSCLC. PMID:26666824

  3. Essiac? and Flor-Essence? herbal tonics stimulate the in vitro growth of human breast cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Kulp, K S; Montgomery, J L; McLimans, B; Latham, E R; Shattuck, D L; Klotz, D M; Bennett, L M

    2005-10-07

    People diagnosed with cancer often self-administer complementary and alternative medicines (CAMs) to supplement their conventional treatments, improve health, or prevent recurrence. Flor-Essence{reg_sign} and Essiac{reg_sign} Herbal Tonics are commercially available complex mixtures of herbal extracts sold as dietary supplements and used by cancer patients based on anecdotal evidence that they can treat or prevent disease. In this study, we evaluated Flor-Essence{reg_sign} and Essiac{reg_sign} for their effects on the growth of human tumor cells in culture. The effect of Flor-Essence{reg_sign} and Essiac{reg_sign} herbal tonics on cell proliferation was tested in MCF-7, MDA-MB-436, MDA-MB-231, and T47D cancer cells isolated from human breast tumors. Estrogen receptor (ER) dependent activation of a luciferase reporter construct was tested in MCF-7 cells. Specific binding to the ER was tested using an ICI 182,780 competition assay. Flor-Essence{reg_sign} and Essiac{reg_sign} herbal tonics at 1%, 2%, 4% and 8% stimulated cell proliferation relative to untreated controls and activated ER dependent luciferase activity in MCF-7 cells. A 10{sup -7} M concentration of ICI 870,780 inhibited the induction of ER dependent luciferase activity by Flor-Essence{reg_sign} and Essiac{reg_sign}, but did not affect cell proliferation. Flor-Essence{reg_sign} and Essiac{reg_sign} Herbal Tonics can stimulate the growth of human breast cancer cells through ER mediated as well as ER independent mechanisms of action. Cancer patients and health care providers can use this information to make informed decisions about the use of these CAMs.

  4. In vitro and in vivo growth suppression of human papillomavirus 16-positive cervical cancer cells by CRISPR/Cas9

    International Nuclear Information System (INIS)

    Highlights: • Established CRISPR/Cas9 targeting promoter of HPV 16 and targeting E6, E7 transcript. • CRISPR/Cas9 resulted in accumulation of p53 and p21, reduced the proliferation of cervical cancer cells. • Finding inhibited tumorigenesis and growth of mice incubated by cells with CRISPR/Cas9. • CRISPR/Cas9 will be a new treatment strategy, in cervical and other HPV-associated cancer therapy. - Abstract: Deregulated expression of high-risk human papillomavirus oncogenes (E6 and E7) is a pivotal event for pathogenesis and progression in cervical cancer. Both viral oncogenes are therefore regarded as ideal therapeutic targets. In the hope of developing a gene-specific therapy for HPV-related cancer, we established CRISPR/Cas9 targeting promoter of HPV 16 E6/E7 and targeting E6, E7 transcript, transduced the CRISPR/Cas9 into cervical HPV-16-positive cell line SiHa. The results showed that CRISPR/Cas9 targeting promoter, as well as targeting E6 and E7 resulted in accumulation of p53 and p21 protein, and consequently remarkably reduced the abilities of proliferation of cervical cancer cells in vitro. Then we inoculated subcutaneously cells into nude mice to establish the transplanted tumor animal models, and found dramatically inhibited tumorigenesis and growth of mice incubated by cells with CRISPR/Cas9 targeting (promoter+E6+E7)-transcript. Our results may provide evidence for application of CRISPR/Cas9 targeting HR-HPV key oncogenes, as a new treatment strategy, in cervical and other HPV-associated cancer therapy

  5. In vitro and in vivo growth suppression of human papillomavirus 16-positive cervical cancer cells by CRISPR/Cas9

    Energy Technology Data Exchange (ETDEWEB)

    Zhen, Shuai, E-mail: usa_2002@163.com [Baoji Maternal and Child Health Hospital, 2 Xinjian Road East, WeiBin District, Baoji City, 721000, Shanxi Province (China); Xijing Hospital, Fourth Military Medical University, Xi’an (China); Department of Pharmacology and Toxicology, Beijing Institute of Radiation Medicine, Beijing 100850 (China); Kyoto University, Kyoto 606-8507 (Japan); Hua, Ling [Department of Pharmacology and Toxicology, Beijing Institute of Radiation Medicine, Beijing 100850 (China); Takahashi, Y.; Narita, S. [Kyoto University, Kyoto 606-8507 (Japan); Liu, Yun-Hui [Department of Pharmacology and Toxicology, Beijing Institute of Radiation Medicine, Beijing 100850 (China); Li, Yan [Baoji Hospital of Traditional Chinese Medicine, No 43, BaoFu Road, Baoji City, Shanxi Province (China)

    2014-08-08

    Highlights: • Established CRISPR/Cas9 targeting promoter of HPV 16 and targeting E6, E7 transcript. • CRISPR/Cas9 resulted in accumulation of p53 and p21, reduced the proliferation of cervical cancer cells. • Finding inhibited tumorigenesis and growth of mice incubated by cells with CRISPR/Cas9. • CRISPR/Cas9 will be a new treatment strategy, in cervical and other HPV-associated cancer therapy. - Abstract: Deregulated expression of high-risk human papillomavirus oncogenes (E6 and E7) is a pivotal event for pathogenesis and progression in cervical cancer. Both viral oncogenes are therefore regarded as ideal therapeutic targets. In the hope of developing a gene-specific therapy for HPV-related cancer, we established CRISPR/Cas9 targeting promoter of HPV 16 E6/E7 and targeting E6, E7 transcript, transduced the CRISPR/Cas9 into cervical HPV-16-positive cell line SiHa. The results showed that CRISPR/Cas9 targeting promoter, as well as targeting E6 and E7 resulted in accumulation of p53 and p21 protein, and consequently remarkably reduced the abilities of proliferation of cervical cancer cells in vitro. Then we inoculated subcutaneously cells into nude mice to establish the transplanted tumor animal models, and found dramatically inhibited tumorigenesis and growth of mice incubated by cells with CRISPR/Cas9 targeting (promoter+E6+E7)-transcript. Our results may provide evidence for application of CRISPR/Cas9 targeting HR-HPV key oncogenes, as a new treatment strategy, in cervical and other HPV-associated cancer therapy.

  6. Conjugated docosahexaenoic acid suppresses KPL-1 human breast cancer cell growth in vitro and in vivo: potential mechanisms of action

    International Nuclear Information System (INIS)

    The present study was conducted to examine the effect of conjugated docosahexaenoic acid (CDHA) on cell growth, cell cycle progression, mode of cell death, and expression of cell cycle regulatory and/or apoptosis-related proteins in KPL-1 human breast cancer cell line. This effect of CDHA was compared with that of docosahexaenoic acid (DHA). KPL-1 cell growth was assessed by colorimetric 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay; cell cycle progression and mode of cell death were examined by flow cytometry; and levels of expression of p53, p21Cip1/Waf1, cyclin D1, Bax, and Bcl-2 proteins were examined by Western blotting analysis. In vivo tumor growth was examined by injecting KPL-1 cells subcutaneously into the area of the right thoracic mammary fat pad of female athymic mice fed a CDHA diet. CDHA inhibited KPL-1 cells more effectively than did DHA (50% inhibitory concentration for 72 hours: 97 μmol/l and 270 μmol/l, respectively). With both CDHA and DHA growth inhibition was due to apoptosis, as indicated by the appearance of a sub-G1 fraction. The apoptosis cascade involved downregulation of Bcl-2 protein; Bax expression was unchanged. Cell cycle progression was due to G0/G1 arrest, which involved increased expression of p53 and p21Cip1/Waf1, and decreased expression of cyclin D1. CDHA modulated cell cycle regulatory proteins and apoptosis-related proteins in a manner similar to that of parent DHA. In the athymic mouse system 1.0% dietary CDHA, but not 0.2%, significantly suppressed growth of KPL-1 tumor cells; CDHA tended to decrease regional lymph node metastasis in a dose dependent manner. CDHA inhibited growth of KPL-1 human breast cancer cells in vitro more effectively than did DHA. The mechanisms of action involved modulation of apoptosis cascade and cell cycle progression. Dietary CDHA at 1.0% suppressed KPL-1 cell growth in the athymic mouse system

  7. Models of Growth Heterogeneous Cancer Cells with Chains Markoviens and Estimation of Their Fractal Dimension

    Directory of Open Access Journals (Sweden)

    Labib Sadek Terrissa

    2011-09-01

    Full Text Available Although little work in biometrics uses fractal geometry, we will discuss here biometrics cancer tissue examined under a microscope or simulated. The main purpose of our work is the simulation of the heterogeneous growth of cancerous tumors and the analysis of the appearance of their textures. The problem is to quantify the irregularity of their edges, which help enormously oncologists to give diagnoses to evaluate the treatment issued to their patients. We propose new algorithms, which generates growth models with the ability to produce a border irregularity similar to that of cancerous tumors and value their fractal dimension. The established models have two types of parameters: Algorithms describing the structure, and Scalar to quantify aspects modeled

  8. Ionizing Radiation Promotes Migration and Invasion of Cancer Cells Through Transforming Growth Factor-Beta-Mediated Epithelial-Mesenchymal Transition

    Energy Technology Data Exchange (ETDEWEB)

    Zhou Yongchun [Department of Radiation Oncology, Xijing Hospital Fourth Military Medical University, Xi' an (China); Department of Radiation Medicine, College of Preventive Medicine, Xijing Hospital Fourth Military Medical University, Xi' an (China); Liu Junye; Li Jing; Zhang Jie [Department of Radiation Medicine, College of Preventive Medicine, Xijing Hospital Fourth Military Medical University, Xi' an (China); Xu Yuqiao [Department of Pathology, Xijing Hospital Fourth Military Medical University, Xi' an (China); Zhang Huawei; Qiu Lianbo; Ding Guirong [Department of Radiation Medicine, College of Preventive Medicine, Xijing Hospital Fourth Military Medical University, Xi' an (China); Su Xiaoming [Department of Radiation Oncology, 306th Hospital of PLA, Beijing (China); Mei Shi [Department of Radiation Oncology, Xijing Hospital Fourth Military Medical University, Xi' an (China); Guo Guozhen, E-mail: guozhenguo@hotmail.com [Department of Radiation Medicine, College of Preventive Medicine, Xijing Hospital Fourth Military Medical University, Xi' an (China)

    2011-12-01

    Purpose: To examine whether ionizing radiation enhances the migratory and invasive abilities of cancer cells through transforming growth factor (TGF-{beta})-mediated epithelial-mesenchymal transition (EMT). Methods and Materials: Six cancer cell lines originating from different human organs were irradiated by {sup 60}Co {gamma}-ray at a total dose of 2 Gy, and the changes associated with EMT, including morphology, EMT markers, migration and invasion, were observed by microscope, Western blot, immunofluorescence, scratch assay, and transwell chamber assay, respectively. Then the protein levels of TGF-{beta} in these cancer cells were detected by enzyme-linked immunosorbent assay, and the role of TGF-{beta} signaling pathway in the effect of ionizing radiation on EMT was investigate by using the specific inhibitor SB431542. Results: After irradiation with {gamma}-ray at a total dose of 2 Gy, cancer cells presented the mesenchymal phenotype, and compared with the sham-irradiation group the expression of epithelial markers was decreased and of mesenchymal markers was increased, the migratory and invasive capabilities were strengthened, and the protein levels of TGF-{beta} were enhanced. Furthermore, events associated with EMT induced by IR in A549 could be reversed through inhibition of TGF-{beta} signaling. Conclusions: These results suggest that EMT mediated by TGF-{beta} plays a critical role in IR-induced enhancing of migratory and invasive capabilities in cancer cells.

  9. Depletion of OLFM4 gene inhibits cell growth and increases sensitization to hydrogen peroxide and tumor necrosis factor-alpha induced-apoptosis in gastric cancer cells

    Directory of Open Access Journals (Sweden)

    Liu Rui-hua

    2012-04-01

    Full Text Available Abstract Background Human olfactomedin 4 (OLFM4 gene is a secreted glycoprotein more commonly known as the anti-apoptotic molecule GW112. OLFM4 is found to be frequently up-regulated in many types of human tumors including gastric cancer and it was believed to play significant role in the progression of gastric cancer. Although the function of OLFM4 has been indicated in many studies, recent evidence strongly suggests a cell or tissue type-dependent role of OLFM4 in cell growth and apoptosis. The aim of this study is to examine the role of gastric cancer-specific expression of OLFM4 in cell growth and apoptosis resistance. Methods OLFM4 expression was eliminated by RNA interference in SGC-7901 and MKN45 cells. Cell proliferation, anchorage-independent growth, cell cycle and apoptosis were characterized in vitro. Tumorigenicity was analyzed in vivo. The apoptosis and caspase-3 activation in response to hydrogen peroxide (H2O2 or tumor necrosis factor-alpha (TNF α were assessed in the presence or absence of caspase inhibitor Z-VAD-fmk. Results The elimination of OLFM4 protein by RNA interference in SGC-7901 and MKN45 cells significantly inhibits tumorigenicity both in vitro and in vivo by induction of cell G1 arrest (all P 2O2 or TNF α-induced apoptosis and caspase-3 activity (all P 2O2 or TNF α-induced apoptosis in OLFM4 knockdown cells (all P Conclusion Our study suggests that depletion of OLFM4 significantly inhibits tumorigenicity of the gastric cancer SGC-7901 and MKN45 cells. Blocking OLFM4 expression can sensitize gastric cancer cells to H2O2 or TNF α treatment by increasing caspase-3 dependent apoptosis. A combination strategy based on OLFM4 inhibition and anticancer drugs treatment may provide therapeutic potential in gastric cancer intervention.

  10. A novel rabbit anti-hepatocyte growth factor monoclonal neutralizing antibody inhibits tumor growth in prostate cancer cells and mouse xenografts

    International Nuclear Information System (INIS)

    The hepatocyte growth factor and its receptor c-Met are correlated with castration-resistance in prostate cancer. Although HGF has been considered as an attractive target for therapeutic antibodies, the lack of cross-reactivity of monoclonal antibodies with human/mouse HGFs is a major obstacle in preclinical developments. We generated a panel of anti-HGF RabMAbs either blocking HGF/c-Met interaction or inhibiting c-Met phosphorylation. We selected one RabMAb with mouse cross-reactivity and demonstrated that it blocked HGF-stimulated downstream activation in PC-3 and DU145 cells. Anti-HGF RabMAb inhibited not only the growth of PC-3 cells but also HGF-dependent proliferation in HUVECs. We further demonstrated the efficacy and potency of the anti-HGF RabMAb in tumor xenograft mice models. Through these in vitro and in vivo experiments, we explored a novel therapeutic antibody for advanced prostate cancer. - Highlights: • HGF is an attractive target for castration-refractory prostate cancer. • We generated and characterized a panel of anti-HGF rabbit monoclonal antibodies. • More than half of these anti-HGF RabMAbs was cross-reactive with mouse HGF. • Anti-HGF RabMAb blocks HGF-stimulated phosphorylation and cell growth in vitro. • Anti-HGF RabMAb inhibits tumor growth and angiogenesis in xenograft mice

  11. A novel rabbit anti-hepatocyte growth factor monoclonal neutralizing antibody inhibits tumor growth in prostate cancer cells and mouse xenografts

    Energy Technology Data Exchange (ETDEWEB)

    Yu, Yanlan; Chen, Yicheng; Ding, Guoqing; Wang, Mingchao; Wu, Haiyang; Xu, Liwei; Rui, Xuefang; Zhang, Zhigen, E-mail: srrshurology@163.com

    2015-08-14

    The hepatocyte growth factor and its receptor c-Met are correlated with castration-resistance in prostate cancer. Although HGF has been considered as an attractive target for therapeutic antibodies, the lack of cross-reactivity of monoclonal antibodies with human/mouse HGFs is a major obstacle in preclinical developments. We generated a panel of anti-HGF RabMAbs either blocking HGF/c-Met interaction or inhibiting c-Met phosphorylation. We selected one RabMAb with mouse cross-reactivity and demonstrated that it blocked HGF-stimulated downstream activation in PC-3 and DU145 cells. Anti-HGF RabMAb inhibited not only the growth of PC-3 cells but also HGF-dependent proliferation in HUVECs. We further demonstrated the efficacy and potency of the anti-HGF RabMAb in tumor xenograft mice models. Through these in vitro and in vivo experiments, we explored a novel therapeutic antibody for advanced prostate cancer. - Highlights: • HGF is an attractive target for castration-refractory prostate cancer. • We generated and characterized a panel of anti-HGF rabbit monoclonal antibodies. • More than half of these anti-HGF RabMAbs was cross-reactive with mouse HGF. • Anti-HGF RabMAb blocks HGF-stimulated phosphorylation and cell growth in vitro. • Anti-HGF RabMAb inhibits tumor growth and angiogenesis in xenograft mice.

  12. MicroRNA-376c suppresses non-small-cell lung cancer cell growth and invasion by targeting LRH-1-mediated Wnt signaling pathway.

    Science.gov (United States)

    Jiang, Wenjun; Tian, Ye; Jiang, Shu; Liu, Siyang; Zhao, Xitong; Tian, Dali

    2016-05-13

    MicroRNAs (miRNAs) that negatively regulate gene expression have emerged as novel therapeutic tools for cancer treatment. In this study, we investigated the potential role of Liver receptor homolog-1 (LRH-1), a novel oncogene, in non-small-cell lung cancer (NSCLC), and examined the regulation of LRH-1 by miRNAs. We found that LRH-1 was highly overexpressed in NSCLC cell lines. Knockdown of LRH-1 by small interfering RNA significantly inhibited NSCLC cell growth and invasion. miR-376c directly targeted the 3'-untranslated region (UTR) of LRH-1 and negatively regulated LRH-1 expression, as detected by dual-luciferase reporter assay, real-time quantitative polymerase chain reaction and Western blot analysis. Further data showed that miR-376c expression was inversely correlated with LRH-1 expression in clinical cancer samples. Overexpression of miR-376c could inhibit NSCLC cell growth and invasion as well as Wnt signaling. In contrast, depletion of miR-376c exhibited the opposite effects. Moreover, these effects of miR-376c overexpression were partially abrogated by overexpression of LRH-1. Taken together, these results indicate that LRH-1 is involved in regulating the growth and invasion of NSCLC cells and that miR-376c inhibits NSCLC cell growth and invasion by targeting LRH-1, providing a novel insight into the potential for development of anti-cancer drugs for NSCLC. PMID:27049310

  13. Vascular endothelial growth inhibitor affects the invasion, apoptosis and vascularisation in breast cancer cell line MDA-MB-231

    Institute of Scientific and Technical Information of China (English)

    Gao Yinguang; Ge Zhicheng; Zhang Zhongtao; Bai Zhigang; Ma Xuemei; Wang Yu

    2014-01-01

    Background Breast cancer is one of the most common malignant female diseases worldwide.It is a significant threat to every woman's health.Vascular endothelial growth inhibitor (VEGI) is known to be abundant in endothelial cells.According to previous literature,overexpression of VEGI has been shown to inhibit tumor neovascularisation and progression in cellular and animal models,but there has been limited research on the significance of VEGI in the breast cancer.Methods In our study,cell lines MDA-MB-231 were first constructed in which VEGI mediated by lentivirus over-expressed.The effects of VEGI over-expression on MDA-MB-231 cells were investigated both in vitro and in vivo.The expression of VEGI in the MDA-MB-231 cells after infection of lentivirus was analyzed using real-time PCR and Western blotting.The effect of the biological characteristics of MDA-MB-231 cells was assessed by growth,invasion,adhesion,and migration assay with subcutaneous tumor-bearing nude mice models.Then the growth curves of the subcutaneous tumors were studied.Expressions of VEGI,CD31 and CD34 in the tumors were analyzed by immunohistochemistry and apoptosis was detected by flow cytometry and immunohistochemistry.Results Infection of MDA-MB-231 cells within the lentivirus resulted in approximately a 1 000-fold increase in the expression of VEGI.As can be seen in the invasion,adhesion and migration assay,the over-expression of VEGI can inhibit the ability of MDA-MB-231 cells during migration,adhesion and invasion.The volume of the subcutaneous tumor in the over-expression group was distinctly and significantly less than that of the control groups.Immunohistochemistry analysis of the tumor biopsies cleady showed the expression of VEGI in the over-expression group increased while CD31 and CD34 decreased significantly.In vitro and in vivo,the early apoptosis rate and the apoptosis index were increased within the VEGI over-expression group as compared with the control group.Conclusions Taken

  14. XCR1 promotes cell growth and migration and is correlated with bone metastasis in non-small cell lung cancer

    International Nuclear Information System (INIS)

    Bone metastasis occurs in approximately 30–40% patients with advanced non-small cell lung cancer (NSCLC), but the mechanism underlying this bone metastasis remains poorly understood. The chemokine super family is believed to play an important role in tumor metastasis in lung cancer. The chemokine receptor XCR1 has been identified to promote cell proliferation and migration in oral cancer and ovarian carcinoma, but the role of XCR1 in lung cancer has not been reported. In this study, we demonstrated for the first time that XCR1 was overexpressed in lung cancer bone metastasis as compared with that in patients with primary lung cancer. In addition, the XCR1 ligand XCL1 promoted the proliferation and migration of lung cancer cells markedly, and knockdown of XCR1 by siRNA abolished the effect of XCL1 in cell proliferation and migration. Furthermore, we identified JAK2/STAT3 as a novel downstream pathway of XCR1, while XCL1/XCR1 increased the mRNA level of the downstream of JAK2/STAT3 including PIM1, JunB, TTP, MMP2 and MMP9. These results indicate that XCR1 is a new potential therapeutic target for the treatment of lung cancer bone metastasis. - Highlights: • XCR1 is overexpressed in bone metastasis compared with primary NSCLC. • XCR1 activation by XCL1 promotes lung cancer cell proliferation and migration. • JAK2/STAT3 is a novel potential downstream pathway of XCR1

  15. XCR1 promotes cell growth and migration and is correlated with bone metastasis in non-small cell lung cancer

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Ting; Han, Shuai; Wu, Zhipeng; Han, Zhitao; Yan, Wangjun; Liu, Tielong; Wei, Haifeng; Song, Dianwen; Zhou, Wang, E-mail: brilliant212@163.com; Yang, Xinghai, E-mail: cnspineyang@163.com; Xiao, Jianru, E-mail: jianruxiao83@163.com

    2015-08-21

    Bone metastasis occurs in approximately 30–40% patients with advanced non-small cell lung cancer (NSCLC), but the mechanism underlying this bone metastasis remains poorly understood. The chemokine super family is believed to play an important role in tumor metastasis in lung cancer. The chemokine receptor XCR1 has been identified to promote cell proliferation and migration in oral cancer and ovarian carcinoma, but the role of XCR1 in lung cancer has not been reported. In this study, we demonstrated for the first time that XCR1 was overexpressed in lung cancer bone metastasis as compared with that in patients with primary lung cancer. In addition, the XCR1 ligand XCL1 promoted the proliferation and migration of lung cancer cells markedly, and knockdown of XCR1 by siRNA abolished the effect of XCL1 in cell proliferation and migration. Furthermore, we identified JAK2/STAT3 as a novel downstream pathway of XCR1, while XCL1/XCR1 increased the mRNA level of the downstream of JAK2/STAT3 including PIM1, JunB, TTP, MMP2 and MMP9. These results indicate that XCR1 is a new potential therapeutic target for the treatment of lung cancer bone metastasis. - Highlights: • XCR1 is overexpressed in bone metastasis compared with primary NSCLC. • XCR1 activation by XCL1 promotes lung cancer cell proliferation and migration. • JAK2/STAT3 is a novel potential downstream pathway of XCR1.

  16. Metformin-mediated growth inhibition involves suppression of the IGF-I receptor signalling pathway in human pancreatic cancer cells

    International Nuclear Information System (INIS)

    Epidemiological studies have shown direct associations between type 2 diabetes and obesity, both conditions associated with hyperglycaemia and hyperinsulinemia, and the risk of pancreatic cancer. Up to 80% of pancreatic cancer patients present with either new-onset type 2 diabetes or impaired glucose tolerance at the time of diagnosis. Recent population studies indicate that the incidence of pancreatic cancer is reduced among diabetics taking metformin. In this study, the effects of exposure of pancreatic cancer cells to high glucose levels on their growth and response to metformin were investigated. The human pancreatic cancer cell lines AsPC-1, BxPC-3, PANC-1 and MIAPaCa-2 were grown in normal (5 mM) or high (25 mM) glucose conditions, with or without metformin. The influence by metformin on proliferation, apoptosis and the AMPK and IGF-IR signalling pathways were evaluated in vitro. Metformin significantly reduced the proliferation of pancreatic cancer cells under normal glucose conditions. Hyperglycaemia however, protected against the metformin-induced growth inhibition. The anti-proliferative actions of metformin were associated with an activation of AMP-activated protein kinase AMPKThr172 together with an inhibition of the insulin/insulin-like growth factor-I (IGF-I) receptor activation and downstream signalling mediators IRS-1 and phosphorylated Akt. Furthermore, exposure to metformin during normal glucose conditions led to increased apoptosis as measured by poly(ADP-ribose) polymerase (PARP) cleavage. In contrast, exposure to high glucose levels promoted a more robust IGF-I response and Akt activation which correlated to stimulated AMPKSer485 phosphorylation and impaired AMPKThr172 phosphorylation, resulting in reduced anti-proliferative and apoptotic effects by metformin. Our results indicate that metformin has direct anti-tumour activities in pancreatic cancer cells involving AMPKThr172 activation and suppression of the insulin/IGF signalling pathways

  17. Synergistic Effect of Cold Atmospheric Plasma and Drug Loaded Core-shell Nanoparticles on Inhibiting Breast Cancer Cell Growth

    Science.gov (United States)

    Zhu, Wei; Lee, Se-Jun; Castro, Nathan J.; Yan, Dayun; Keidar, Michael; Zhang, Lijie Grace

    2016-01-01

    Nano-based drug delivery devices allowing for effective and sustained targeted delivery of therapeutic agents to solid tumors have revolutionized cancer treatment. As an emerging biomedical technique, cold atmospheric plasma (CAP), an ionized non-thermal gas mixture composed of various reactive oxygen species, reactive nitrogen species, and UV photons, shows great potential for cancer treatment. Here we seek to develop a new dual cancer therapeutic method by integrating promising CAP and novel drug loaded core-shell nanoparticles and evaluate its underlying mechanism for targeted breast cancer treatment. For this purpose, core-shell nanoparticles were synthesized via co-axial electrospraying. Biocompatible poly (lactic-co-glycolic acid) was selected as the polymer shell to encapsulate anti-cancer therapeutics. Results demonstrated uniform size distribution and high drug encapsulation efficacy of the electrosprayed nanoparticles. Cell studies demonstrated the effectiveness of drug loaded nanoparticles and CAP for synergistic inhibition of breast cancer cell growth when compared to each treatment separately. Importantly, we found CAP induced down-regulation of metastasis related gene expression (VEGF, MTDH, MMP9, and MMP2) as well as facilitated drug loaded nanoparticle uptake which may aid in minimizing drug resistance-a major problem in chemotherapy. Thus, the integration of CAP and drug encapsulated nanoparticles provides a promising tool for the development of a new cancer treatment strategy. PMID:26917087

  18. FHL2 inhibits the Id3-promoted proliferation and invasive growth of human MCF-7 breast cancer cells

    Institute of Scientific and Technical Information of China (English)

    CHEN Yi-hong; WU Zhi-qiang; ZHAO Ya-li; SI Yi-ling; GUO Ming-zhou; HAN Wei-dong

    2012-01-01

    Background Id3 plays a key role in the progression of breast cancer.Previously,four and a half LIM protein (FHL2) was identified as a repressor of Id family proteins by interacting with them.This study aimed to investigate the effects of FHL2 on the transcriptional regulation and oncogenic activities of Id3 in human breast cancer cells.Methods Cell transfection was performed with SuperFect reagent.Stable transfectants that overexpressed Id3 were obtained by selection on G418.The level of Id3 protein was determined by Western blotting analysis.Dual luciferase assays were used to measure the effect of Id3 and FHL2 on E47-mediated transcriptional activity in MCF-7 human breast cancer cells.The MTT assay was used to measure cell proliferation.The transwell assay was used to measure the invasive capacity of MCF-7 cancer cells.Results Id3 markedly repressed transcription mediated by the basic helix-loop-helix (bHLH) factor E47 in MCF-7 cells.This Id3-mediated repression was effectively antagonized by FHL2.Overexpression of Id3 markedly promoted the proliferation and invasive capacity of MCF-7 cells; however,these effects were significantly suppressed by the overexpression of FHL2.Conclusions FHL2 can inhibit the proliferation and invasive growth of human breast cancer cells by repressing the functional activity of Id3.The functional roles of FHL2-1d3 signaling in the development of human breast cancer need further research.

  19. Metformin inhibits pancreatic cancer cell and tumor growth and downregulates Sp transcription factors

    OpenAIRE

    Nair, Vijayalekshmi; Pathi, Satya; Jutooru, Indira; Sreevalsan, Sandeep; Basha, Riyaz; Abdelrahim, Maen; Samudio, Ismael; Safe, Stephen

    2013-01-01

    Metformin is a widely used antidiabetic drug, and epidemiology studies for pancreatic and other cancers indicate that metformin exhibits both chemopreventive and chemotherapeutic activities. Several metformin-induced responses and genes are similar to those observed after knockdown of specificity protein (Sp) transcription factors Sp1, Sp3 and Sp4 by RNA interference, and we hypothesized that the mechanism of action of metformin in pancreatic cancer cells was due, in part, to downregulation o...

  20. Evaluation of transforming growth factor-β1 suppress Pokemon/epithelial-mesenchymal transition expression in human bladder cancer cells.

    Science.gov (United States)

    Li, Wei; Kidiyoor, Amritha; Hu, Yangyang; Guo, Changcheng; Liu, Min; Yao, Xudong; Zhang, Yuanyuan; Peng, Bo; Zheng, Junhua

    2015-02-01

    Transforming growth factor-β1 (TGF-β1) plays a dual role in apoptosis and in proapoptotic responses in the support of survival in a variety of cells. The aim of this study was to determine the function of TGF-β1 in bladder cancer cells and the relationship with POK erythroid myeloid ontogenic factor (Pokemon). TGF-β1 and its receptors mediate several tumorigenic cascades that regulate cell proliferation, migration, and survival of bladder cancer cells. Bladder cancer cells T24 were treated with different levels of TGF-β1. Levels of Pokemon, E-cadherin, Snail, MMP2, MMP9, Twist, VEGF, and β-catenin messenger RNA (mRNA) and protein were examined by real-time quantitative fluorescent PCR and Western blot analysis, respectively. The effects of TGF-β1 on epithelial-mesenchymal transition of T24 cells were evaluated with wound-healing assay, proliferation of T24 was evaluated with reference to growth curves with MTT assay, and cell invasive ability was investigated by Transwell assay. Data show that Pokemon was inhibited by TGF-β1 treatment; the gene and protein of E-cadherin and β-catenin expression level showed decreased markedly after TGF-β1 treatment (P Pokemon, β-catenin, and E-cadherin. The high expression of TGF-β1 leads to an increase in the phenotype and apical-base polarity of epithelial cells. These changes of cells may result in the recurrence and progression of bladder cancer at last. Related mechanism is worthy of further investigation. PMID:25722217

  1. Novel medicinal mushroom blend suppresses growth and invasiveness of human breast cancer cells.

    Science.gov (United States)

    Jiang, Jiahua; Sliva, Daniel

    2010-12-01

    Mushrooms are an integral part of Traditional Chinese Medicine (TCM), and have been used for millennia to prevent or treat a variety of diseases. Currently mushrooms or their extracts are used globally in the form of dietary supplements. In the present study we have evaluated the anticancer effects of the dietary supplement, MycoPhyto® Complex (MC), a novel medicinal mushroom blend which consists of a blend of mushroom mycelia from the species Agaricus blazei, Cordyceps sinensis, Coriolus versicolor, Ganoderma lucidum, Grifola frondosa and Polyporus umbellatus, and β-1,3-glucan isolated from the yeast, Saccharomyces cerevisiae. Here, we show that MC demonstrates cytostatic effects through the inhibition of cell proliferation and cell cycle arrest at the G2/M phase of highly invasive human breast cancer cells MDA-MB-231. DNA-microarray analysis revealed that MC inhibits expression of cell cycle regulatory genes (ANAPC2, ANAPC2, BIRC5, Cyclin B1, Cyclin H, CDC20, CDK2, CKS1B, Cullin 1, E2F1, KPNA2, PKMYT1 and TFDP1). Moreover, MC also suppresses the metastatic behavior of MDA-MB-231 by the inhibition of cell adhesion, cell migration and cell invasion. The potency of MC to inhibit invasiveness of breast cancer cells is linked to the suppression of secretion of the urokinase plasminogen activator (uPA) from MDA-MB-231 cells. In conclusion, the MC dietary supplement could have potential therapeutic value in the treatment of invasive human breast cancer. PMID:21042722

  2. Preparation of epidermal growth factor (EGF) conjugated iron oxide nanoparticles and their internalization into colon cancer cells

    International Nuclear Information System (INIS)

    Epidermal growth factor (EGF) was conjugated with carboxymethyldextran (CMDx) coated iron oxide magnetic nanoparticles using carbodiimide chemistry to obtain magnetic nanoparticles that target the epidermal growth factor receptor (EGFR). Epidermal growth factor modified magnetic nanoparticles were colloidally stable when suspended in biological buffers such as PBS and cell culture media. Both targeted and non-targeted nanoparticles were incubated with CaCo-2 cancer cells, known to overexpress EGFR. Nanoparticle localization within the cell was visualized by confocal laser scanning microscopy and light microscopy using Prussian blue stain. Results showed that targeted magnetic nanoparticles were rapidly accumulated in both flask-shaped small vesicles and large circular endocytic structures. Internalization patterns suggest that both clathrin-dependent and clathrin-independent receptors mediated endocytosis mechanisms are responsible for nanoparticle internalization.

  3. Combined therapy with disintegrin and melphalan as a new strategy in inhibition of endometrial cancer cell line (Ishikawa growth.

    Directory of Open Access Journals (Sweden)

    Wołczyński Sławomir

    2010-01-01

    Full Text Available Endometrial cancer is one of the most frequently diagnosed cancer in females with prevalence of 22 in 100,000 women. The etiology of the cancer remains unclear. Despite significant progress towards understanding the patho-mechanism of the disease, effective treatment is still lacking. The results of the study suggest that combined treatment of Ishikawa cells for 24 h with disintegrin and then for 24 h with melphalan severely inhibits important biological functions of the cells. We showed that such strategy have a potent cytotoxic effect. The mechanism of process undergoes probably through inhibition of integrin - dependent signaling. In this study we shown down regulation of Shc and FAK proteins in cells treated with echistatin and melphalan. It suggests that signaling pathways that involve Shc and FAK participation may represent target for antineoplastic strategy. The functional significance of the combined treatment of Ishikwa cells with echistatin and melphalan was found at the level of collagen biosynthesis. Decreased biosynthesis of collagen in extracellular matrix may suppress cell growth and induce apoptosis. The treatment with echistatin and melphalan also showed decreased expression of IGF receptor in comparison to the cells treated with both compounds separately. The data presented suggest that combined therapy with disintegrin - echistatin and alkyalting drug - mephalan may represent a new approach to more effective and safe cancer therapy.

  4. Acetyl-CoA synthetase 2 promotes acetate utilization and maintains cancer cell growth under metabolic stress.

    Science.gov (United States)

    Schug, Zachary T; Peck, Barrie; Jones, Dylan T; Zhang, Qifeng; Grosskurth, Shaun; Alam, Israt S; Goodwin, Louise M; Smethurst, Elizabeth; Mason, Susan; Blyth, Karen; McGarry, Lynn; James, Daniel; Shanks, Emma; Kalna, Gabriela; Saunders, Rebecca E; Jiang, Ming; Howell, Michael; Lassailly, Francois; Thin, May Zaw; Spencer-Dene, Bradley; Stamp, Gordon; van den Broek, Niels J F; Mackay, Gillian; Bulusu, Vinay; Kamphorst, Jurre J; Tardito, Saverio; Strachan, David; Harris, Adrian L; Aboagye, Eric O; Critchlow, Susan E; Wakelam, Michael J O; Schulze, Almut; Gottlieb, Eyal

    2015-01-12

    A functional genomics study revealed that the activity of acetyl-CoA synthetase 2 (ACSS2) contributes to cancer cell growth under low-oxygen and lipid-depleted conditions. Comparative metabolomics and lipidomics demonstrated that acetate is used as a nutritional source by cancer cells in an ACSS2-dependent manner, and supplied a significant fraction of the carbon within the fatty acid and phospholipid pools. ACSS2 expression is upregulated under metabolically stressed conditions and ACSS2 silencing reduced the growth of tumor xenografts. ACSS2 exhibits copy-number gain in human breast tumors, and ACSS2 expression correlates with disease progression. These results signify a critical role for acetate consumption in the production of lipid biomass within the harsh tumor microenvironment. PMID:25584894

  5. In Vitro Growth Inhibitory Activities of Natural Products from Irciniid Sponges against Cancer Cells: A Comparative Study.

    Science.gov (United States)

    BenRedjem Romdhane, Yosr; Elbour, Monia; Carbone, Marianna; Ciavatta, Maria Letizia; Gavagnin, Margherita; Mathieu, Véronique; Lefranc, Florence; Ktari, Leila; Ben Mustapha, Karim; Boudabous, Abdellatif; Kiss, Robert; Mollo, Ernesto

    2016-01-01

    Marine sponges of the Irciniidae family contain both bioactive furanosesterterpene tetronic acids (FTAs) and prenylated hydroquinones (PHQs). Both classes of compounds are known for their anti-inflammatory, antioxidant, and antimicrobial properties and known to display growth inhibitory effects against various human tumor cell lines. However, the different experimental conditions of the reported in vitro bioassays, carried out on different cancer cell lines within separate studies, prevent realistic actual discrimination between the two classes of compounds from being carried out in terms of growth inhibitory effects. In the present work, a chemical investigation of irciniid sponges from Tunisian coasts led to the purification of three known FTAs and three known PHQs. The in vitro growth inhibitory properties of the six purified compounds have been evaluated in the same experiment in a panel of five human and one murine cancer cell lines displaying various levels of sensitivity to proapoptotic stimuli. Surprisingly, FTAs and PHQs elicited distinct profiles of growth inhibitory-responses, differing by one to two orders of magnitude in favor of the PHQs in all cell lines. The obtained comparative results are discussed in the light of a better selection of drug candidates from natural sources. PMID:27597966

  6. Antiproliferative effect of growth hormone-releasing hormone (GHRH antagonist on ovarian cancer cells through the EGFR-Akt pathway

    Directory of Open Access Journals (Sweden)

    Varga Jozsef

    2010-05-01

    Full Text Available Abstract Background Antagonists of growth hormone-releasing hormone (GHRH are being developed for the treatment of various human cancers. Methods MTT assay was used to test the proliferation of SKOV3 and CaOV3. The splice variant expression of GHRH receptors was examined by RT-PCR. The expression of protein in signal pathway was examined by Western blotting. siRNA was used to block the effect of EGFR. Results In this study, we investigated the effects of a new GHRH antagonist JMR-132, in ovarian cancer cell lines SKOV3 and CaOV3 expressing splice variant (SV1 of GHRH receptors. MTT assay showed that JMR-132 had strong antiproliferative effects on SKOV3 and CaOV3 cells in both a time-dependent and dose-dependent fashion. JMR-132 also induced the activation and increased cleaved caspase3 in a time- and dose-dependent manner in both cell lines. In addition, JMR-132 treatments decreased significantly the epidermal growth factor receptor (EGFR level and the phosphorylation of Akt (p-Akt, suggesting that JMR-132 inhibits the EGFR-Akt pathway in ovarian cancer cells. More importantly, treatment of SKOV3 and CaOV3 cells with 100 nM JMR-132 attenuated proliferation and the antiapoptotic effect induced by EGF in both cell lines. After the knockdown of the expression of EGFR by siRNA, the antiproliferative effect of JMR-132 was abolished in SKOV3 and CaOV3 cells. Conclusions The present study demonstrates that the inhibitory effect of the GHRH antagonist JMR-132 on proliferation is due, in part, to an interference with the EGFR-Akt pathway in ovarian cancer cells.

  7. Inhibition of insulin-like growth factor-1 receptor signaling enhances growth-inhibitory and proapoptotic effects of gefitinib (Iressa) in human breast cancer cells

    International Nuclear Information System (INIS)

    Gefitinib (Iressa, ZD 1839, AstraZeneca) blocks the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) and inhibits proliferation of several human cancer cell types including breast cancer. Phase II clinical trials with gefitinib monotherapy showed an objective response of 9 to 19% in non-small-cell lung cancer patients and less than 10% for breast cancer, and phase III results have indicated no benefit of gefitinib in combination with chemotherapy over chemotherapy alone. In order to improve the antineoplastic activity of gefitinib, we investigated the effects of blocking the signalling of the insulin-like growth factor 1 receptor (IGF-1R), a tyrosine kinase with a crucial role in malignancy that is coexpressed with EGFR in most human primary breast carcinomas. AG1024 (an inhibitor of IGF-1R) was used with gefitinib for treatment of MDA468, MDA231, SK-BR-3, and MCF-7 breast cancer lines, which express similar levels of IGF-1R but varying levels of EGFR. Proliferation assays, apoptosis induction studies, and Western blot analyses were conducted with cells treated with AG1024 and gefitinib as single agents and in combination. Gefitinib and AG1024 reduced proliferation in all lines when used as single agents, and when used in combination revealed an additive-to-synergistic effect on cell growth inhibition. Flow cytometry measurements of cells stained with annexin V-propidium iodide and cells stained for caspase-3 activation indicated that adding an IGF-1R-targeting strategy to gefitinib results in higher levels of apoptosis than are achieved with gefitinib alone. Gefitinib either reduced or completely inhibited p42/p44 Erk kinase phosphorylation, depending on the cell line, while Akt phosphorylation was reduced by a combination of the two agents. Overexpression of IGF-1R in SK-BR-3 cells was sufficient to cause a marked enhancement in gefitinib resistance. These results indicate that IGF-1R signaling reduces the antiproliferative effects of

  8. Targeting the EGFR/PCNA signaling suppresses tumor growth of triple-negative breast cancer cells with cell-penetrating PCNA peptides.

    Directory of Open Access Journals (Sweden)

    Yung-Luen Yu

    Full Text Available Tyrosine 211 (Y211 phosphorylation of proliferation cell nuclear antigen (PCNA coincides with pronounced cancer cell proliferation and correlates with poor survival of breast cancer patients. In epidermal growth factor receptor (EGFR tyrosine kinase inhibitor (TKI-resistant cells, both nuclear EGFR (nEGFR expression and PCNA Y211 phosphorylation are increased. Moreover, the resistance to EGFR TKI is a major clinical problem in treating EGFR-overexpressing triple-negative breast cancer (TNBC. Thus, effective treatment to combat resistance is urgently needed. Here, we show that treatment of cell-penetrating PCNA peptide (CPPP inhibits growth and induces apoptosis of human TNBC cells. The Y211F CPPP specifically targets EGFR and competes directly for PCNA tyrosine Y211 phosphorylation and prevents nEGFR from binding PCNA in vivo; it also suppresses tumor growth by sensitizing EGFR TKI resistant cells, which have enhanced nEGFR function and abrogated classical EGFR membrane signaling. Furthermore, we identify an active motif of CPPP, RFLNFF (RF6 CPPP, which is necessary and sufficient to inhibit TKI-resistant TNBC cell growth of orthotopic implanted tumor in mice. Finally, the activity of its synthetic retro-inverted derivative, D-RF6 CPPP, on an equimolar basis, is more potent than RF6 CPPP. Our study reveals a drug candidate with translational potential for the future development of safe and effective therapeutic for EGFR TKI resistance in TNBC.

  9. Phosphoproteome analysis demonstrates the potential role of THRAP3 phosphorylation in androgen-independent prostate cancer cell growth.

    Science.gov (United States)

    Ino, Yoko; Arakawa, Noriaki; Ishiguro, Hitoshi; Uemura, Hiroji; Kubota, Yoshinobu; Hirano, Hisashi; Toda, Tosifusa

    2016-04-01

    Elucidating the androgen-independent growth mechanism is critical for developing effective treatment strategies to combat androgen-independent prostate cancer. We performed a comparative phosphoproteome analysis using a prostate cancer cell line, LNCaP, and an LNCaP-derived androgen-independent cell line, LNCaP-AI, to identify phosphoproteins involved in this mechanism. We performed quantitative comparisons of the phosphopeptide levels in tryptic digests of protein extracts from these cell lines using MS. We found that the levels of 69 phosphopeptides in 66 proteins significantly differed between LNCaP and LNCaP-AI. In particular, we focused on thyroid hormone receptor associated protein 3 (THRAP3), which is a known transcriptional coactivator of the androgen receptor. The phosphorylation level of THRAP3 was significantly lower at S248 and S253 in LNCaP-AI cells. Furthermore, pull-down assays showed that 32 proteins uniquely bound to the nonphosphorylatable mutant form of THRAP3, whereas 31 other proteins uniquely bound to the phosphorylation-mimic form. Many of the differentially interacting proteins were identified as being involved with RNA splicing and processing. These results suggest that the phosphorylation state of THRAP3 at S248 and S253 might be involved in the mechanism of androgen-independent prostate cancer cell growth by changing the interaction partners. PMID:26841317

  10. 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.

  11. Cytosolic phospholipase A2 activation correlates with HER2 overexpression and mediates estrogen-dependent breast cancer cell growth.

    LENUS (Irish Health Repository)

    Caiazza, Francesco

    2010-05-01

    Cytosolic phospholipase A(2)alpha (cPLA(2)alpha) catalyzes the hydrolysis of membrane glycerol-phospholipids to release arachidonic acid as the first step of the eicosanoid signaling pathway. This pathway contributes to proliferation in breast cancer, and numerous studies have demonstrated a crucial role of cyclooxygenase 2 and prostaglandin E(2) release in breast cancer progression. The role of cPLA(2)alpha activation is less clear, and we recently showed that 17beta-estradiol (E2) can rapidly activate cPLA(2)alpha in MCF-7 breast cancer cells. Overexpression or gene amplification of HER2 is found in approximately 30% of breast cancer patients and correlates with a poor clinical outcome and resistance to endocrine therapy. This study reports the first evidence for a correlation between cPLA(2)alpha enzymatic activity and overexpression of the HER2 receptor. The activation of cPLA(2)alpha in response to E2 treatment was biphasic with the first phase dependent on trans-activation through the matrix metalloproteinase-dependent release of heparin-bound epidermal growth factor. EGFR\\/HER2 heterodimerization resulted in downstream signaling through the ERK1\\/2 cascade to promote cPLA(2)alpha phosphorylation at Ser505. There was a correlation between HER2 and cPLA(2)alpha expression in six breast cancer cell lines examined, and inhibition of HER2 activation or expression in the SKBR3 cell line using herceptin or HER2-specific small interfering RNA, respectively, resulted in decreased activation and expression of cPLA(2)alpha. Pharmacological blockade of cPLA(2)alpha using a specific antagonist suppressed the growth of both MCF-7 and SKBR3 cells by reducing E2-induced proliferation and by stimulating cellular apoptosis and necrosis. This study highlights cPLAalpha(2) as a potential target for therapeutic intervention in endocrine-dependent and endocrine-independent breast cancer.

  12. Activation of Nerve Growth Factor-Induced Bα by Methylene-Substituted Diindolylmethanes in Bladder Cancer Cells Induces Apoptosis and Inhibits Tumor GrowthS⃞

    OpenAIRE

    Dae Cho, Sung; Lee, Syng-Ook; Chintharlapalli, Sudhakar; Abdelrahim, Maen; Khan, Shaheen; Yoon, Kyungsil; Kamat, Ashish M.; Safe, Stephen

    2010-01-01

    Nerve growth factor-induced B (NGFI-B) genes are orphan nuclear receptors, and NGFI-Bα (Nur77, TR3) is overexpressed in bladder tumors and bladder cancer cells compared with nontumorous bladder tissue. 1,1-Bis(3′-indolyl)-1-(p-methoxyphenyl)-methane (DIM-C-pPhOCH3) and 1,1-bis(3′-indolyl)-1-(p-phenyl)methane have previously been identified as activators of Nur77, and both compound...

  13. Tumor growth effects of rapamycin on human biliary tract cancer cells

    Directory of Open Access Journals (Sweden)

    Heuer Matthias

    2012-06-01

    Full Text Available Abstract Background Liver transplantation is an important treatment option for patients with liver-originated tumors including biliary tract carcinomas (BTCs. Post-transplant tumor recurrence remains a limiting factor for long-term survival. The mammalian target of rapamycin-targeting immunosuppressive drug rapamycin could be helpful in lowering BTC recurrence rates. Therein, we investigated the antiproliferative effect of rapamycin on BTC cells and compared it with standard immunosuppressants. Methods We investigated two human BTC cell lines. We performed cell cycle and proliferation analyses after treatment with different doses of rapamycin and the standard immunosuppressants, cyclosporine A and tacrolimus. Results Rapamycin inhibited the growth of two BTC cell lines in vitro. By contrast, an increase in cell growth was observed among the cells treated with the standard immunosuppressants. Conclusions These results support the hypothesis that rapamycin inhibits BTC cell proliferation and thus might be the preferred immunosuppressant for patients after a liver transplantation because of BTC.

  14. The Frequency of Epidermal Growth Factor Receptor Mutation of Nonsmall Cell Lung Cancer according to the Underlying Pulmonary Diseases

    Directory of Open Access Journals (Sweden)

    Kazuhiro Usui

    2011-01-01

    Full Text Available Background. Although epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs are effective in patients with nonsmall cell lung cancer with epidermal growth factor receptor (EGFR mutation, EGFR-TKIs have a risk of inducing fatal interstitial lung disease (ILD. The selection of chemotherapy based on the EGFR mutation status is recommended, however, the frequency of EGFR mutation in patients with ILD and the efficacy and safety of EGFR-TKI in patients with ILD and EGFR mutation are unknown. Methods. We retrospectively reviewed the association of the EGFR mutation status of nonsmall cell lung cancer and pulmonary diseases. Based on high-resolution computed tomography (HRCT performed at diagnosis of lung cancer, patients were categorized into three groups: normal, emphysema, and fibrosis. Results. Of 198 patients with nonsmall cell lung cancer, we identified 52 (26.3% patients with an EGFR mutation. EGFR mutations were identified in 43 (35.2% of 122 patients with normal lungs, 8 (13.6% of 59 with emphysema, and 1 (5.9% of 17 with pulmonary fibrosis. Of the 52 patients with EGFR mutation, 43 patients received gefitinib. One patient with an EGFR mutation and fibrosis developed fatal ILD. There was not a significant difference in median overall survival from gefitinib treatment between never-smokers and smokers (797 days versus not reached; =0.96. Conclusions. Patients with sensitive EGFR mutation and normal lungs may benefit from an EGFR-TKI treatment even if they have smoking history.

  15. Effect of the knockdown of death-associated protein 1 expression on cell adhesion, growth and migration in breast cancer cells.

    Science.gov (United States)

    Wazir, Umar; Sanders, Andrew J; Wazir, Ali; Baig, Ruqia Mehmood; Jiang, Wen G; Ster, Irina C; Sharma, Anup K; Mokbel, Kefah

    2015-03-01

    Death-associated protein 1 (DAP1) is a highly conserved phosphoprotein involved in the regulation of autophagy. A previous clinical study by our group suggested an association between low DAP1 expression and clinicopathological parameters of human breast cancer. In the present study, we aimed to determine the role of DAP1 in cancer cell behaviour in the context of human breast cancer. We developed knockdown sublines of MCF7 and MDA-MB‑231, and performed growth, adhesion and invasion assays and electric cell-substrate impedance sensing (ECIS) studies of the post-wound migration of cells. In addition, we studied the mRNA expression of caspase 8 and 9, DELE, IPS1, cyclin D1 and p21 in the control and knockdown sublines. Knockdown was associated with increased adhesion and migration, significantly so in the MDA-MB-231DAP1kd cell subline (p=0.029 and p=0.001, respectively). Growth in MCF7 cells showed a significant suppression on day 3 (p=0.029), followed by an increase in growth matching the controls on day 5. While no change in the apoptotic response to serum starvation could be attributed to DAP1 knockdown, the expression of known components of the apoptosis pathway (caspase 8) and cell cycle (p21) was significantly reduced in the MCF7DAP1kd cell subline (p≤0.05), while in MDA-MB-231DAP1kd the expression of a pro-apoptotic molecule, IPS1, was suppressed (p≤0.05). DAP1 may have an important role in cell adhesion, migration and growth in the context of breast cancer and has significant associations with the apoptosis pathway. Furthermore, we believe that delayed increase in growth observed in the MCF7DAP1kd cell subline may indicate activation of a strongly pro-oncogenic pathway downstream of DAP1. PMID:25530065

  16. Inhibitory Effect of CT120B, an Alternative Splice Variant of CT120A,on Lung Cancer Cell Growth

    Institute of Scientific and Technical Information of China (English)

    Dong-Ning PAN; Jin-Jun LI; Lin WEI; Ming YAO; Da-Fang WAN; Jian-Ren GU

    2005-01-01

    The expression product of ct120a, a novel gene isolated from human chromosome 17p13.3in our laboratory, was predicted to have seven transmembrane domains and could cause malignant transformation of mouse NIH3T3 cells. There existed an mRNA splicing variant of ct120a, namely ct120b,which had a 96-nucleotide deletion and produced an in-frame loss of 32 amino acids from codon 136 to codon 167 of CT120A. The CT120B protein was predicted to have six transmembrane domains. In this study, we observed that the green fluorescent protein-tagged CT120B was localized on plasma membrane and in cytoplasm in SPC-A-1 cells. The expression of CT120B/A in normal lung tissue and in lung cancer cells was also examined. Results showed that the stable CT120B overexpression in SPC-A-1 cells resulted in a reduction of cell growth rate, and inhibited tumorigenecity and anchorage-independent growth in nude mice. The functions of CT120A and CT120B for cell growth appeared antagonistic. We suggested that the delayed G1/S phase transition might contribute to the inhibitory activities of CT120B on cell growth and that the deleted 32 amino acids missing in CT120B might be essential for the oncogenetic activities of CT120A.

  17. CCL21/CCR7 up-regulate vascular endothelial growth factor-D expression via ERK pathway in human non-small cell lung cancer cells

    OpenAIRE

    Sun, Limei; Zhang, Qingfu; LI Yang; Tang, Na; Qiu, Xueshan

    2015-01-01

    Lymphangiogenesis has received considerable attention and become a new research hotspot of tumor metastasis. Recently, C-C chemokine receptor 7 (CCR7) is known to promote metastasis of non-small cell lung cancer (NSCLC) cells into lymph nodes. In this study, we investigated the relationship between CCL21/CCR7 and the lymphangiogenic factor vascular endothelial growth factor (VEGF)-D in human lung cancer cells and its impact on patients’ prognosis. We found that CCL21/CCR7 increase the express...

  18. Macroscopic dynamics of cancer growth

    Science.gov (United States)

    Menchón, S. A.; Condat, C. A.

    2007-04-01

    Macroscopic modeling is used to describe various aspects of cancer growth. A recently proposed “dysnamical exponent” hypothesis is critically examined in the context of the angiogenic development. It is also shown that the emergence of necroses facilitates the growth of avascular tumors; the model yields an excellent fit to available experimental data, allowing for the determination of growth parameters. Finally, the global effects of an applied antitumoral immunotherapy are investigated. It is shown that, in the long run, the application of a therapeutical course leads to bigger tumors by weakening the intraspecific competition between surviving viable cancer cells. The strength of this model lies in its simplicity and in the amount of information that can be gleaned using only very general ideas.

  19. Effects of darbufelone on the growth of tumor xenograft with SGC-7901 gastric cancer cells in nude mouse

    Directory of Open Access Journals (Sweden)

    Xiao-meng XU

    2011-02-01

    Full Text Available Objective To evaluate the effect of darbufelone,a 5-lipoxygenase/cyclooxygenase-2(5-LOX/COX-2 dual inhibitor,on the growth of subcutaneous tumor xenograft of SGC-7901 gastric cancer cells and its mechanism.Methods The xenograft model of human gastric carcinoma with SGC-7901 gastric cancer cells was reproduced in nude mice.Fourteen nude mice were randomly divided into the darbufelone group and the control group(7 each.The mice were consecutively given intragastric administration with 45mg/(kg d darbufelone in darbufelone group,or NS in control group for 4 weeks.The tumor volume in each group was measured regularly,and the tumor growth inhibition was calculated.The xenograft,liver,kidneys,spleen and lungs of nude mice were observed pathologically after HE staining.The expressions of mRNA and protein of 5-LOX,COX-2,PCNA,Bcl-2 and caspase-3 in transplanted tumor were detected by RT-PCR and immunohistochemistry.Results Darbufelone showed significant inhibitory effects,with an inhibition ratio of 58.42%,on the growth of tumor xenograft in vivo.The volume and weight of tumor in darbufelone group decreased significantly compared with that in control group(P < 0.05.Darbufelone inhibited the growth of tumor xenograft with no adverse effect.Immunohistochemistry and RT-PCR analyses showed that darbufelone effectively inhibited the expression of mRNA and protein of 5-LOX,COX-2,PCNA,Bcl-2,while increased the expression of caspase-3 compared with that in the control group(P < 0.05.Conclusions Darbufelone can inhibit the growth of gastric carcinoma in vivo,the mechanism may be related to inhibition of growth of cancer cells and the induction of apoptosis.

  20. A novel long noncoding RNA AK001796 acts as an oncogene and is involved in cell growth inhibition by resveratrol in lung cancer

    Energy Technology Data Exchange (ETDEWEB)

    Yang, Qiaoyuan [Institute for Chemical Carcinogenesis, State Key Laboratory of Respiratory Diseases, Guangzhou Medical University, Guangzhou 510182 (China); Xu, Enwu [Department of Thoracic Surgery, General Hospital of Guangzhou Military Command of Chinese People' s Liberation Army, Guangzhou 510010 (China); Dai, Jiabin; Liu, Binbin; Han, Zhiyuan; Wu, Jianjun; Zhang, Shaozhu; Peng, Baoying [Institute for Chemical Carcinogenesis, State Key Laboratory of Respiratory Diseases, Guangzhou Medical University, Guangzhou 510182 (China); Zhang, Yajie [Department of Pathology, Guangzhou Medical University, Guangzhou 510182 (China); Jiang, Yiguo, E-mail: jiangyiguo@vip.163.com [Institute for Chemical Carcinogenesis, State Key Laboratory of Respiratory Diseases, Guangzhou Medical University, Guangzhou 510182 (China)

    2015-06-01

    Lung cancer is the most common form of cancer throughout the world. The specific targeting of long noncoding RNAs (lncRNAs) by resveratrol opened a new avenue for cancer chemoprevention. In this study, we found that 21 lncRNAs were upregulated and 19 lncRNAs were downregulated in lung cancer A549 cells with 25 μmol/L resveratrol treatment determined by microarray analysis. AK001796, the lncRNA with the most clearly altered expression, was overexpressed in lung cancer tissues and cell lines, but its expression was downregulated in resveratrol-treated lung cancer cells. By monitoring cell proliferation and growth in vitro and tumor growth in vivo, we observed a significant reduction in cell viability in lung cancer cells and a slow growth in the tumorigenesis following AK001796 knockdown. We also found that AK001796 knockdown caused a cell-cycle arrest, with significant increases in the percentage of cells in G{sub 0}/G{sub 1} in lung cancer cells. By using cell cycle pathway-specific PCR arrays, we detected changes in a number of cell cycle-related genes related to lncRNA AK001796 knockdown. We further investigated whether AK001796 participated in the anticancer effect of resveratrol and the results showed that reduced lncRNA AK001796 level potentially impaired the inhibitory effect of resveratrol on cell proliferation. To our knowledge, this is the first study to report the changes in an lncRNA expression profile induced by resveratrol in lung cancer. - Highlights: • LncRNA AK001796 played an oncogenic role in lung carcinogenesis. • LncRNA AK001796 was downregulated in resveratrol-treated lung cancer cells. • LncRNA AK001796 was involved in the inhibition of cell growth by resveratrol.

  1. A novel long noncoding RNA AK001796 acts as an oncogene and is involved in cell growth inhibition by resveratrol in lung cancer

    International Nuclear Information System (INIS)

    Lung cancer is the most common form of cancer throughout the world. The specific targeting of long noncoding RNAs (lncRNAs) by resveratrol opened a new avenue for cancer chemoprevention. In this study, we found that 21 lncRNAs were upregulated and 19 lncRNAs were downregulated in lung cancer A549 cells with 25 μmol/L resveratrol treatment determined by microarray analysis. AK001796, the lncRNA with the most clearly altered expression, was overexpressed in lung cancer tissues and cell lines, but its expression was downregulated in resveratrol-treated lung cancer cells. By monitoring cell proliferation and growth in vitro and tumor growth in vivo, we observed a significant reduction in cell viability in lung cancer cells and a slow growth in the tumorigenesis following AK001796 knockdown. We also found that AK001796 knockdown caused a cell-cycle arrest, with significant increases in the percentage of cells in G0/G1 in lung cancer cells. By using cell cycle pathway-specific PCR arrays, we detected changes in a number of cell cycle-related genes related to lncRNA AK001796 knockdown. We further investigated whether AK001796 participated in the anticancer effect of resveratrol and the results showed that reduced lncRNA AK001796 level potentially impaired the inhibitory effect of resveratrol on cell proliferation. To our knowledge, this is the first study to report the changes in an lncRNA expression profile induced by resveratrol in lung cancer. - Highlights: • LncRNA AK001796 played an oncogenic role in lung carcinogenesis. • LncRNA AK001796 was downregulated in resveratrol-treated lung cancer cells. • LncRNA AK001796 was involved in the inhibition of cell growth by resveratrol

  2. Metformin selectively targets cancer stem cells, and acts together with chemotherapy to block tumor growth and prolong remission

    OpenAIRE

    Hirsch, Heather A; Iliopoulos, Dimitrios; Tsichlis, Philip N.; Struhl, Kevin

    2009-01-01

    The cancer stem cell hypothesis suggests that, unlike most cancer cells within a tumor, cancer stem cells resist chemotherapeutic drugs and can regenerate the various cell types in the tumor, thereby causing relapse of the disease. Thus, drugs that selectively target cancer stem cells offer great promise for cancer treatment, particularly in combination with chemotherapy. Here, we show that low doses of metformin, a standard drug for diabetes, inhibits cellular transformation and selectively ...

  3. ShRNA-mediated gene silencing of β-catenin inhibits growth of human colon cancer cells

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    AIM: To observe the gene silencing mediated by the specific shRNA targeted against β-catenin and its effect on cell proliferation and cycle distribution in the human colon cancer cell line Colo205.METHODS: Two shRNA plasmid vectors against β-catenin were constructed and transfected into Colo205 cells with LipofectamineTM2000. The down-regulations of β-catenin, c-myc and cyclinD1 expressions were detected by RT-PCR and western blot analysis. The cell proliferation inhibitions were determined by MTT assay and soft agar colony formation assay. The effect of these two β-catenin shRNAs on cell cycle distribution and apoptosis was examined by flow cytometry.RESULTS: These two shRNA vectors targeted against β-catenin efficiently suppressed the expression of β-catenin and its down stream genes, c-myc and cyclinD1. The expression inhibition rates were around 40%-50% either at the mRNA or at the protein level.The shRNA-mediated gene silencing of β-catenin resulted in significant inhibition of cell growth both on the culture plates and in the soft agar. Moreover, the cancer cells showed significant G0/G1 arrest and increased apoptosis at 72 h post transfection due to gene silencing.CONCLUSION: These specific shRNAs targeted against β-catenin could have a gene silencing effect and block the WNT signaling pathway. They could inhibit cell growth, increase apoptosis, and induce cell cycle arrest in Colo205 cells. ShRNA interference against β-catenin is of potential value in gene therapy of colon cancer.

  4. Transforming growth factor-beta signaling network regulates plasticity and lineage commitment of lung cancer cells

    OpenAIRE

    Ischenko, I; Liu, J.; Petrenko, O; Hayman, M J

    2014-01-01

    Identification of target cells in lung tumorigenesis and characterization of the signals that control their behavior is an important step toward improving early cancer diagnosis and predicting tumor behavior. We identified a population of cells in the adult lung that bear the EpCAM+CD104+CD49f+CD44+CD24loSCA1+ phenotype and can be clonally expanded in culture, consistent with the properties of early progenitor cells. We show that these cells, rather than being restricted to one tumor type, ca...

  5. Molecular decoy to the Y-box binding protein-1 suppresses the growth of breast and prostate cancer cells whilst sparing normal cell viability.

    Directory of Open Access Journals (Sweden)

    Jennifer H Law

    Full Text Available The Y-box binding protein-1 (YB-1 is an oncogenic transcription/translation factor that is activated by phosphorylation at S102 whereby it induces the expression of growth promoting genes such as EGFR and HER-2. We recently illustrated by an in vitro kinase assay that a novel peptide to YB-1 was highly phosphorylated by the serine/threonine p90 S6 kinases RSK-1 and RSK-2, and to a lesser degree PKCα and AKT. Herein, we sought to develop this decoy cell permeable peptide (CPP as a cancer therapeutic. This 9-mer was designed as an interference peptide that would prevent endogenous YB-1(S102 phosphorylation based on molecular docking. In cancer cells, the CPP blocked P-YB-1(S102 and down-regulated both HER-2 and EGFR transcript level and protein expression. Further, the CPP prevented YB-1 from binding to the EGFR promoter in a gel shift assay. Notably, the growth of breast (SUM149, MDA-MB-453, AU565 and prostate (PC3, LNCap cancer cells was inhibited by ∼90% with the CPP. Further, treatment with this peptide enhanced sensitivity and overcame resistance to trastuzumab in cells expressing amplified HER-2. By contrast, the CPP had no inhibitory effect on the growth of normal immortalized breast epithelial (184htert cells, primary breast epithelial cells, nor did it inhibit differentiation of hematopoietic progenitors. These data collectively suggest that the CPP is a novel approach to suppressing the growth of cancer cells while sparing normal cells and thereby establishes a proof-of-concept that blocking YB-1 activation is a new course of cancer therapeutics.

  6. Abrogation of Gli3 expression suppresses the growth of colon cancer cells via activation of p53

    Energy Technology Data Exchange (ETDEWEB)

    Kang, Han Na [Graduate School of Medicine, Korea University College of Medicine, Korea University, Seoul 136-705 (Korea, Republic of); Oh, Sang Cheul; Kim, Jun Suk [Division of Oncology/Hematology, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul 136-705 (Korea, Republic of); Yoo, Young A., E-mail: ydanbi@korea.ac.kr [Brain Korea 21 Program for Biomedical Science, Korea University College of Medicine, Korea University, Seoul 136-705 (Korea, Republic of)

    2012-03-10

    p53, the major human tumor suppressor, appears to be related to sonic hedgehog (Shh)-Gli-mediated tumorigenesis. However, the role of p53 in tumor progression by the Shh-Gli signaling pathway is poorly understood. Herein we investigated the critical regulation of Gli3-p53 in tumorigenesis of colon cancer cells and the molecular mechanisms underlying these effects. RT-PCR analysis indicated that the mRNA level of Shh and Gli3 in colon tumor tissues was significantly higher than corresponding normal tissues (P < 0.001). The inhibition of Gli3 by treatment with Gli3 siRNA resulted in a clear decrease in cell proliferation and enhanced the level of expression of p53 proteins compared to treatment with control siRNA. The half-life of p53 was dramatically increased by treatment with Gli3 siRNA. In addition, treatment with MG132 blocked MDM2-mediated p53 ubiquitination and degradation, and led to accumulation of p53 in Gli3 siRNA-overexpressing cells. Importantly, ectopic expression of p53 siRNA reduced the ability of Gli3 siRNA to suppress proliferation of those cells compared with the cells treated with Gli3 siRNA alone. Moreover, Gli3 siRNA sensitized colon cancer cells to treatment with anti-cancer agents (5-FU and bevacizumab). Taken together, our studies demonstrate that loss of Gli3 signaling leads to disruption of the MDM2-p53 interaction and strongly potentiate p53-dependent cell growth inhibition in colon cancer cells, indicating a basis for the rational use of Gli3 antagonists as a novel treatment option for colon cancer.

  7. Abrogation of Gli3 expression suppresses the growth of colon cancer cells via activation of p53

    International Nuclear Information System (INIS)

    p53, the major human tumor suppressor, appears to be related to sonic hedgehog (Shh)–Gli-mediated tumorigenesis. However, the role of p53 in tumor progression by the Shh–Gli signaling pathway is poorly understood. Herein we investigated the critical regulation of Gli3–p53 in tumorigenesis of colon cancer cells and the molecular mechanisms underlying these effects. RT-PCR analysis indicated that the mRNA level of Shh and Gli3 in colon tumor tissues was significantly higher than corresponding normal tissues (P < 0.001). The inhibition of Gli3 by treatment with Gli3 siRNA resulted in a clear decrease in cell proliferation and enhanced the level of expression of p53 proteins compared to treatment with control siRNA. The half-life of p53 was dramatically increased by treatment with Gli3 siRNA. In addition, treatment with MG132 blocked MDM2-mediated p53 ubiquitination and degradation, and led to accumulation of p53 in Gli3 siRNA-overexpressing cells. Importantly, ectopic expression of p53 siRNA reduced the ability of Gli3 siRNA to suppress proliferation of those cells compared with the cells treated with Gli3 siRNA alone. Moreover, Gli3 siRNA sensitized colon cancer cells to treatment with anti-cancer agents (5-FU and bevacizumab). Taken together, our studies demonstrate that loss of Gli3 signaling leads to disruption of the MDM2–p53 interaction and strongly potentiate p53-dependent cell growth inhibition in colon cancer cells, indicating a basis for the rational use of Gli3 antagonists as a novel treatment option for colon cancer.

  8. Co-inhibition of epidermal growth factor receptor and insulin-like growth factor receptor 1 enhances radiosensitivity in human breast cancer cells

    International Nuclear Information System (INIS)

    Over-expression of epidermal growth factor receptor (EGFR) or insulin-like growth factor-1 receptor (IGF-1R) have been shown to closely correlate with radioresistance of breast cancer cells. This study aimed to investigate the impact of co-inhibition of EGFR and IGF-1R on the radiosensitivity of two breast cancer cells with different profiles of EGFR and IGF-1R expression. The MCF-7 (EGFR +/−, IGF-1R +++) and MDA-MB-468 (EGFR +++, IGF-1R +++) breast cancer cell lines were used. Radiosensitizing effects were determined by colony formation assay. Apoptosis and cell cycle distribution were measured by flow cytometry. Phospho-Akt and phospho-Erk1/2 were quantified by western blot. In vivo studies were conducted using MDA-MB-468 cells xenografted in nu/nu mice. In MDA-MB-468 cells, the inhibition of IGF-1R upregulated the p-EGFR expression. Either EGFR (AG1478) or IGF-1R inhibitor (AG1024) radiosensitized MDA-MB-468 cells. In MCF-7 cells, radiosensitivity was enhanced by AG1024, but not by AG1478. Synergistical radiosensitizing effect was observed by co-inhibition of EGFR and IGF-1R only in MDA-MB-468 cells with a DMF10% of 1.90. The co-inhibition plus irradiation significantly induced more apoptosis and arrested the cells at G0/G1 phase in MDA-MB-468 cells. Only co-inhibition of EGFR and IGF-1R synergistically diminished the expression of p-Akt and p-Erk1/2 in MDA-MB-468 cells. In vivo studies further verified the radiosensitizing effects by co-inhibition of both pathways in a MDA-MB-468 xenograft model. Our data suggested that co-inhibition of EGFR and IGF-1R synergistically radiosensitized breast cancer cells with both EGFR and IGF-1R high expression. The approach may have an important therapeutic implication in the treatment of breast cancer patients with high expression of EGFR and IGF-1R

  9. Contributions of the Epidermal Growth Factor Receptor to Acquisition of Platinum Resistance in Ovarian Cancer Cells

    OpenAIRE

    Granados, Michaela L.; Hudson, Laurie G.; Samudio-Ruiz, Sabrina L.

    2015-01-01

    Acquisition of platinum resistance following first line platinum/taxane therapy is commonly observed in ovarian cancer patients and prevents clinical effectiveness. There are few options to prevent platinum resistance; however, demethylating agents have been shown to resensitize patients to platinum therapy thereby demonstrating that DNA methylation is a critical contributor to the development of platinum resistance. We previously reported the Epidermal Growth Factor Receptor (EGFR) is a nove...

  10. Growth arrest and apoptosis via caspase activation of dioscoreanone in human non-small-cell lung cancer A549 cells

    OpenAIRE

    Hansakul, Pintusorn; Aree, Kalaya; Tanuchit, Sermkiat; Itharat, Arunporn

    2014-01-01

    Background Dioscoreanone (DN) isolated from Dioscorea membranacea Pierre has been reported to exert potent cytotoxic effects against particular types of cancer. The present study was carried out to investigate the cytotoxicity of DN against a panel of different human lung cancer cell lines. The study further examined the underlying mechanisms of its anticancer activity in the human lung adenocarcinoma cell line A549. Methods Antiproliferative effects of DN were determined by SRB and CFSE assa...

  11. Insulin-like growth factor I stimulates telomerase activity in prostate cancer cells.

    Science.gov (United States)

    Wetterau, Lawrence A; Francis, Malik J; Ma, Liqun; Cohen, Pinchas

    2003-07-01

    IGF-I has been implicated in the pathogenesis of human cancer. We sought to establish a role for IGF-I in the regulation of telomerase, an enzyme critically involved in cancer cell immortalization. Telomerase activity was assayed in LAPC-4, PC-3, and DU-145 prostate cancer cell lines treated with and without IGF-I/IGF-I analogs. Relative expression of human telomerase reverse transcriptase (hTERT) mRNA and protein was determined by quantitative RT-PCR and Western immunoblot, respectively. IGF-I stimulated baseline telomerase activity in all three cell lines, ranging from 2- to 10-fold (P IGF concentrations as low as 10 ng/ml and was maximal at 100 ng/ml. Stimulation was noted by 0.5 h, was maximal by 8 h, and persisted to 48 h. A similar 3-fold enhancement (P Long-R3 IGF-I, but not in response to [Ala(31),Leu(60)]IGF-I. Pretreatment with the Akt kinase inhibitor wortmannin abolished the stimulatory IGF effect, whereas blockade of MAPK activity did not. Lastly, IGF-I provoked a 2-fold increase in hTERT mRNA and protein expression (P IGF-I clearly stimulates telomerase activity in prostate cancer cells through a dual mode of action, including early rapid effects probably involving phosphorylation of hTERT by Akt and later up-regulation of hTERT expression. PMID:12843187

  12. S-Adenosylmethionine Inhibits the Growth of Cancer Cells by Reversing the Hypomethylation Status of c-myc and H-ras in Human Gastric Cancer and Colon Cancer

    Directory of Open Access Journals (Sweden)

    Jin Luo, Yan-Ni Li, Fei Wang, Wei-Ming Zhang, Xin Geng

    2010-01-01

    Full Text Available A global DNA hypomethylation might activate oncogene transcription, thus promoting carcinogenesis and tumor development. S-Adenosylmethionine (SAM serves as a major methyl donor in biological transmethylation events. The object of this study is to explore the influence of SAM on the status of methylation at the promoter of the oncogenes c-myc, H-ras and tumor-suppressor gene p16 (INK4a, as well as its inhibitory effect on cancer cells. The results indicated that SAM treatment inhibited cell growth in gastric cancer cells and colon cancer cells, and the inhibition efficiency was significantly higher than that in the normal cells. Under standard growth conditions, C-myc and H-ras promoters were hypomethylated in gastric cancer cells and colon cancer cells. SAM treatment resulted in a heavy methylation of these promoters, which consequently downregulated mRNA and protein levels. In contrast, there was no significant difference in mRNA and protein levels of p16 (INK4a with and without SAM treatment. SAM can effectively inhibit the tumor cells growth by reversing the DNA hypomethylation on promoters of oncogenes, thus down-regulating their expression. With no influence on the expression of the tumor suppressor genes, such as P16, SAM could be used as a potential drug for cancer therapy.

  13. Expression and clinical significance of dendritic cell and transforming growth factor-beta 1 in cervical cancer

    Institute of Scientific and Technical Information of China (English)

    Zhao; Shan; Rong; Fengnian

    2006-01-01

    Objective:To explore the density and mature status of Dendritic cell(DC) in cervical cancer and correlation with the expression of transforming growth factor-beta 1(TGF-β1).Methods:Streptavidin-peroxidase(SP) immunohistochemistry methods were used to detect S-100 DC and the expression of TGF-β1 in 20 normal cervical tissues and 53 cervical cancer tissues without any sort of chemotherapy or radiation therapy prior to resection.Medical records were reviewed,clinicopathological variables were retrieved and used for analysis.Results:Two types of DC were observed under the microscope.The expression of DC in cervical cancer was significantly higher than that in normal tissues(23.34 cells/mm2 vs 29.91 cells/mm2,P<0.05),and significantly higher in early stage than that in advanced stage(P<0.05).The expression of TGF-β1 was significantly higher in cervical cancer than that in normal tissues (P<0.025).However,there was no correaction between TGF-β1 and lymph nodes metastasis.The index of DC in cervical cancer was negatively correlated to the expression of TGF-β1 in tumor cells (r=-0.8875,P=0.0001).Conclusion:Maturation of DC in cervical cancer is inhibited.The decreased number of DC and the higher expression of TGF-β1 are due to the failure of the immunity,these may play an important role in the development of the cervical cancer.

  14. Pre-osteoblastic MC3T3-E1 cells promote breast cancer growth in bone in a murine xenograft model

    Institute of Scientific and Technical Information of China (English)

    Thomas M. Bodenstine; Benjamin H. Beck; Xuemei Cao; Leah M. Cook; Aimen Ismai; J. Kent Powers; Andrea M. Mastro; Danny R. Welch

    2011-01-01

    The bones are the most common sites of breast cancer metastasis. Upon arrival within the bone microenvironment, breast cancer cells coordinate the activities of stromal cells, resulting in an increase in osteoclast activity and bone matrix degradation. In late stages of bone metastasis, breast cancer cells induce apoptosis in osteoblasts, which further exacerbates bone loss. However, in early stages, breast cancer cells induce osteoblasts to secrete inflammatory cytokines purported to drive tumor progression. To more thoroughly evaluate the role of osteoblasts in early stages of breast cancer metastasis to the bones, we used green fluorescent protein-labeled human breast cancer cell lines MDA-MB-231 and MDA-MB-435, which both induce osteolysis after intra-femoral injection in athymic mice, and the murine pre-osteoblastic cell line MC3T3-E1 to modulate osteoblast populations at the sites of breast cancer metastasis. Breast cancer cells were injected directly into the femur with or without equal numbers of MC3T3-E1 cells. Tumors grew significantly larger when co-injected with breast cancer cells and MC3T3-E1 cells than injected with breast cancer cells alone. Osteolysis was induced in both groups, indicating that MC3T3-E1 cells did not block the ability of breast cancer cells to cause bone destruction. MC3T3-E1 cells promoted tumor growth out of the bone into the extraosseous stroma. These data suggest that breast cancer cells and osteoblasts communicate during early stages of bone metastasis and promote tumor growth.

  15. AZD9291 in epidermal growth factor receptor inhibitor—resistant non-small-cell lung cancer

    Science.gov (United States)

    2016-01-01

    Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in advanced EGFR mutant non-small cell lung cancer have an objective response rate (ORR) of approximately 60–70% and a median progression free-survival (PFS) of approximately 10-13 months. Studies of tumor biopsies performed after progression on EGFR TKI revealed that 50-60% of EGFR mutant NSCLC developed an EGFR exon 20 T790M mutation as a mechanism of acquired resistance. AZD9291 is a third generation irreversible EGFR TKI with activity against the activating EGFR mutation, the T790M acquired resistance mutation, and relative sparing of the wild-type EGFR. AZD9291 was investigated in a phase I trial with expansion cohorts in patients with disease progression after EGFR TKI. Patients with and without detectable T790M mutations were enrolled in the trial. The ORR in patients with centrally confirmed and without detectable T790M mutations was 61% (95% CI, 52–70%) and 21% (95% CI, 12–34%), respectively. The PFS observed in patients with centrally confirmed and without detectable T790M mutations was 9.6 months (95% CI, 8.3 to not reached) and 2.8 months (95% CI, 2.1–4.3 months), respectively. At the dose for further investigation, 80 mg daily, the rate of all grade 3-5 drug related adverse events was 11%, and the rates of grade 3 diarrhea and rash were 1% and 0%, respectively. The identification of the T790M resistance mutation and the subsequent development of an agent against the mechanism of resistance provide a template for future drug development for acquired resistance to targeted therapy. PMID:26958499

  16. AZD9291 in epidermal growth factor receptor inhibitor-resistant non-small-cell lung cancer.

    Science.gov (United States)

    Stinchcombe, Thomas E

    2016-02-01

    Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in advanced EGFR mutant non-small cell lung cancer have an objective response rate (ORR) of approximately 60-70% and a median progression free-survival (PFS) of approximately 10-13 months. Studies of tumor biopsies performed after progression on EGFR TKI revealed that 50-60% of EGFR mutant NSCLC developed an EGFR exon 20 T790M mutation as a mechanism of acquired resistance. AZD9291 is a third generation irreversible EGFR TKI with activity against the activating EGFR mutation, the T790M acquired resistance mutation, and relative sparing of the wild-type EGFR. AZD9291 was investigated in a phase I trial with expansion cohorts in patients with disease progression after EGFR TKI. Patients with and without detectable T790M mutations were enrolled in the trial. The ORR in patients with centrally confirmed and without detectable T790M mutations was 61% (95% CI, 52-70%) and 21% (95% CI, 12-34%), respectively. The PFS observed in patients with centrally confirmed and without detectable T790M mutations was 9.6 months (95% CI, 8.3 to not reached) and 2.8 months (95% CI, 2.1-4.3 months), respectively. At the dose for further investigation, 80 mg daily, the rate of all grade 3-5 drug related adverse events was 11%, and the rates of grade 3 diarrhea and rash were 1% and 0%, respectively. The identification of the T790M resistance mutation and the subsequent development of an agent against the mechanism of resistance provide a template for future drug development for acquired resistance to targeted therapy. PMID:26958499

  17. Inhibitory effect of snake venom toxin on NF-κB activity prevents human cervical cancer cell growth via increase of death receptor 3 and 5 expression.

    Science.gov (United States)

    Lee, Hye Lim; Park, Mi Hee; Hong, Ji Eun; Kim, Dae Hwan; Kim, Ji Young; Seo, Hyen Ok; Han, Sang-Bae; Yoon, Joo Hee; Lee, Won Hyoung; Song, Ho Sueb; Lee, Ji In; Lee, Ung Soo; Song, Min Jong; Hong, Jin Tae

    2016-02-01

    We previously found that snake venom toxin inhibits nuclear factor kappa B (NF-κB) activity in several cancer cells. NF-κB is implicated in cancer cell growth and chemoresistance. In our present study, we investigated whether snake venom toxin (SVT) inhibits NF-κB, thereby preventing human cervical cancer cell growth (Ca Ski and C33A). SVT (0-12 μg/ml) inhibited the growth of cervical cancer cells by the induction of apoptotic cell death. These inhibitory effects were associated with the inhibition of NF-κB activity. However, SVT dose dependently increased the expression of death receptors (DRs): DR3, DR5 and DR downstream pro-apoptotic proteins. Exploration of NF-κB inhibitor (Phenylarsine oxide, 0.1 μM) synergistically further increased SVT-induced DR3 and DR5 expressions accompanied with further inhibition of cancer cells growth. Moreover, deletion of DR3 and DR5 by small interfering RNA significantly abolished SVT-induced cell growth inhibitory effects, as well as NF-κB inactivation. Using TNF-related apoptosis-inducing ligand resistance cancer cells (A549 and MCF-7), we also found that SVT enhanced the susceptibility of chemoresistance of these cancer cells through down-regulation of NF-κB, but up-regulation of DR3 and DR5. In vivo study also showed that SVT (0.5 and 1 mg/kg) inhibited tumor growth accompanied with inactivation of NF-κB. Thus, our present study indicates that SVT could be applicable as an anticancer agent for cervical cancer, or as an adjuvant agent for chemoresistant cancer cells. PMID:25417048

  18. Adenovirus-mediated expression of both antisense ODC and AdoMetDC inhibited colorectal cancer cell growth in vitro

    Institute of Scientific and Technical Information of China (English)

    Bing ZHANG; Xian-xi LIU; Yan ZHANG; Chun-ying JIANG; Qing-shan TENG; Hai-yan HU; Wei WANG; Lei GONG

    2006-01-01

    Aim: To construct a recombinant adenovirus that can simultaneously express both antisense ornithine decarboxylase (ODC) and adenosylmethionine decarboxylase (AdoMetDC) and detect its inhibitory effect on the intracellular polyamine pool and colorectal cancer cell growth. Methods: A 205-bp cDNA of AdoMetDC was reverse-inserted into recombinant pAdTrack-ODCas vectors and recombined with pAdEasy-1 vectors in AdEasy-1 cells. Positive clones were selected and transfected into the packaging cell HEK293 after they were linearized by Pad. Green fluorescent protein expression was used to monitor the process of adenovirus packaging. The ODC and AdoMetDC protein levels were identified by western blotting, and intracellular polyamine content was detected by reverse-phase high performance liquid chromatography. A viable cell count was used to determine the growth of HT-29 cells with or without exogenous polyamine. Results: Sequencing confirmed that AdoMetDC cDNA was successfully ligated into the pAdTrack-ODCas vector. GFP expression in 293 cells during virus packing and amplification was observed by fluorescence microscopy. Western blotting demonstrated that both ODC and AdoMetDC were downregulated by Ad-ODC-AdoMetDCas, and consequently 3 kinds of polyamine (putrescine, spermidine and spermine) were reduced to very low levels. HT-29 cell growth was significantly inhibited as compared with control conditions, and growth arrest was not reversed by exogenous putrescine. Conclusion: The successfully constructed recombinant adenovirus, Ad-ODC-AdoMetDCas, blocked polyamine synthesis and has therapeutic potential for treating colorectal cancer in vitro.

  19. Alphastatin downregulates vascular endothelial cells sphingosine kinase activity and suppresses tumor growth in nude mice bearing human gastric cancer xenografts

    Institute of Scientific and Technical Information of China (English)

    Lin Chen; Tao Li; Rong Li; Bo Wei; Zheng Peng

    2006-01-01

    AIM: To investigate whether alphastatin could inhibit human gastric cancer growth and furthermore whether sphingosine kinase (SPK) activity is involved in this process.METHODS: Using migration assay, MTT assay and Matrigel assay, the effect of alphastatin on vascular endothelial cells (ECs) was evaluated in vitro. SPK and endothelial differentiation gene (EDG)-1, -3, -5 mRNAs were detected by reverse transcription-polymerase chain reaction (RT-PCR). SPK activity assay was used to evaluate the effect of alphastatin on ECs. Matrigel plug assay in nude mice was used to investigate the effect of alphastatin on angiogenesis in vivo. Female nude mice were subcutaneously implanted with human gastric cancer cells (BGC823) for the tumor xenografts studies.Micro vessel density was analyzed in Factor Ⅷ-stained tumor sections by the immunohistochemical SP method.RESULTS: In vitro, alphastatin inhibited the migration and tube formation of ECs, but had no effect on proliferation of ECs. RT-PCR analysis demonstrated that ECs expressed SPK and EDG-1, -3, -5 mRNAs. In vivo,alphastatin sufficiently suppressed neovascularization of the tumor in the nude mice. Daily administration of alphastatin produced significant tumor growth suppression. Immunohistochemical studies of tumor tissues revealed decreased micro vessel density in alphastatin-treated animals as compared with controls.CONCLUSION: Downregulating ECs SPK activity may be one of the mechanisms that alphastatin inhibits gastric cancer angiogenesis. Alphastatin might be a useful and relatively nontoxic adjuvant therapy in the treatment of gastric cancer.

  20. Growth inhibitory effect of polyunsaturated fatty acids (PUFAs on colon cancer cells via their growth inhibitory metabolites and fatty acid composition changes.

    Directory of Open Access Journals (Sweden)

    Chengcheng Zhang

    Full Text Available Colorectal cancer is common. Polyunsaturated fatty acids (PUFAs exert growth-inhibitory and pro-apoptotic effects on colon cancer cells. Metabolites of PUFAs such as prostaglandins (PGs, leukotrienes (LTs and lipoxins (LXs play a significant role in colon cancer.Human colon cancer LoVo and RKO cells were cultured with different concentration of PUFAs and 5-fluorouracil (5-FU in vitro. Cell morphological changes, fatty acid composition, formation of PGE2, LTB4 and LXA4 and expression of COX-2, ALOX5, PGD synthase (PGDS, microsomal prostaglandin E synthase (mPGES were assessed in LoVo and RKO cells when supplemented with PUFAs and 5-FU.PUFAs and 5-FU inhibited growth of LoVo and RKO cells to the same extent at the doses used and produced significant alterations in their shape. As expected, higher concentrations of supplemented PUFAs were noted in the cells compared to control. LA, GLA, AA, ALA and EPA supplementation to LoVo cells suppressed production of PGE2, LTB4,and ALOX5, mPGES expression, but enhanced that of LXA4; whereas DHA enhanced PGE2 and LXA4 synthesis but decreased LTB4 formation and COX-2, ALOX5, mPGES expression. In contrast, 5-FU enhanced formation of PGE2, LTB4 and mPGES expression, but suppressed LXA4 synthesis and COX-2 expression. PGE2, LTB4 synthesis and ALOX5 expression was suppressed by LA, GLA, ALA and DHA; whereas AA, EPA and 5-FU enhanced PGE2 but paradoxically AA decreased and EPA and 5-FU enhanced LTB4 synthesis in RKO cells. All the PUFAs tested enhanced, while 5-FU decreased LXA4 formation in RKO cells; whereas GLA, AA, and 5-FU augmented while LA, ALA, EPA and DHA enhanced COX-2 expression in RKO cells.Tumoricidal action of PUFAs on colorectal LoVo and RKO cancer cells in vitro was associated with increased formation of LXA4, decreased synthesis of PGE2 and LTB4 and suppressed expression of COX-2, ALOX5, mPGES, whereas 5-FU produced contrasting actions on these indices.

  1. PPARγ induces growth inhibition and apoptosis through upregulation of insulin-like growth factor-binding protein-3 in gastric cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Kim, S.Y. [Department of Pediatrics, Chonbuk National University Hospital, Jeonju (Korea, Republic of); Biomedical Research Institute, School of Medicine, Chonbuk National University Hospital, Jeonju (Korea, Republic of); Kim, M.S.; Lee, M.K. [Department of Pediatrics, Chonbuk National University Hospital, Jeonju (Korea, Republic of); Kim, J.S.; Yi, H.K. [Department of Biochemistry, School of Dentistry, Chonbuk National University, Jeonju (Korea, Republic of); Nam, S.Y. [Department of Alternative Therapy, Jeonju University, Jeonju (Korea, Republic of); Lee, D.Y.; Hwang, P.H. [Department of Pediatrics, Chonbuk National University Hospital, Jeonju (Korea, Republic of); Biomedical Research Institute, School of Medicine, Chonbuk National University Hospital, Jeonju (Korea, Republic of)

    2015-01-13

    Peroxisome proliferator activator receptor-gamma (PPARγ) is a ligand-activated transcriptional factor involved in the carcinogenesis of various cancers. Insulin-like growth factor-binding protein-3 (IGFBP-3) is a tumor suppressor gene that has anti-apoptotic activity. The purpose of this study was to investigate the anticancer mechanism of PPARγ with respect to IGFBP-3. PPARγ was overexpressed in SNU-668 gastric cancer cells using an adenovirus gene transfer system. The cells in which PPARγ was overexpressed exhibited growth inhibition, induction of apoptosis, and a significant increase in IGFBP-3 expression. We investigated the underlying molecular mechanisms of PPARγ in SNU-668 cells using an IGFBP-3 promoter/luciferase reporter system. Luciferase activity was increased up to 15-fold in PPARγ transfected cells, suggesting that PPARγ may directly interact with IGFBP-3 promoter to induce its expression. Deletion analysis of the IGFBP-3 promoter showed that luciferase activity was markedly reduced in cells without putative p53-binding sites (-Δ1755, -Δ1795). This suggests that the critical PPARγ-response region is located within the p53-binding region of the IGFBP-3 promoter. We further demonstrated an increase in PPARγ-induced luciferase activity even in cells treated with siRNA to silence p53 expression. Taken together, these data suggest that PPARγ exhibits its anticancer effect by increasing IGFBP-3 expression, and that IGFBP-3 is a significant tumor suppressor.

  2. PPARγ induces growth inhibition and apoptosis through upregulation of insulin-like growth factor-binding protein-3 in gastric cancer cells

    International Nuclear Information System (INIS)

    Peroxisome proliferator activator receptor-gamma (PPARγ) is a ligand-activated transcriptional factor involved in the carcinogenesis of various cancers. Insulin-like growth factor-binding protein-3 (IGFBP-3) is a tumor suppressor gene that has anti-apoptotic activity. The purpose of this study was to investigate the anticancer mechanism of PPARγ with respect to IGFBP-3. PPARγ was overexpressed in SNU-668 gastric cancer cells using an adenovirus gene transfer system. The cells in which PPARγ was overexpressed exhibited growth inhibition, induction of apoptosis, and a significant increase in IGFBP-3 expression. We investigated the underlying molecular mechanisms of PPARγ in SNU-668 cells using an IGFBP-3 promoter/luciferase reporter system. Luciferase activity was increased up to 15-fold in PPARγ transfected cells, suggesting that PPARγ may directly interact with IGFBP-3 promoter to induce its expression. Deletion analysis of the IGFBP-3 promoter showed that luciferase activity was markedly reduced in cells without putative p53-binding sites (-Δ1755, -Δ1795). This suggests that the critical PPARγ-response region is located within the p53-binding region of the IGFBP-3 promoter. We further demonstrated an increase in PPARγ-induced luciferase activity even in cells treated with siRNA to silence p53 expression. Taken together, these data suggest that PPARγ exhibits its anticancer effect by increasing IGFBP-3 expression, and that IGFBP-3 is a significant tumor suppressor

  3. Gastrin-Releasing Peptide Receptor Mediates Activation of the Epidermal Growth Factor Receptor in Lung Cancer Cells

    Directory of Open Access Journals (Sweden)

    Sufi Mary Thomas

    2005-04-01

    Full Text Available Gastrin-releasing peptide receptor (GRPR and the epidermal growth factor receptor (EGFR are expressed in several cancers including non-small cell lung carcinoma (NSCLC. Here we demonstrate the activation of EGFR by the GRPR ligand, gastrin-releasing peptide (GRP, in NSCLC cells. GRP induced rapid activation of p44/42 MAPK in lung cancer cells through EGFR. GRP-mediated activation of MAPK in NSCLC cells was abrogated by pretreatment with the anti-EGFR-neutralizing antibody, C225. Pretreatment of NSCLC cells with neutralizing antibodies to the EGFR ligands, TGF-α or HB-EGF, also decreased GRP-mediated MAPK activation. On matrix metalloproteinase (MMP inhibition, GRP failed to activate MAPK in NSCLC cells. EGF and GRP both stimulated NSCLC proliferation, and inhibition of either EGFR or GRPR resulted in cell death. Combining a GRPR antagonist with the EGFR tyrosine kinase inhibitor, gefitinib, resulted in additive cytotoxic effects. Additive effects were seen at gefitinib concentrations from 1 to 18μM, encompassing the ID50 values of both gefitinib-sensitive and gefitinib-resistant NSCLC cell lines. Because a major effect of GRPR appears to be promoting the release of EGFR ligand, this study suggests that a greater inhibition of cell proliferation may occur by abrogating EGFR ligand release in consort with inhibition of EGFR.

  4. Interleukin-22 Is Frequently Expressed in Small- and Large-Cell Lung Cancer and Promotes Growth in Chemotherapy-Resistant Cancer Cells

    OpenAIRE

    Kobold, Sebastian; Völk, Stefanie; Clauditz, Till; Küpper, Natascha Jennifer; Minner, Sarah; Tufman, Amanda; Düwell, Peter; Lindner, Michael; Koch, Ina; Heidegger, Simon; Rothenfußer, Simon; Schnurr, Max; Huber, Rudolf Maria; Wilczak, Waldemar; Endres, Stefan

    2013-01-01

    Introduction: In lung cancer, interleukin-22 (IL-22) expression within primary tissue has been demonstrated, but the frequency and the functional consequence of IL-22 signaling have not been addressed. This study aims at analyzing the cellular effects of IL-22 on lung carcinoma cell lines and the prognostic impact of IL-22 tissue expression in lung cancer patients. Methods: Biological effects of IL-22 signaling were investigated in seven lung cancer cell lines by Western blot, flow cytometry,...

  5. WIF1, a Wnt pathway inhibitor, regulates SKP2 and c-myc expression leading to G1 arrest and growth inhibition ofhuman invasive urinary bladder cancer cells

    OpenAIRE

    Tang, Yaxiong; Simoneau, Anne R; Liao, Wu-Xiang; Yi, Guo; Hope, Christopher; Liu, Feng; Li, Shunqiang; Xie, Jun; Holcombe, Randall F; Jurnak, Frances A.; Mercola, Dan; Hoang, Bang H.; Zi, Xiaolin

    2009-01-01

    Epigenetic silencing of secreted wingless-type (Wnt) antagonists through hypermethylation is associated with tobacco smoking and with invasive bladder cancer. The secreted Wnt inhibitory factor-1 (WIF1) has shown consistent growth-inhibitory effect on various cancer cell lines. Therefore,we assessed the mechanisms of action of WIF1 by either restoring WIF1 expression in invasive bladder cancer cell lines (T24 and TSU-PR1) or using a recombinant protein containing functional WIF1 domain. Both ...

  6. Inhibitory effects of antisense phosphorothioate oligodeoxynucleotides on pancreatic cancer cell Bxpc-3 telomerase activity and cell growth in vitro

    Institute of Scientific and Technical Information of China (English)

    Yun-Feng Wang; Ke-Jian Guo; Bei-Ting Huang; Yong Liu; Xiao-Yun Tang; Jian-Jun Zhang; Qiang Xia

    2006-01-01

    AIM: To investigate the effect of telomerase hTERT gene antisense oligonucleotide (hTERT-ASO) on proliferation and telomerase activity of pancreatic cancer cell line Bxpc-3.METHODS: MTT assay was used to detect the effect of different doses of hTERT-ASO on proliferation of Bxpc-3 cell for different times. To study the anti-tumor activity,the cells were divided into there groups: Control group (pancreatic cancer cell Bxpc-3); antisense oligonucleotide (hTERT-ASO) group; and nosense oligonucleotide group decorated with phosphorothioate. Telomerase activity was detected using TRAP-PCR-ELISA. Cell DNA distribution was examined using flow cytometry assay.Cell apoptosis was observed by transmission electron microscope in each group.RESULTS: After treatment with 6 mmol/L hTERTASO, cell proliferation was inhibited in dose- and timedependent manner. The telomerase activity decreased after treatment with hTERT-ASO for 72 h. Flow cytometry showed the cell number of G0/G1 phase increased from 2.7% to 14.7%, the cell number of S phase decreased from 72.7% to 51.0%, and a sub-G1 stage cell apoptosis peak appeared in front of G1 stage.CONCLUSION: Telomerase antisense oligodeoxynucleotide can inhibit the proliferation of pancreatic cancer cell line Bxpc-3 and decrease the telomerase activity and increase cell apoptosis rate in vitro.

  7. High TDP43 expression is required for TRIM16-induced inhibition of cancer cell growth and correlated with good prognosis of neuroblastoma and breast cancer patients.

    Science.gov (United States)

    Kim, Patrick Y; Tan, Owen; Liu, Bing; Trahair, Toby; Liu, Tao; Haber, Michelle; Norris, Murray D; Marshall, Glenn M; Cheung, Belamy B

    2016-05-01

    Tripartite Motif-containing protein 16 (TRIM16) is a member of a large family of tripartite motif (TRIM) proteins, that has been implicated in the pathogenesis of multiple cancers. However, the mechanism by which TRIM16 acts as a tumour suppressor is currently unknown. We used the versatile yeast two-hybrid assay on a cDNA library from human testes, which has relative high TRIM16 expression, to identify potential TRIM16-binding proteins. We identified transactive response DNA-binding protein 43 (TDP43) as a novel TRIM16 binding protein. Co-immunoprecipitation assay demonstrated that TDP43 bound TRIM16 in neuroblastoma and breast cancer cells. Enforced over-expression of TRIM16 increased the protein half-life of TDP43, through the inhibition of the proteosomal degradation pathway. High levels of TRIM16 and TDP43 are associated with good prognosis in both human neuroblastoma and breast cancer tissues. Importantly, we found TDP43 expression was required for TRIM16-induced inhibition of neuroblastoma and breast cancer cell growth and the repressive effect of TRIM16 on cell cycle regulatory proteins, E2F1 and pRb. Taken together, our data suggest that TRIM16 and TDP43 are both good prognosis indicators; also we showed that TRIM16 inhibits cancer cell viability by a novel mechanism involving interaction and stabilisation of TDP43 with consequent effects on E2F1 and pRb proteins. PMID:26902425

  8. Induction of reactive oxygen species generation inhibits epithelial-mesenchymal transition and promotes growth arrest in prostate cancer cells.

    Science.gov (United States)

    Das, Trinath P; Suman, Suman; Damodaran, Chendil

    2014-07-01

    Oxidative stress is one causative factor of the pathogenesis and aggressiveness of most of the cancer types, including prostate cancer (CaP). A moderate increase in reactive oxygen species (ROS) induces cell proliferation whereas excessive amounts of ROS promote apoptosis. In this study, we explored the pro-oxidant property of 3,9-dihydroxy-2-prenylcoumestan (psoralidin [pso]), a dietary agent, on CaP (PC-3 and C4-2B) cells. Pso greatly induced ROS generation (more than 20-fold) that resulted in the growth inhibition of CaP cells. Overexpression of anti-oxidant enzymes superoxide dismutase 1 (SOD1), SOD2, and catalase, or pretreatment with the pharmacological inhibitor N-acetylcysteine (NAC) significantly attenuated both pso-mediated ROS generation and pso-mediated growth inhibition in CaP cells. Furthermore, pso administration significantly inhibited the migratory and invasive property of CaP cells by decreasing the transcription of β-catenin, and slug, which promote epithelial-mesenchymal transition (EMT), and by concurrently inducing E-cadherin expression in CaP cells. Pso-induced ROS generation in CaP cells resulted in loss of mitochondrial membrane potential, cytochrome-c release, and activation of caspase-3 and -9 and poly (ADP-ribose) polymerase (PARP), which led to apoptosis. On the other hand, overexpression of anti-oxidants rescued pso-mediated effects on CaP cells. These findings suggest that increasing the threshold of intracellular ROS could prevent or treat CaP growth and metastasis. PMID:23475579

  9. Inhibition of STAT3 expression by siRNA suppresses growth and induces apoptosis in laryngeal cancer cells

    Institute of Scientific and Technical Information of China (English)

    Li-fang GAO; De-qi XU; Lian-ji WEN; Xing-yi ZHANG; Yue-ting SHAO; Xue-jian ZHAO

    2005-01-01

    Aim: To determine the inhibitory effect of the synthetic STAT3 siRNA on the expression of STAT3 gene in human laryngeal cancer cell lines Hep2 and to investigate the effect of STAT3 siRNA on growth and apoptosis in Hep2 cells. Methods:A pair of DNA templates coding siRNA against STAT3-mRNA was synthesized to reconstruct plasmid of pSilencerl.0-U6 siRNA-STAT3. Hep2 cells were transfected with RPMI-1640 media (untreated), plasmid (empty), and STAT3 siRNA,respectively. Northern blot and Western blot analysis of STAT3 and pTyr-STAT3 expression in Hep2 cells and Western blot analysis of Bcl-2 expression in the Hep2 cell was performed 72 h after transfection. MTT, flow cytometry, and AO/EB assay were used for determination of cells proliferation and apoptosis in Hep2 cells. Results: pTyr-STAT3 was markedly expressed in untreated Hep2 cells and the vector-treated Hep2 cells, whereas pTyr-STAT3 expression was significantly reduced in STAT3 siRNA-transfected Hep2 cells, indicating that STAT3 siRNA inhibited the activity of STAT3. Transfection of Hep2 cells with STAT3 siRNA significantly inhibited STAT3 expression at both mRNA and protein level in Hep2 cells and the inhibition was characterized by time-dependent transfection. Treatment of Hep2 cells with STAT3 siRNA resulted in dose-dependent growth inhibition of Hep2, this significantly increased apoptotic cell rate, and decreased Bcl-2 expression level in Hep2 cells. STAT3 siRNA had an effect on induction of either early or late stage apoptosis. Conclusion: This study demonstrates that STAT3 siRNA effectively inhibits STAT3 gene expression in Hep2 cells leading to growth suppression and induction of apoptosis in Hep2 cells. The use of siRNA technique may provide a novel therapeutic approach to treat laryngeal cancer and other malignant tumors expressing constitutively activated STAT3.

  10. Astragalus saponins downregulate vascular endothelial growth factor under cobalt chloride-stimulated hypoxia in colon cancer cells

    Directory of Open Access Journals (Sweden)

    Law Pui-Ching

    2012-09-01

    Full Text Available Abstract Background Our ongoing research has revealed that total saponins extracted from the medicinal herb Radix Astragali (AST exhibits significant growth-inhibitory and proapoptotic effects in human cancer cells. In the present study, the potential of AST in controlling angiogenesis was further investigated with elaboration of the underlying molecular mechanism in human colon cancer cell and tumor xenograft. Results AST decreased the protein level of VEGF and bFGF in HCT 116 colon cancer cells in a time- and dose-dependent manner. Among the Akt/mTOR signal transduction molecules being examined, AST caused PTEN upregulation, reduction in Akt phosphorylation and subsequent activation of mTOR. AST also suppressed the induction of HIF-1α and VEGF under CoCl2-mimicked hypoxia. These effects were intensified by combined treatment of AST with the mTOR inhibitor rapamycin. Despite this, our data also indicate that AST could attenuate cobalt chloride-evoked COX-2 activation, while such effect on COX-2 and its downstream target VEGF was intensified when indomethacin was concurrently treated. The anti-carcinogenic action of AST was further illustrated in HCT 116 xenografted athymic nude mice. AST significantly suppressed tumor growth and reduced serum VEGF level in vivo. In the tumor tissues excised from AST-treated animals, protein level of p-Akt, p-mTOR, VEGF, VEGFR1 and VEGFR2 was down-regulated. Immunohistochemistry has also revealed that AST effectively reduced the level of COX-2 in tumor sections when compared with that in untreated control. Conclusion Taken together, these findings suggest that AST exerts anti-carcinogenic activity in colon cancer cells through modulation of mTOR signaling and downregulation of COX-2, which together reduce VEGF level in tumor cells that could potentially suppress angiogenesis.

  11. CSBF/C10orf99, a novel potential cytokine, inhibits colon cancer cell growth through inducing G1 arrest.

    Science.gov (United States)

    Pan, Wen; Cheng, Yingying; Zhang, Heyu; Liu, Baocai; Mo, Xiaoning; Li, Ting; Li, Lin; Cheng, Xiaojing; Zhang, Lianhai; Ji, Jiafu; Wang, Pingzhang; Han, Wenling

    2014-01-01

    Cytokines are soluble proteins that exert their functions by binding specific receptors. Many cytokines play essential roles in carcinogenesis and have been developed for the treatment of cancer. In this study, we identified a novel potential cytokine using immunogenomics designated colon-derived SUSD2 binding factor (CSBF), also known as chromosome 10 open reading frame 99 (C10orf99). CSBF/C10orf99 is a classical secreted protein with predicted molecular mass of 6.5 kDa, and a functional ligand of Sushi Domain Containing 2 (SUSD2). CSBF/C10orf99 has the highest expression level in colon tissue. Both CSBF/C10orf99 and SUSD2 are down-regulated in colon cancer tissues and cell lines with different regulation mechanisms. CSBF/C10orf99 interacts with SUSD2 to inhibit colon cancer cell growth and induce G1 cell cycle arrest by down-regulating cyclin D and cyclin-dependent kinase 6 (CDK6). CSBF/C10orf99 displays a bell-shaped activity curve with the optimal effect at ~10 ng/ml. Its growth inhibitory effects can be blocked by sSUSD2-Fc soluble protein. Our results suggest that CSBF/C10orf99 is a novel potential cytokine with tumor suppressor functions. PMID:25351403

  12. Deep Proteomics of Breast Cancer Cells Reveals that Metformin Rewires Signaling Networks Away from a Pro-growth State.

    Science.gov (United States)

    Sacco, Francesca; Silvestri, Alessandra; Posca, Daniela; Pirrò, Stefano; Gherardini, Pier Federico; Castagnoli, Luisa; Mann, Matthias; Cesareni, Gianni

    2016-03-23

    Metformin is the most frequently prescribed drug for type 2 diabetes. In addition to its hypoglycemic effects, metformin also lowers cancer incidence. This anti-cancer activity is incompletely understood. Here, we profiled the metformin-dependent changes in the proteome and phosphoproteome of breast cancer cells using high-resolution mass spectrometry. In total, we quantified changes of 7,875 proteins and 15,813 phosphosites after metformin changes. To interpret these datasets, we developed a generally applicable strategy that overlays metformin-dependent changes in the proteome and phosphoproteome onto a literature-derived network. This approach suggested that metformin treatment makes cancer cells more sensitive to apoptotic stimuli and less sensitive to pro-growth stimuli. These hypotheses were tested in vivo; as a proof-of-principle, we demonstrated that metformin inhibits the p70S6K-rpS6 axis in a PP2A-phosphatase dependent manner. In conclusion, analysis of deep proteomics reveals both detailed and global mechanisms that contribute to the anti-cancer activity of metformin. PMID:27135362

  13. Novel STAT3 phosphorylation inhibitors exhibit potent growth-suppressive activity in pancreatic and breast cancer cells.

    Science.gov (United States)

    Lin, Li; Hutzen, Brian; Zuo, Mingxin; Ball, Sarah; Deangelis, Stephanie; Foust, Elizabeth; Pandit, Bulbul; Ihnat, Michael A; Shenoy, Satyendra S; Kulp, Samuel; Li, Pui-Kai; Li, Chenglong; Fuchs, James; Lin, Jiayuh

    2010-03-15

    The constitutive activation of signal transducer and activator of transcription 3 (STAT3) is frequently detected in most types of human cancer where it plays important roles in survival, drug resistance, angiogenesis, and other functions. Targeting constitutive STAT3 signaling is thus an attractive therapeutic approach for these cancers. We have recently developed novel small-molecule STAT3 inhibitors, known as FLLL31 and FLLL32, which are derived from curcumin (the primary bioactive compound of turmeric). These compounds are designed to bind selectively to Janus kinase 2 and the STAT3 Src homology-2 domain, which serve crucial roles in STAT3 dimerization and signal transduction. Here we show that FLLL31 and FLLL32 are effective inhibitors of STAT3 phosphorylation, DNA-binding activity, and transactivation in vitro, leading to the impediment of multiple oncogenic processes and the induction of apoptosis in pancreatic and breast cancer cell lines. FLLL31 and FLLL32 also inhibit colony formation in soft agar and cell invasion and exhibit synergy with the anticancer drug doxorubicin against breast cancer cells. In addition, we show that FLLL32 can inhibit the induction of STAT3 phosphorylation by IFNalpha and interleukin-6 in breast cancer cells. We also show that administration of FLLL32 can inhibit tumor growth and vascularity in chicken embryo xenografts as well as substantially reduce tumor volumes in mouse xenografts. Our findings highlight the potential of these new compounds and their efficacy in targeting pancreatic and breast cancers that exhibit constitutive STAT3 signaling. PMID:20215512

  14. Lung cancer - small cell

    Science.gov (United States)

    Cancer - lung - small cell; Small cell lung cancer; SCLC ... About 15% of all lung cancer cases are SCLC. Small cell lung cancer is slightly more common in men than women. Almost all cases of SCLC ...

  15. Lung cancer - small cell

    Science.gov (United States)

    Cancer - lung - small cell; Small cell lung cancer; SCLC ... About 15% of all lung cancer cases are SCLC. Small cell lung cancer is slightly more common in men than women. Almost all cases of SCLC are ...

  16. Analysis of a mathematical model for the growth of cancer cells

    CERN Document Server

    Kohlmann, Martin

    2011-01-01

    In this paper, a two-dimensional model for the growth of multi-layer tumors is presented. The model consists of a free boundary problem for the tumor cell membrane and the tumor is supposed to grow or shrink due to cell proliferation or cell dead. The growth process is caused by a diffusing nutrient concentration $\\sigma$ and is controlled by an internal cell pressure $p$. We assume that the tumor occupies a strip-like domain with a fixed boundary at $y=0$ and a free boundary $y=\\rho(x)$, where $\\rho$ is a $2\\pi$-periodic function. First, we prove the existence of solutions $(\\sigma,p,\\rho)$ and that the model allows for peculiar stationary solutions. As a main result we establish that these equilibrium points are locally asymptotically stable under small perturbations.

  17. Extracellular Sulfatases, Elements of the Wnt Signaling Pathway, Positively Regulate Growth and Tumorigenicity of Human Pancreatic Cancer Cells

    Science.gov (United States)

    Nawroth, Roman; van Zante, Annemieke; Cervantes, Sara; McManus, Michael; Hebrok, Matthias; Rosen, Steven D.

    2007-01-01

    Background Heparan sulfate proteoglycans (HSPGs) are control elements in Wnt signaling, which bind extracellularly to Wnt ligands and regulate their ability to interact with signal transduction receptors on the cell surface. Sulf-1 and Sulf-2 are novel extracellular sulfatases that act on internal glucosamine-6-sulfate (6S) modifications within HSPGs and thereby modulate HSPG interactions with various signaling molecules, including Wnt ligands. Emerging evidence indicates the importance of reactivated Wnt signaling in a number of cancers, including pancreatic adenocarcinoma. Principle Findings Both Sulf proteins were upregulated in human pancreatic adenocarcinoma tumors and were broadly expressed in human pancreatic adenocarcinoma cell lines. Expression of human extracellular sulfatases Sulf-1 and Sulf-2 enhanced Wnt signaling in a reconstituted system. Three of four pancreatic adenocarcinoma cell lines tested exhibited autocrine Wnt signaling, in that extracellular Wnt ligands were required to initiate downstream Wnt signaling. Exposure of these pancreatic adenocarcinoma cells to a catalytically inactive form of Sulf-2 or siRNA-mediated silencing of endogenous Sulf-2 inhibited both Wnt signaling and cell growth. Sulf-2 silencing in two of these lines resulted in markedly reduced tumorigenesis in immunocompromised mice. Conclusions/Significance We have identified the Sulfs as potentiators of autocrine Wnt signaling in pancreatic cancer cells and have demonstrated their contribution to the growth and tumorigenicity of these cells. Since the Sulfs are extracellular enzymes, they would be attractive targets for therapy of pancreatic cancer. Our results run counter to the prevailing view in the literature that the Sulfs are negative regulators of tumorigenesis. PMID:17460759

  18. Adenovirus-mediated Expression of both Antisense Ornithine Decarboxylase and S-adenosylmethionine Decarboxylase Inhibits Lung Cancer Cell Growth

    Institute of Scientific and Technical Information of China (English)

    Hui TIAN; Xianxi LIU; Bing ZHANG; Qifeng SUN; Dongfeng SUN

    2007-01-01

    Polyamine biosynthesis is controlled primarily by ornithine decarboxylase (ODC) and Sadenosylmethionine decarboxylase (AdoMetDC). Antisense sequences of ODC and AdoMetDC genes were cloned into an adenoviral vector (named Ad-ODC-AdoMetDCas). To evaluate the effects of recombinant adenovirus Ad-ODC-AdoMetDCas that can simultaneously express both antisense ODC and AdoMetDC,the human lung cancer cell line A-549 was infected with Ad-ODC-AdoMetDCas or the control vector.Viable cell counting, determination of polyamine concentrations, cell cycle analysis, and Matrigel invasion assays were carried out to assess the properties of tumor growth and invasiveness. Our study showed that adenovirus-mediated antisense ODC and AdoMetDC expression inhibits tumor cell growth through blocking the polyamine synthesis pathway. Tumor cells were arrested at the G1 phase after gene transfer and the invasiveness was reduced. It suggested that the recombinant adenovirus Ad-ODC-AdoMetDCas might be a new anticancer reagent in the treatment of lung cancers.

  19. Modulation of Δ9-tetrahydrocannabinol-induced MCF-7 breast cancer cell growth by cyclooxygenase and aromatase

    International Nuclear Information System (INIS)

    Δ9-Tetrahydrocannabinol (Δ9-THC), a major constituent of marijuana, has been shown to stimulate the growth of MCF-7 breast cancer cells through cannabinoid receptor-independent signaling [Takeda, S., Yamaori, S., Motoya, E., Matsunaga, T., Kimura, T., Yamamoto, I., Watanabe, K., 2008. Δ9-Tetrahydrocannabinol enhances MCF-7 cell proliferation via cannabinoid receptor-independent signaling. Toxicology 245, 141-146]. Although the growth of MCF-7 cells is known to be stimulated by 17β-estradiol (E2), the interaction of Δ9-THC and E2 in MCF-7 cell growth is not fully clarified so far. In the present study, by using E2-sensitive MCF-7 cells that have expressed cyclooxygenase-2 (COX-2) and cytochrome P450 19 (aromatase), we studied whether or not COX-2 and aromatase are involved in Δ9-THC-mediated MCF-7 cell proliferation. It was shown that Δ9-THC-induced MCF-7 cell growth was inhibited by COX-2 inhibitors and was stimulated by arachidonic acid (a COX substrate). However, the growth of MCF-7 cells induced by Δ9-THC was not stimulated by PGE2, and the expression of aromatase was not affected by COX-2 inhibitors, arachidonic acid, and PGE2, suggesting that there is a disconnection between COX-2 (PGE2) and aromatase in Δ9-THC-mediated MCF-7 cell proliferation. On the other hand, Δ9-THC-induced MCF-7 cell growth was elevated by two kinds of aromatase inhibitors. Taken together with the evidence that Δ9-THC-induced MCF-7 cell proliferation was interfered with testosterone (an aromatase substrate) and exogenously provided E2, it is suggested that (1) the growth stimulatory effects of Δ9-THC are mediated by the product(s) of COX-2 except for PGE2, (2) the action of Δ9-THC is modulated by E2, and (3) COX-2 and aromatase are individually engaged in the proliferation of MCF-7 cells induced by Δ9-THC.

  20. Estrogen-mediated mechanisms to control the growth and apoptosis of breast cancer cells: a translational research success story.

    Science.gov (United States)

    McDaniel, Russell E; Maximov, Philipp Y; Jordan, V Craig

    2013-01-01

    The treatment and prevention of solid tumors have proved to be a major challenge for medical science. The paradigms for success in the treatment of childhood leukemia, Hodgkin's disease, Burkett's lymphoma, and testicular carcinoma with cytotoxic chemotherapy did not translate to success in solid tumors--the majority of cancers that kill. In contrast, significant success has accrued for patients with breast cancer with antihormone treatments (tamoxifen or aromatase inhibitors) that are proved to enhance survivorship, and remarkably, there are now two approved prevention strategies using either tamoxifen or raloxifene. This was considered impossible 40 years ago. We describe the major clinical advances with nonsteroidal antiestrogens that evolved into selective estrogen receptor modulators (SERMs) which successfully exploited the ER target selectively inside a woman's body. The standard paradigm that estrogen stimulates breast cancer growth has been successfully exploited for over 4 decades with therapeutic strategies that block (tamoxifen, raloxifene) or reduce (aromatase inhibitors) circulating estrogens in patients to stop breast tumor growth. But this did not explain why high-dose estrogen treatment that was the standard of care to treat postmenopausal breast cancer for 3 decades before tamoxifen caused tumor regression. This paradox was resolved with the discovery that breast cancer resistance to long-term estrogen deprivation causes tumor regression with physiologic estrogen through apoptosis. The new biology of estrogen action has been utilized to explain the findings in the Women's Health Initiative that conjugated equine estrogen alone given to postmenopausal women, average age 68, will produce a reduction of breast cancer incidence and mortality compared to no treatment. Estrogen is killing nascent breast cancer cells in the ducts of healthy postmenopausal women. The modulation of the ER using multifunctional medicines called SERMs has provided not only

  1. Klotho inhibits growth and promotes apoptosis in human lung cancer cell line A549

    Directory of Open Access Journals (Sweden)

    Zhao Weihong

    2010-07-01

    Full Text Available Abstract Background Klotho, as a new anti-aging gene, can shed into circulation and act as a multi-functional humoral factor that influences multiple biological processes. Recently, published studies suggest that klotho can also serve as a potential tumor suppressor. The aim of this study is to investigate the effects and possible mechanisms of action of klotho in human lung cancer cell line A549. Methods In this study, plasmids encoding klotho or klotho specific shRNAs were constructed to overexpress or knockdown klotho in vitro. A549 cells were respectively treated with pCMV6-MYC-KL or klotho specific shRNAs. The MTT assay was used to evaluate the cytotoxic effects of klotho and flow cytometry was utilized to observe and detect the apoptosis of A549 cells induced by klotho. The activation of IGF-1/insulin signal pathways in A549 cells treated by pCMV6-MYC-KL or shRNAs were evaluated by western blotting. The expression levels of bcl-2 and bax transcripts were evaluated by quantitative reverse transcription-polymerase chain reaction (qRT-PCR. Results Overexpression of klotho reduced the proliferation of lung cancer A549 cells, whereas klotho silencing in A549 cells enhanced proliferation. Klotho did not show any effects on HEK-293 cells. Klotho overexpression in A549 cells was associated with reduced IGF-1/insulin-induced phosphorylation of IGF-1R (IGF-1 receptor/IR (insulin receptor (P P P P P Conclusions Klotho can inhibit proliferation and increase apoptosis of A549 cells, this may be partly due to the inhibition of IGF-1/insulin pathways and involving regulating the expression of the apoptosis-related genes bax/bcl-2. Thus, klotho can serve as a potential tumor suppressor in A549 cells.

  2. Effects of inoculation site and Matrigel on growth and metastasis of human breast cancer cells.

    OpenAIRE

    L. Bao; Matsumura, Y; Baban, D.; Sun, Y.; Tarin, D

    1994-01-01

    The co-injection of extracellular matrix components, such as Matrigel, with human tumour cells into nude mice has been reported to facilitate tumour formation and growth, but it is unknown whether such components exert similar effects on tumour progression and metastasis. Metastatic behaviour is known to be enhanced when tumour cells are implanted orthotopically, and it is inferred that full and efficient expression of this phenotype may involve some interactions with local connective tissue ...

  3. Norstictic Acid Inhibits Breast Cancer Cell Proliferation, Migration, Invasion, and In Vivo Invasive Growth Through Targeting C-Met.

    Science.gov (United States)

    Ebrahim, Hassan Y; Elsayed, Heba E; Mohyeldin, Mohamed M; Akl, Mohamed R; Bhattacharjee, Joydeep; Egbert, Susan; El Sayed, Khalid A

    2016-04-01

    Breast cancer is a major health problem affecting the female population worldwide. The triple-negative breast cancers (TNBCs) are characterized by malignant phenotypes, worse patient outcomes, poorest prognosis, and highest mortality rates. The proto-oncogenic receptor tyrosine kinase c-Met is usually dysregulated in TNBCs, contributing to their oncogenesis, tumor progression, and aggressive cellular invasiveness that is strongly linked to tumor metastasis. Therefore, c-Met is proposed as a promising candidate target for the control of TNBCs. Lichens-derived metabolites are characterized by their structural diversity, complexity, and novelty. The chemical space of lichen-derived metabolites has been extensively investigated, albeit their biological space is still not fully explored. The anticancer-guided fractionation of Usnea strigosa (Ach.) lichen extract led to the identification of the depsidone-derived norstictic acid as a novel bioactive hit against breast cancer cell lines. Norstictic acid significantly suppressed the TNBC MDA-MB-231 cell proliferation, migration, and invasion, with minimal toxicity to non-tumorigenic MCF-10A mammary epithelial cells. Molecular modeling, Z'-LYTE biochemical kinase assay and Western blot analysis identified c-Met as a potential macromolecular target. Norstictic acid treatment significantly suppressed MDA-MB-231/GFP tumor growth of a breast cancer xenograft model in athymic nude mice. Lichen-derived natural products are promising resources to discover novel c-Met inhibitors useful to control TNBCs. PMID:26744260

  4. Arsenic trioxide: impact on the growth and differentiation of cancer cells and possible use in cancer therapy

    Directory of Open Access Journals (Sweden)

    Ewelina Hoffman

    2013-08-01

    Full Text Available Arsenic trioxide (As2O3 has recently been identified as an effective drug in different types of cancer therapy. It is a useful pharmacological agent in acute promyelocytic leukemia (APL treatment, especially the form that is resistant to conventional chemotherapy with all-trans retinoic acid (ATRA. What is more, laboratory data suggest that As2O3 is also active when it comes to several solid tumor cell lines. However, the mechanism of action is not fully understood. As2O3 in high doses triggers apoptosis, while in lower concentrations it induces partial differentiation. The As2O3 mechanism of action involves effects on mitochondrial transmembrane potential which lead to apoptosis. It also acts on the activity of JNK kinase, glutathione, caspases, NF-ĸB nuclear factor or pro- and antiapoptotic proteins. This publication presents the current knowledge about the influence of arsenic trioxide in cancer cells.

  5. KLF2 is downregulated in pancreatic ductal adenocarcinoma and inhibits the growth and migration of cancer cells.

    Science.gov (United States)

    Zhang, Dexiang; Dai, Yuedi; Cai, Yuankun; Suo, Tao; Liu, Han; Wang, Yueqi; Cheng, Zhijian; Liu, Houbao

    2016-03-01

    Members of the Kruppel-like factor (KLF) family have been considered as the tumor suppressors for their inhibitory effects on cell proliferation. Dysregulation of KLF2, a member of KLF family, has been observed in various cancer types. However, its expression pattern and functions in the pancreatic ductal adenocarcinoma (PDAC) are unknown. In this study, we examined the expression of KLF2 in PDAC clinical samples and evaluated the functions of KLF2 in the progression of PDAC. KLF2 is shown to be downregulated in PDAC clinical samples and overexpression of KLF2 inhibits the growth, migration, and metastasis of PDAC cancer cells. KLF2 interacts with beta-catenin and negatively regulates the beta-catenin/TCF signaling. Taken together, this study suggests the suppressive functions of KLF2 in PDAC. PMID:26449825

  6. Ganodermanontriol (GDNT) exerts its effect on growth and invasiveness of breast cancer cells through the down-regulation of CDC20 and uPA

    International Nuclear Information System (INIS)

    Highlights: ► Ganodermanontriol (GDNT), a Ganoderma mushroom alcohol, inhibits growth of breast cancer cells. ► CDC20 is over-expressed in tumors but not in the tumor surrounding tissue in breast cancer patients. ► GDNT inhibits expression of CDC20 in breast cancer cells. ► GDNT inhibits cell adhesion, cell migration and cell invasion of breast cancer cells. ► GDNT inhibits secretion of uPA and down-regulates expression of uPAR in breast cancer cells. -- Abstract: Ganoderma lucidum is a medicinal mushroom that has been recognized by Traditional Chinese Medicine (TCM). Although some of the direct anticancer activities are attributed to the presence of triterpenes—ganoderic and lucidenic acids—the activity of other compounds remains elusive. Here we show that ganodermanontriol (GDNT), a Ganoderma alcohol, specifically suppressed proliferation (anchorage-dependent growth) and colony formation (anchorage-independent growth) of highly invasive human breast cancer cells MDA-MB-231. GDNT suppressed expression of the cell cycle regulatory protein CDC20, which is over-expressed in precancerous and breast cancer cells compared to normal mammary epithelial cells. Moreover, we found that CDC20 is over-expressed in tumors when compared to the tissue surrounding the tumor in specimens from breast cancer patients. GDNT also inhibited invasive behavior (cell adhesion, cell migration, and cell invasion) through the suppression of secretion of urokinase-plasminogen activator (uPA) and inhibited expression of uPA receptor. In conclusion, mushroom GDNT is a natural agent that has potential as a therapy for invasive breast cancers.

  7. Ganodermanontriol (GDNT) exerts its effect on growth and invasiveness of breast cancer cells through the down-regulation of CDC20 and uPA

    Energy Technology Data Exchange (ETDEWEB)

    Jiang, Jiahua; Jedinak, Andrej [Cancer Research Laboratory, Methodist Research Institute, Indiana University Health, Indianapolis, IN (United States); Sliva, Daniel, E-mail: dsliva@iuhealth.org [Cancer Research Laboratory, Methodist Research Institute, Indiana University Health, Indianapolis, IN (United States); Department of Medicine, School of Medicine, Indiana University, Indianapolis, IN (United States); Indiana University Simon Cancer Center, School of Medicine, Indiana University, Indianapolis, IN (United States)

    2011-11-18

    Highlights: Black-Right-Pointing-Pointer Ganodermanontriol (GDNT), a Ganoderma mushroom alcohol, inhibits growth of breast cancer cells. Black-Right-Pointing-Pointer CDC20 is over-expressed in tumors but not in the tumor surrounding tissue in breast cancer patients. Black-Right-Pointing-Pointer GDNT inhibits expression of CDC20 in breast cancer cells. Black-Right-Pointing-Pointer GDNT inhibits cell adhesion, cell migration and cell invasion of breast cancer cells. Black-Right-Pointing-Pointer GDNT inhibits secretion of uPA and down-regulates expression of uPAR in breast cancer cells. -- Abstract: Ganoderma lucidum is a medicinal mushroom that has been recognized by Traditional Chinese Medicine (TCM). Although some of the direct anticancer activities are attributed to the presence of triterpenes-ganoderic and lucidenic acids-the activity of other compounds remains elusive. Here we show that ganodermanontriol (GDNT), a Ganoderma alcohol, specifically suppressed proliferation (anchorage-dependent growth) and colony formation (anchorage-independent growth) of highly invasive human breast cancer cells MDA-MB-231. GDNT suppressed expression of the cell cycle regulatory protein CDC20, which is over-expressed in precancerous and breast cancer cells compared to normal mammary epithelial cells. Moreover, we found that CDC20 is over-expressed in tumors when compared to the tissue surrounding the tumor in specimens from breast cancer patients. GDNT also inhibited invasive behavior (cell adhesion, cell migration, and cell invasion) through the suppression of secretion of urokinase-plasminogen activator (uPA) and inhibited expression of uPA receptor. In conclusion, mushroom GDNT is a natural agent that has potential as a therapy for invasive breast cancers.

  8. Alpha-linolenic acid regulates the growth of breast and cervical cancer cell lines through regulation of NO release and induction of lipid peroxidation

    Directory of Open Access Journals (Sweden)

    Ruchika Kaul-Ghanekar

    2013-02-01

    Full Text Available In the present work, we have analyzed the effect of the essential fatty acid, alpha linolenic acid (ALA on nitric oxide release as well as induction of lipid peroxidation in breast (MCF-7 and MDA-MB-231 and cervical (SiHa and HeLa cancer cell lines. ALA-treated cells showed a dose-dependent decrease in cell viability in both breast and cervical cancer cell lines without affecting the viability of non-cancerous transformed HEK 293 cells. Both types of cancer cells treated with ALA demonstrated a significant reduction in nitric oxide (NO release with a simultaneous increase in lipid peroxidation (LPO. This was followed by a decrease in the mitochondrial membrane potential as well as activation of caspase 3 leading to apoptosis. Thus, ALA regulated the growth of cancer cell lines through induction of lipid peroxidation and modulation of nitric oxide release resulting in apoptosis.

  9. Prox1 Promotes Expansion of the Colorectal Cancer Stem Cell Population to Fuel Tumor Growth and Ischemia Resistance

    Directory of Open Access Journals (Sweden)

    Zoltán Wiener

    2014-09-01

    Full Text Available Colorectal cancer (CRC initiation and growth is often attributed to stem cells, yet little is known about the regulation of these cells. We show here that a subpopulation of Prox1-transcription-factor-expressing cells have stem cell activity in intestinal adenomas, but not in the normal intestine. Using in vivo models and 3D ex vivo organoid cultures of mouse adenomas and human CRC, we found that Prox1 deletion reduced the number of stem cells and cell proliferation and decreased intestinal tumor growth via induction of annexin A1 and reduction of the actin-binding protein filamin A, which has been implicated as a prognostic marker in CRC. Loss of Prox1 also decreased autophagy and the survival of hypoxic tumor cells in tumor transplants. Thus, Prox1 is essential for the expansion of the stem cell pool in intestinal adenomas and CRC without being critical for the normal functions of the gut.

  10. Inhibition of Human Cervical Cancer Cell Growth by Ethanolic Extract of Boerhaavia diffusa Linn. (Punarnava Root

    Directory of Open Access Journals (Sweden)

    Rakhi Srivastava

    2011-01-01

    Full Text Available In Indian traditional medicine, Boerhaavia diffusa (punarnava roots have been widely used for the treatment of dyspepsia, jaundice, enlargement of spleen, abdominal pain and as an anti-stress agent. Pharmacological evaluation of the crude ethanolic extract of B. diffusa roots has been shown to possess antiproliferative and immunomodulatory properties. The extract of B. diffusa was studied for anti-proliferative effects on the growth of HeLa cells and for its effect on cell cycle. Bio-assays of extracts from B. diffusa root showed that a methanol : chloroform fraction (BDF 5 had an antiproliferative effect on HeLa cells. After 48 h of exposure, this fraction at a concentration of 200 μg mL−1 significantly reduced cell proliferation with visible morphological changes in HeLa cells. Cell cycle analysis suggests that antiproliferative effect of BDF 5 could be due to inhibition of DNA synthesis in S-phase of cell cycle in HeLa cells, whereas no significant change in cell cycle was detected in control cells. The fraction BDF 5 caused cell death via apoptosis as evident from DNA fragmentation and caspase-9 activation. Thus the extract has potential to be evaluated in detail to assess the molecular mechanism-mediated anticancer activities of this plant.

  11. 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.

  12. Production of immunoreactive insulin-like growth factor I and response to exogenous IGF-I in small cell lung cancer cell lines

    International Nuclear Information System (INIS)

    Small cell lung cancer (SCLC) cell lines were examined for the presence of insulin-like growth factor I-related protein (IGF-I) in cell pellets and culture media. IGF-I immunoreactivity was detected in 11/14 pellets, ranging from 12 to 76 mIU/mg soluble protein. The IGF-I levels in the cell pellets showed a correlation to the corresponding culture media. IGF-I binding sites were found in all tested cell lines. The maximum binding (Bmax) ranged from 131 to 1,230 fmol/mg protein and the dissociation constant (KD) from 0.89 to 5.21 nM. The incorporation of [3H]thymidine in the presence of recombinant human IGF-I resulted in a clearly increased DNA synthesis in two of seven cell lines. Thus, IGF-I may be an important growth factor in SCLC

  13. San Huang Decoction downregulates Aurora kinase A to inhibit breast cancer cell growth and enhance chemosenstivity to anti-tumor drugs.

    Science.gov (United States)

    Xu, Yanlei; Chen, Xu; Chen, Xiyan; Bian, Weihe; Yao, Chang; Zhang, Xiaoqing; Zhu, Xiaoshu; Chen, Jiajing; Ye, Xiaozhou

    2016-08-01

    Our study aimed to explore whether San Huang Decoction (SHD) inhibited the development of breast cancer by regulating Aurora A. Human breast cancer cell lines MCF-7 and MDA-MB-231 were cultured and SHD extract was prepared. Cell growth assay and apoptosis analysis were respectively performed to detect the effects of SHD on breast cancer cells. In addition, the effects of SHD on the expression of Aurora A and p53 were determined by RT-PCR and western blot. Besides, we used Aurora A siRNA to knock down Aurora A. We then co-administrated SHD and tamoxifen or epirubicin to detect the effect of SHD on chemosensitivity to tamoxifen or epirubicin. SHD treatment significantly inhibited cell growth in a dose-dependent manner. Moreover, SHD treatment resulted in a marked decrease in Aurora A expression and obvious increase in p53 expression. In addition, knockdown of Aurora A induced cell growth inhibition, which was similar to the effect of SHD treatment. Besides, SHD exerted an additive effect on cell growth inhibition and apoptosis induction when breast cancer cells were co-administration of SHD with tamoxifen or epirubicin. Our study indicates that SHD treatment may inhibit cell growth and enhance chemosenstivity to other anti-tumor drugs in breast cancer via down-regulation of Aurora A. PMID:27461831

  14. Proanthocyanidins inhibit in vitro and in vivo growth of human non-small cell lung cancer cells by inhibiting the prostaglandin E(2) and prostaglandin E(2) receptors.

    Science.gov (United States)

    Sharma, Som D; Meeran, Syed M; Katiyar, Santosh K

    2010-03-01

    Overexpression of cyclooxygenase-2 (COX-2) and prostaglandins (PG) is linked to a wide variety of human cancers. Here, we assessed whether the chemotherapeutic effect of grape seed proanthocyanidins (GSP) on non-small cell lung cancer (NSCLC) cells is mediated through the inhibition of COX-2 and PGE(2)/PGE(2) receptor expression. The effects of GSPs on human NSCLC cell lines in terms of proliferation, apoptosis, and expression of COX-2, PGE(2), and PGE(2) receptors were determined using Western blotting, fluorescence-activated cell sorting analysis, and reverse transcription-PCR. In vitro treatment of NSCLC cells (A549, H1299, H460, H226, and H157) with GSPs resulted in significant growth inhibition and induction of apoptosis, which were associated with the inhibitory effects of GSPs on the overexpression of COX-2, PGE(2), and PGE(2) receptors (EP1 and EP4) in these cells. Treatment of cells with indomethacin, a pan-COX inhibitor, or transient transfection of cells with COX-2 small interfering RNA, also inhibited cell growth and induced cell death. The effects of a GSP-supplemented AIN76A control diet fed to nude mice bearing tumor xenografts on the expression of COX-2, PGE(2), and PGE(2) receptors in the xenografts were also evaluated. The growth-inhibitory effect of dietary GSPs (0.5%, w/w) on the NSCLC xenograft tumors was associated with the inhibition of COX-2, PGE(2), and PGE(2) receptors (EP1, EP3, and EP4) in tumors. This preclinical study provides evidence that the chemotherapeutic effect of GSPs on lung cancer cells in vitro and in vivo is mediated, at least in part, through the inhibition of COX-2 expression and subsequently the inhibition of PGE(2) and PGE(2) receptors. PMID:20145019

  15. Interaction between angiotensin II and relaxin 2 in the progress of growth and spread of prostate cancer cells.

    Science.gov (United States)

    Domińska, Kamila; Ochędalski, Tomasz; Kowalska, Karolina; Matysiak-Burzyńska, Zuzanna Elżbieta; Płuciennik, Elżbieta; Piastowska-Ciesielska, Agnieszka Wanda

    2016-06-01

    Deregulation of locally secreted hormones, such as angiotensin II (Ang II) and relaxin 2 (RLN2), has been linked to a higher risk of select cancers or a poor prognosis in patients. In this study, for the first time a common effect of Ang II and RLN2 in relation to various aspects of prostate cancer development and metastasis are presented. Four independent colorimetric assays were used to analyze cell viability and proliferation. The changes of cell adhesion to extracellular matrix proteins and invasion/aggressiveness ability of prostate cancer cells (LNCaP, PC3) before and after peptides treatment, were also investigated. The findings suggest that the both investigated systems, have an impact on cell growth/division or spread, to some degree via overlapping signal transduction pathways. Intermediate or sometimes poorer results were achieved by using a combination of both hormones than when each was used individually. It seems that Ang II and RLN2 can play a significant role in increasing the aggressiveness of prostate tumors by up-regulating BIRC5 expression and MMP-2 and MMP-9 secretion. In addition, we speculate that Ang II and RLN2 are involved in the transition from the androgen-dependent to the androgen-independent phenotype via modulation of the expression of androgen receptors. PMID:27035428

  16. Inhibition of metabotropic glutamate receptor 1 suppresses tumor growth and angiogenesis in experimental non-small cell lung cancer.

    Science.gov (United States)

    Xia, Hui; Zhao, Ying-Nan; Yu, Chang-Hai; Zhao, Yun-Long; Liu, Yang

    2016-07-15

    Metabotropic glutamate receptor 1 (mGlu1 receptor) is expressed in many cancer cell types as compared to normal counterparts underscoring its potential role in tumor behavior. The aim of present study was to test the role of mGlu1 receptor in experimental non-small cell lung cancer (NSCLC). First, protein expression of mGlu1 receptor was higher in human NSCLC cell lines, including both adenocarcinoma and squamous carcinoma subtypes, when compared to normal bronchial epithelial cells. Inhibition of mGlu1 receptor by BAY36-7620 (an mGlu1 receptor-specific inhibitor) inhibited tumor growth and prolonged survival of mice with tumors of A549 or H1299. Treatment with BAY36-7620 suppressed AKT phosphorylation in A549 tumors and pre-treatment with BAY36-7620 blocked the L-quisqualate (a potent mGlu1 receptor agonist)-induced AKT phosphorylation in A549 cells. Treatment with BAY36-7620 reduced cellular proliferation of A549 cells. Treatment with BAY36-7620 enhanced cleaved PARP levels and reduced protein expression of bcl-2, HIF-1α, and VEGF. In contrast, treatment with L-quisqualate reduced cleaved PARP levels and enhanced protein expression of bcl-2, HIF-1α, VEGF, and IL-8, which was reversed by co-incubation with MK2206 (an AKT inhibitor). Pre-treatment with BAY36-7620 blocked the VEGF-induced AKT phosphorylation in HUVECs. Treatment of HUVECs with L-quisqualate resulted in enhancement of capillary tube formation, which was reversed by co-incubation with MK2206. Furthermore, mGlu1 receptor knockdown suppressed tumor growth and prolonged survival of mice with tumors of A549 or H1299. Collectively, inhibition of mGlu1 receptor suppressed tumor growth and angiogenesis in experimental NSCLC. PMID:27132814

  17. Berberine in combination with cisplatin suppresses breast cancer cell growth through induction of DNA breaks and caspase-3-dependent apoptosis.

    Science.gov (United States)

    Zhao, Yuwan; Jing, Zuolei; Li, Yan; Mao, Weifeng

    2016-07-01

    Berberine (BBR) is an isoquinoline alkaloid extracted from medicinal plants such as Hydrastis canadensis, Berberis aristata and Coptis chinensis. BBR displays a number of beneficial roles in the treatment of various types of cancers, yet the precise mechanisms of its action remain unclear. Cisplatin is an effective cancer chemotherapeutic agent and functions by generating DNA damage, promoting DNA damage-induced cell cycle arrest and apoptosis; however, its efficacy is challenged by the resistance of tumor cells in clinical application. The aim of the present study was to investigate the effects of BBR in combination with cisplatin on human breast cancer cells. MTT assay showed that BBR inhibited breast cancer MCF-7 cell growth with a 50% inhibitory concentration (IC50) value of 52.178±1.593 µM and the IC50 value of cisplatin was 49.541±1.618 µM, while in combination with 26 µM BBR, the IC50 value of cisplatin was 5.759±0.76 µM. BBR sensitized the MCF-7 cells to cisplatin in a time- and dose-dependent manner. After treatment of BBR and cisplatin, the cellular pro-apoptotic capase-3 and cleaved capspase-3 and caspase-9 were upregulated and the anti-apoptotic Bcl-2 was downregulated. Importantly, BBR restrained the expression of cellular PCNA, and immunofluoresence analysis of γH2AX showed that BBR increased the DNA damages induced by cisplatin. Taken together, the results demonstrated that BBR sensitized MCF-7 cells to cisplatin through induction of DNA breaks and caspase-3-dependent apoptosis. PMID:27177238

  18. 3-Bromopyruvate and sodium citrate target glycolysis, suppress survivin, and induce mitochondrial-mediated apoptosis in gastric cancer cells and inhibit gastric orthotopic transplantation tumor growth

    OpenAIRE

    WANG, TING-AN; Zhang, Xiao-Dong; GUO, XING-YU; XIAN, SHU-LIN; Lu, Yun-Fei

    2015-01-01

    Glycolysis is the primary method utilized by cancer cells to produce the energy (adenosine triphosphate, ATP) required for cell proliferation. Therefore, inhibition of glycolysis may inhibit tumor growth. We previously found that both 3-bromopyruvate (3-BrPA) and sodium citrate (SCT) can inhibit glycolysis in vitro; however, the underlying inhibitory mechanisms remain unclear. In the present study, we used a human gastric cancer cell line (SGC-7901) and an orthotopic transplantation tumor mod...

  19. Macrophage-derived IL-1β stimulates Wnt signaling and growth of colon cancer cells; a crosstalk interrupted by vitamin D3

    OpenAIRE

    Kaler, Pawan; Augenlicht, Leonard; Klampfer, Lidija

    2009-01-01

    Tumor associated macrophages mediate the link between inflammation and cancer progression. Here we showed that macrophage-derived soluble factors induce canonical Wnt signaling in colon cancer cells and promote their growth. Tumor cells induced the release of IL-1β from macrophages, which induced phosphorylation of GSK3β, stabilized β-catenin, enhanced TCF-dependent gene activation, and induced the expression of Wnt target genes in tumor cells. Neutralization experiments using anti IL-1β spec...

  20. Sunitinib significantly suppresses the proliferation, migration, apoptosis resistance, tumor angiogenesis and growth of triple-negative breast cancers but increases breast cancer stem cells.

    Science.gov (United States)

    Chinchar, Edmund; Makey, Kristina L; Gibson, John; Chen, Fang; Cole, Shelby A; Megason, Gail C; Vijayakumar, Srinivassan; Miele, Lucio; Gu, Jian-Wei

    2014-01-01

    The majority of triple-negative breast cancers (TNBCs) are basal-like breast cancers. However there is no reported study on anti-tumor effects of sunitinib in xenografts of basal-like TNBC (MDA-MB-468) cells. In the present study, MDA-MB-231, MDA-MB-468, MCF-7 cells were cultured using RPMI 1640 media with 10% FBS. Vascular endothelia growth factor (VEGF) protein levels were detected using ELISA (R & D Systams). MDA-MB-468 cells were exposed to sunitinib for 18 hours for measuring proliferation (3H-thymidine incorporation), migration (BD Invasion Chamber), and apoptosis (ApopTag and ApoScreen Anuexin V Kit). The effect of sunitinib on Notch-1 expression was determined by Western blot in cultured MDA-MB-468 cells. 10(6) MDA-MB-468 cells were inoculated into the left fourth mammary gland fat pad in athymic nude-foxn1 mice. When the tumor volume reached 100 mm(3), sunitinib was given by gavage at 80 mg/kg/2 days for 4 weeks. Tumor angiogenesis was determined by CD31 immunohistochemistry. Breast cancer stem cells (CSCs) isolated from the tumors were determined by flow cytometry analysis using CD44(+)/CD24(-) or low. ELISA indicated that VEGF was much more highly expressed in MDA-MB-468 cells than MDA-MB-231 and MCF-7 cells. Sunitinib significantly inhibited the proliferation, invasion, and apoptosis resistance in cultured basal like breast cancer cells. Sunitinib significantly increased the expression of Notch-1 protein in cultured MDA-MB-468 or MDA-MB-231 cells. The xenograft models showed that oral sunitinib significantly reduced the tumor volume of TNBCs in association with the inhibition of tumor angiogeneisis, but increased breast CSCs. These findings support the hypothesis that the possibility should be considered of sunitinib increasing breast CSCs though it inhibits TNBC tumor angiogenesis and growth/progression, and that effects of sunitinib on Notch expression and hypoxia may increase breast cancer stem cells. This work provides the groundwork for an

  1. EGCG inhibits activation of the insulin-like growth factor-1 receptor in human colon cancer cells

    International Nuclear Information System (INIS)

    The IGF/IGF-1R system, which includes the IGF, IGF-1R, and IGFBPs proteins, plays an important role in the development and growth of colorectal cancer. We previously reported that in the HT29 human colon cancer cell line EGCG, the major biologically active component of green tea, inhibits activation of the RTKs EGFR, HER2, and HER3, and that this is associated with inhibition of multiple downstream signaling pathways. Since IGF-1R is also a RTK, in this study we examined the effects of EGCG on the activity of IGF/IGF-1R system in human colon cancer cells. We found that the colon cancer cell lines Caco2, HT29, SW837, and SW480 express high levels of the IGF-1R receptor, and that both SW837 and SW480 cells display constitutive activation of this receptor. Treatment of SW837 cells with 20 μg/ml of EGCG (the IC50 concentration for growth inhibition) caused within 6 h a decrease in the phosphorylated (i.e., activated) form of the IGF-1R protein. At 12 h, there was a decrease in the levels of both IGF-1 protein and mRNA and within 3-6 h there was an increase in the levels of both IGFBP-3 protein and mRNA. The increased expression of the latter protein was sustained for at least 48 h. When SW837 cells were treated with EGCG for a longer time, i.e., 96 h, a very low concentration (1.0 μg/ml) of EGCG also caused inhibition of activation of IGF-1R, a decrease in the IGF-1 protein, and an increase in the IGFBP-3 protein. EGCG also caused a decrease in the levels of mRNAs that encode MMPs-7 and -9, proteins that proteolyze IGFBP-3. In addition, treatment with EGCG caused a transient increase in the expression of TGF-β2, an inducer of IGFBP-3 expression. These findings expand the roles of EGCG as an inhibitor of critical RTKs involved in cell proliferation, providing further evidence that EGCG and related compounds may be useful in the chemoprevention or treatment of colorectal cancer

  2. The role of versican G3 domain in regulating breast cancer cell motility including effects on osteoblast cell growth and differentiation in vitro – evaluation towards understanding breast cancer cell bone metastasis

    Directory of Open Access Journals (Sweden)

    Du William

    2012-08-01

    Full Text Available Abstract Background Versican is detected in the interstitial tissues at the invasive margins of breast carcinoma, is predictive of relapse, and negatively impacts overall survival rates. The versican G3 domain is important in breast cancer cell growth, migration and bone metastasis. However, mechanistic studies evaluating versican G3 enhanced breast cancer bone metastasis are limited. Methods A versican G3 construct was exogenously expressed in the 66c14 and the MC3T3-E1 cell line. Cells were observed through light microscopy and viability analyzed by Coulter Counter or determined with colorimetric proliferation assays. The Annexin V-FITC apoptosis detection kit was used to detect apoptotic activity. Modified Chemotactic Boyden chamber migration invasion assays were applied to observe tumor migration and invasion to bone stromal cells and MC3T3-E1 cells. Alkaline phosphatase (ALP staining and ALP ELISA assays were performed to observe ALP activity in MC3T3-E1 cells. Results In the four mouse breast cancer cell lines 67NR, 66c14, 4T07, and 4T1, 4T1 cells expressed higher levels of versican, and showed higher migration and invasion ability to MC3T3-E1 cells and primary bone stromal cells. 4T1 conditioned medium (CM inhibited MC3T3-E1 cell growth, and even lead to apoptosis. Only 4T1 CM prevented MC3T3-E1 cell differentiation, noted by inhibition of alkaline phosphatase (ALP activity. We exogenously expressed a versican G3 construct in a cell line that expresses low versican levels (66c14, and observed that the G3-expressing 66c14 cells showed enhanced cell migration and invasion to bone stromal and MC3T3-E1 cells. This observation was prevented by selective EGFR inhibitor AG1478, selective MEK inhibitor PD 98059, and selective AKT inhibitor Triciribine, but not by selective JNK inhibitor SP 600125. Versican G3 enhanced breast cancer cell invasion to bone stromal cells or osteoblast cells appears to occur through enhancing EGFR/ERK or AKT signaling

  3. Eradicating cancer cells: struggle with a chameleon

    OpenAIRE

    Di, Jiabo; Boer, Tjitske Duiveman-de; Figdor, Carl G.; Torensma, Ruurd

    2011-01-01

    Eradication of cancer stem cells to abrogate tumor growth is a new treatment modality. However, like normal cells cancer cells show plasticity. Differentiated tumor stem cells can acquire stem cell properties when they gain access to the stem cell niche. This indicates that eradicating of stem cells (emptying of the niche) alone will not lead to eradication of the tumor. Treatment should be directed to cancer stem cells ànd more mature cancer cells.

  4. TRPV6 determines the effect of vitamin D3 on prostate cancer cell growth.

    Directory of Open Access Journals (Sweden)

    V'yacheslav Lehen'kyi

    Full Text Available Despite remarkable advances in the therapy and prevention of prostate cancer it is still the second cause of death from cancer in industrialized countries. Many therapies initially shown to be beneficial for the patients were abandoned due to the high drug resistance and the evolution rate of the tumors. One of the prospective therapeutical agents even used in the first stage clinical trials, 1,25-dihydroxyvitamin D3, was shown to be either unpredictable or inefficient in many cases. We have already shown that TRPV6 calcium channel, which is the direct target of 1,25-dihydroxyvitamin D3 receptor, positively controls prostate cancer proliferation and apoptosis resistance (Lehen'kyi et al., Oncogene, 2007. However, how the known 1,25-dihydroxyvitamin D3 antiproliferative effects may be compatible with the upregulation of pro-oncogenic TRPV6 channel remains a mystery. Here we demonstrate that in low steroid conditions 1,25-dihydroxyvitamin D3 upregulates the expression of TRPV6, enhances the proliferation by increasing the number of cells entering into S-phase. We show that these pro-proliferative effects of 1,25-dihydroxyvitamin D3 are directly mediated via the overexpression of TRPV6 channel which increases calcium uptake into LNCaP cells. The apoptosis resistance of androgen-dependent LNCaP cells conferred by TRPV6 channel is drastically inversed when 1,25-dihydroxyvitamin D3 effects were combined with the successful TRPV6 knockdown. In addition, the use of androgen-deficient DU-145 and androgen-insensitive LNCaP C4-2 cell lines allowed to suggest that the ability of 1,25-dihydroxyvitamin D3 to induce the expression of TRPV6 channel is a crucial determinant of the success or failure of 1,25-dihydroxyvitamin D3-based therapies.

  5. Epithelial-mesenchymal transition stimulates human cancer cells to extend microtubule-based invasive protrusions and suppresses cell growth in collagen gel.

    Directory of Open Access Journals (Sweden)

    Jun Oyanagi

    Full Text Available Epithelial-mesenchymal transition (EMT is a crucial event in tumor invasion and metastasis. However, most of past EMT studies have been conducted in the conventional two-dimensional (2D monolayer culture. Therefore, it remains unclear what invasive phenotypes are acquired by EMT-induced cancer cells. To address this point, we attempted to characterize EMT cells in more physiological, three-dimensional (3D collagen gel culture. EMT was induced by treating three human carcinoma cell lines (A549, Panc-1 and MKN-1 with TGF-ß. The TGF-ß treatment stimulated these cells to overexpress the invasion markers laminin γ2 and MT1-MMP in 2D culture, in addition to the induction of well-known morphological change and EMT marker expression. EMT induction enhanced cell motility and adhesiveness to fibronectin and collagen in 2D culture. Although EMT cells showed comparable cell growth to control cells in 2D culture, their growth rates were extremely suppressed in soft agar and collagen gel cultures. Most characteristically, EMT-induced cancer cells commonly and markedly extended invasive protrusions in collagen gel. These protrusions were mainly supported by microtubules rather than actin cytoskeleton. Snail-introduced, stable EMT cells showed similar protrusions in 3D conditions without TGF-ß. Moreover, these protrusions were suppressed by colchicine or inhibitors of heat shock protein 90 (HSP-90 and protein phosphatase 2A. However, MMP inhibitors did not suppress the protrusion formation. These data suggest that EMT enhances tumor cell infiltration into interstitial stroma by extending microtubule-based protrusions and suppressing cell growth. The elevated cell adhesion to fibronectin and collagen and high cell motility also seem important for the tumor invasion.

  6. Ability of Group IVB metallocene polyethers containing dienestrol to arrest the growth of selected cancer cell lines

    International Nuclear Information System (INIS)

    Monomeric Group IVB (Ti, Zr and Hf) metallocenes represent a new class of antitumor compounds. There is literature on the general biological activities of some organotin compounds. Unfortunately, there is little information with respect to the molecular level activity of these organotin compounds. We recently started focusing on the anti-cancer activity of organotin polymers that we had made for other purposes and as part of our platinum anti-cancer effort. For this study, we synthesized a new series of metallocene-containing compounds coupling the metallocene unit with dienestrol, a synthetic, nonsteroidal estrogen. This is part of our effort to couple known moieties that offer antitumor activity with biologically active units hoping to increase the biological activity of the combination. The materials were confirmed to be polymeric using light scattering photometry and the structural repeat unit was verified employing matrix assisted laser desorption ionization mass spectrometry and infrared spectroscopy results. The polymers demonstrated the ability to suppress the growth of a series of tumor cell lines originating from breast, colon, prostrate, and lung cancers at concentrations generally lower than those required for inhibition of cell growth by the commonly used antitumor drug cisplatin. These drugs show great promise in vitro against a number of cancer cell lines and due to their polymeric nature will most likely be less toxic than currently used metal-containing drugs such as cisplatin. These drugs also offer several addition positive aspects. First, the reactants are commercially available so that additional synthetic steps are not needed. Second, synthesis of the polymer is rapid, occurring within about 15 seconds. Third, the interfacial synthetic system is already industrially employed in the synthesis of aromatic nylons and polycarbonates. Thus, the ability to synthesize large amounts of the drugs is straight forward

  7. Herbal Extract SH003 Suppresses Tumor Growth and Metastasis of MDA-MB-231 Breast Cancer Cells by Inhibiting STAT3-IL-6 Signaling

    Directory of Open Access Journals (Sweden)

    Youn Kyung Choi

    2014-01-01

    Full Text Available Cancer inflammation promotes cancer progression, resulting in a high risk of cancer. Here, we demonstrate that our new herbal extract, SH003, suppresses both tumor growth and metastasis of MDA-MB-231 breast cancer cells via inhibiting STAT3-IL-6 signaling path. Our new herbal formula, SH003, mixed extract from Astragalus membranaceus, Angelica gigas, and Trichosanthes kirilowii Maximowicz, suppressed MDA-MB-231 tumor growth and lung metastasis in vivo and reduced the viability and metastatic abilities of MDA-MB-231 cells in vitro. Furthermore, SH003 inhibited STAT3 activation, which resulted in a reduction of IL-6 production. Therefore, we conclude that SH003 suppresses highly metastatic breast cancer growth and metastasis by inhibiting STAT3-IL-6 signaling path.

  8. Growth suppression by transforming growth factor beta 1 of human small-cell lung cancer cell lines is associated with expression of the type II receptor

    DEFF Research Database (Denmark)

    Nørgaard, P; Damstrup, L; Rygaard, K;

    1994-01-01

    observed in two cell lines expressing only type III receptor and in TGF-beta-r negative cell lines. In two cell lines expressing all three receptor types, growth suppression was accompanied by morphological changes. To evaluate the possible involvement of the retinoblastoma protein (pRb) in mediating the...

  9. Chemotherapy cytotoxicity of human MCF-7 and MDA-MB 231 breast cancer cells is altered by osteoblast-derived growth factors.

    OpenAIRE

    Koutsilieris, M; Reyes-Moreno, C.; Choki, I.; Sourla, A.; Doillon, C.; Pavlidis, N.

    1999-01-01

    One-third of women with breast cancer will develop bone metastases and eventually die from disease progression at these sites. Therefore, we analyzed the ability of human MG-63 osteoblast-like cells (MG-63 cells), MG-63 conditioned media (MG-63 CM), insulin-like growth factor I (IGF-I), and transforming growth factor beta 1 (TGF-beta1) to alter the effects of adriamycin on cell cycle and apoptosis of estrogen receptor negative (ER-) MDA-MB-231 and positive (ER+) MCF-7 breast cancer cells, usi...

  10. G protein-coupled receptor kinase 5 mediates Tazarotene-induced gene 1-induced growth suppression of human colon cancer cells

    International Nuclear Information System (INIS)

    Tazarotene-induced gene 1 (TIG1) is a retinoid-inducible type II tumour suppressor gene. The B isoform of TIG1 (TIG1B) inhibits growth and invasion of cancer cells. Expression of TIG1B is frequently downregulated in various cancer tissues; however, the expression and activities of the TIG1A isoform are yet to be reported. Therefore, this study investigated the effects of the TIG1A and TIG1B isoforms on cell growth and gene expression profiles using colon cancer cells. TIG1A and TIG1B stable clones derived from HCT116 and SW620 colon cancer cells were established using the GeneSwitch system; TIG1 isoform expression was induced by mifepristone treatment. Cell growth was assessed using the WST-1 cell proliferation and colony formation assays. RNA interference was used to examine the TIG1 mediating changes in cell growth. Gene expression profiles were determined using microarray and validated using real-time polymerase chain reaction, and Western blot analyses. Both TIG1 isoforms were expressed at high levels in normal prostate and colon tissues and were downregulated in colon cancer cell lines. Both TIG1 isoforms significantly inhibited the growth of transiently transfected HCT116 cells and stably expressing TIG1A and TIG1B HCT116 and SW620 cells. Expression of 129 and 55 genes was altered upon induction of TIG1A and TIG1B expression, respectively, in stably expressing HCT116 cells. Of the genes analysed, 23 and 6 genes were upregulated and downregulated, respectively, in both TIG1A and TIG1B expressing cells. Upregulation of the G-protein-coupled receptor kinase 5 (GRK5) was confirmed using real-time polymerase chain reaction and Western blot analyses in both TIG1 stable cell lines. Silencing of TIG1A or GRK5 expression significantly decreased TIG1A-mediated cell growth suppression. Expression of both TIG1 isoforms was observed in normal prostate and colon tissues and was downregulated in colon cancer cell lines. Both TIG1 isoforms suppressed cell growth and

  11. Silencing NPAS2 promotes cell growth and invasion in DLD-1 cells and correlated with poor prognosis of colorectal cancer

    International Nuclear Information System (INIS)

    Highlights: • NPAS2 mRNA was down-regulated in clinical colorectal cancer tissues. • Low NPAS2 level was associated with the tumor size, TNM stage and distance metastasis in CRC. • Silencing NPAS2 promoted cell proliferation, the wound healing and cell invasion abilities. - Abstract: Emerging evidences show that circadian rhythm disorder is an important factor of tumor initiation and development. Neuronal PAS domain protein2 (NPAS2), which is the largest circadian gene, has been proved to be a novel prognostic biomarker in breast cancer and non-Hodgkin’s lymphoma. However, the potential functions of NPAS2 in colorectal cancer are still unknown. In our present study, we detected the mRNA expressions of NPAS2 in 108 CRC patients by RT-PCR, and found that NPAS2 expression was significantly down-regulated in tumor tissues than that in NATs. Clinicopathologic analysis revealed that low expression of NPAS2 was associated with the tumor size, TNM stage and tumor distance metastasis in colorectal cancer (p < 0.05). Furthermore, we effectively down-regulated NPAS2 mRNA expression by transfecting RNA interfere fragments into DLD-1 cells, and our results in vitro demonstrated that silencing NPAS2 expression could promote cell proliferation, cell invasion and increase the wound healing ability (p < 0.05). However, down-regulating NPAS2 expression did not influence the apoptotic rate in DLD-1 cells (p > 0.05). In conclusion, our study suggested that NPAS2, functioned as a potential tumor suppressor gene, could serve as a promising target and potential prognostic indicator for colorectal cancer

  12. Silencing NPAS2 promotes cell growth and invasion in DLD-1 cells and correlated with poor prognosis of colorectal cancer

    Energy Technology Data Exchange (ETDEWEB)

    Xue, Xiaofeng [Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou 215006 (China); Liu, Fei [Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou 215006 (China); Han, Ye [Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou 215006 (China); Li, Pu [Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Department of Surgery, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025 (China); Yuan, Bin; Wang, Xu; Chen, Yan; Kuang, Yuting [Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou 215006 (China); Zhi, Qiaoming, E-mail: strexboy@163.com [Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou 215006 (China); Zhao, Hong, E-mail: zhaohong600@sina.com [Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou 215006 (China)

    2014-07-25

    Highlights: • NPAS2 mRNA was down-regulated in clinical colorectal cancer tissues. • Low NPAS2 level was associated with the tumor size, TNM stage and distance metastasis in CRC. • Silencing NPAS2 promoted cell proliferation, the wound healing and cell invasion abilities. - Abstract: Emerging evidences show that circadian rhythm disorder is an important factor of tumor initiation and development. Neuronal PAS domain protein2 (NPAS2), which is the largest circadian gene, has been proved to be a novel prognostic biomarker in breast cancer and non-Hodgkin’s lymphoma. However, the potential functions of NPAS2 in colorectal cancer are still unknown. In our present study, we detected the mRNA expressions of NPAS2 in 108 CRC patients by RT-PCR, and found that NPAS2 expression was significantly down-regulated in tumor tissues than that in NATs. Clinicopathologic analysis revealed that low expression of NPAS2 was associated with the tumor size, TNM stage and tumor distance metastasis in colorectal cancer (p < 0.05). Furthermore, we effectively down-regulated NPAS2 mRNA expression by transfecting RNA interfere fragments into DLD-1 cells, and our results in vitro demonstrated that silencing NPAS2 expression could promote cell proliferation, cell invasion and increase the wound healing ability (p < 0.05). However, down-regulating NPAS2 expression did not influence the apoptotic rate in DLD-1 cells (p > 0.05). In conclusion, our study suggested that NPAS2, functioned as a potential tumor suppressor gene, could serve as a promising target and potential prognostic indicator for colorectal cancer.

  13. Downregulation of Cyclophilin A by siRNA diminishes non-small cell lung cancer cell growth and metastasis via the regulation of matrix metallopeptidase 9

    Directory of Open Access Journals (Sweden)

    Qian Zhe

    2012-10-01

    Full Text Available Abstract Background Cyclophilin A (CypA is a cytosolic protein possessing peptidyl-prolyl isomerase activity that was recently reported to be overexpressed in several cancers. Here, we explored the biology and molecular mechanism of CypA in non-small cell lung cancer (NSCLC. Methods The expression of CypA in human NSCLC cell lines was detected by real-time reverse transcription PCR. The RNA interference-mediated knockdown of CypA was established in two NSCLC cell lines (95C and A549. 239836 CypA inhibitor was also used to suppress CypA activity. Tumorigenesis was assessed based on cellular proliferation, colony formation assays, and anchorage-independent growth assays; metastasis was assessed based on wound healing and transwell assays. Results Suppression of CypA expression inhibited the cell growth and colony formation of A549 and 95C cells. CypA knockdown resulted in the inhibition of cell motility and invasion. Significantly, we show for the first time that CypA increased NSCLC cell invasion by regulating the activity of secreted matrix metallopeptidase 9 (MMP9. Likewise, suppression of CypA with 239836 CypA inhibitor decreased cell proliferation and MMP9 activity. Conclusions The suppression of CypA expression was correlated with decreased NSCLC cell tumorigenesis and metastasis.

  14. Shizukaol D, a Dimeric Sesquiterpene Isolated from Chloranthus serratus, Represses the Growth of Human Liver Cancer Cells by Modulating Wnt Signalling Pathway.

    Directory of Open Access Journals (Sweden)

    Lisha Tang

    Full Text Available Natural products have become sources of developing new drugs for the treatment of cancer. To seek candidate compounds that inhibit the growth of liver cancer, components of Chloranthus serratus were tested. Here, we report that shizukaol D, a dimeric sesquiterpene from Chloranthus serratus, exerted a growth inhibition effect on liver cancer cells in a dose- and time-dependent manner. We demonstrated that shizukaol D induced cells to undergo apoptosis. More importantly, shizukaol D attenuated Wnt signalling and reduced the expression of endogenous Wnt target genes, which resulted in decreased expression of β-catenin. Collectively, this study demonstrated that shizukaol D inhibited the growth of liver cancer cells by modulating Wnt pathway.

  15. Annexin A4-nuclear factor-κB feedback circuit regulates cell malignant behavior and tumor growth in gallbladder cancer

    Science.gov (United States)

    Yao, Hou-Shan; Sun, Chang; Li, Xin-Xing; Wang, Yi; Jin, Kai-Zhou; Zhang, Xiao-Ping; Hu, Zhi-Qian

    2016-01-01

    Gallbladder cancer (GBC) is the most common malignant tumor of the biliary system. However, the mechanisms underlying its tumor initiation, progression, and metastasis are not yet fully understood. The annexin A4 (ANXA4) gene is highly expressed in GBC tissues and may play an important role in the initiation and progression of this disease. In this study, we examined the up-regulation of ANXA4 in human GBC tissues and cell lines. Elevated ANXA4 correlated well with invasion depth in GBC patients and predicted a poor prognosis. In vitro, GBC-SD and NOZ cells with ANXA4 knockdown demonstrated increased apoptosis and inhibited cell growth, migration, and invasion. Interactions between ANXA4 and nuclear factor-κB (NF-κB) p65 proteins were detected. In vivo, ANXA4 knockdown inhibited tumor growth of GBC cells in nude mice and down-regulated the expression of downstream factors in the NF-κB signaling pathway. Taken together, these data indicate that up-regulation of ANXA4 leads to activation of the NF-κB pathway and its target genes in a feedback regulatory mechanism via the p65 subunit, resulting in tumor growth in GBC. PMID:27491820

  16. Synthesis and biological evaluation of retinoid-chalcones as inhibitors of colon cancer cell growth

    OpenAIRE

    Mizuno, Cassia S.; Paul, Shiby; Suh, Nanjoo; Rimando, Agnes M.

    2010-01-01

    Based on the observed anticancer activity of chalcones and retinoids, a novel class of retinoid-chalcone hybrids was designed and synthesized. As part of our ongoing studies to discover natural product based anticancer compounds, the retinoid-chalcone hybrids were tested against the colon cancer cell line HT-29. Retinoid like moiety was introduced through Friedel-Crafts alkylation of toluene. Among the synthesized compounds, the cyano derivative (E)-3-(3-oxo-3-(3,5,5,8,8-pentamethyl-5,6,7,8-t...

  17. Role of ornithine decarboxylase in regulation of estrogen receptor alpha expression and growth in human breast cancer cells.

    Science.gov (United States)

    Zhu, Qingsong; Jin, Lihua; Casero, Robert A; Davidson, Nancy E; Huang, Yi

    2012-11-01

    Our previous studies demonstrated that specific polyamine analogues, oligoamines, down-regulated the activity of a key polyamine biosynthesis enzyme, ornithine decarboxylase (ODC), and suppressed expression of estrogen receptor alpha (ERα) in human breast cancer cells. However, the mechanism underlying the potential regulation of ERα expression by polyamine metabolism has not been explored. Here, we demonstrated that RNAi-mediated knockdown of ODC (ODC KD) down-regulated the polyamine pool, and hindered growth in ERα-positive MCF7 and T47D and ERα-negative MDA-MB-231 breast cancer cells. ODC KD significantly induced the expression and activity of the key polyamine catabolism enzymes, spermine oxidase (SMO) and spermidine/spermine N (1)-acetyltransferase (SSAT). However, ODC KD-induced growth inhibition could not be reversed by exogenous spermidine or overexpression of antizyme inhibitor (AZI), suggesting that regulation of ODC on cell proliferation may involve the signaling pathways independent of polyamine metabolism. In MCF7 and T47D cells, ODC KD, but not DFMO treatment, diminished the mRNA and protein expression of ERα. Overexpression of antizyme (AZ), an ODC inhibitory protein, suppressed ERα expression, suggesting that ODC plays an important role in regulation of ERα expression. Decrease of ERα expression by ODC siRNA altered the mRNA expression of a subset of ERα response genes. Our previous analysis showed that oligoamines disrupt the binding of Sp1 family members to an ERα minimal promoter element containing GC/CA-rich boxes. By using DNA affinity precipitation and mass spectrometry analysis, we identified ZBTB7A, MeCP2, PARP-1, AP2, and MAZ as co-factors of Sp1 family members that are associated with the ERα minimal promoter element. Taken together, these data provide insight into a novel antiestrogenic mechanism for polyamine biosynthesis enzymes in breast cancer. PMID:22976807

  18. N-3 poly-unsaturated fatty acids shift estrogen signaling to inhibit human breast cancer cell growth.

    Directory of Open Access Journals (Sweden)

    Wenqing Cao

    Full Text Available Although evidence has shown the regulating effect of n-3 poly-unsaturated fatty acid (n-3 PUFA on cell signaling transduction, it remains unknown whether n-3 PUFA treatment modulates estrogen signaling. The current study showed that docosahexaenoic acid (DHA, C22:6, eicosapentaenoic acid (EPA, C20:5 shifted the pro-survival and proliferative effect of estrogen to a pro-apoptotic effect in human breast cancer (BCa MCF-7 and T47D cells. 17 β-estradiol (E2 enhanced the inhibitory effect of n-3 PUFAs on BCa cell growth. The IC50 of DHA or EPA in MCF-7 cells decreased when combined with E2 (10 nM treatment (from 173 µM for DHA only to 113 µM for DHA+E2, and from 187 µm for EPA only to 130 µm for EPA+E2. E2 also augmented apoptosis in n-3 PUFA-treated BCa cells. In contrast, in cells treated with stearic acid (SA, C18:0 as well as cells not treated with fatty acid, E2 promoted breast cancer cell growth. Classical (nuclear estrogen receptors may not be involved in the pro-apoptotic effects of E2 on the n-3 PUFA-treated BCa cells because ERα agonist failed to elicit, and ERα knockdown failed to block E2 pro-apoptotic effects. Subsequent studies reveal that G protein coupled estrogen receptor 1 (GPER1 may mediate the pro-apoptotic effect of estrogen. N-3 PUFA treatment initiated the pro-apoptotic signaling of estrogen by increasing GPER1-cAMP-PKA signaling response, and blunting EGFR, Erk 1/2, and AKT activity. These findings may not only provide the evidence to link n-3 PUFAs biologic effects and the pro-apoptotic signaling of estrogen in breast cancer cells, but also shed new insight into the potential application of n-3 PUFAs in BCa treatment.

  19. Citrus limon-derived nanovesicles inhibit cancer cell proliferation and suppress CML xenograft growth by inducing TRAIL-mediated cell death.

    Science.gov (United States)

    Raimondo, Stefania; Naselli, Flores; Fontana, Simona; Monteleone, Francesca; Lo Dico, Alessia; Saieva, Laura; Zito, Giovanni; Flugy, Anna; Manno, Mauro; Di Bella, Maria Antonietta; De Leo, Giacomo; Alessandro, Riccardo

    2015-08-14

    Nanosized vesicles are considered key players in cell to cell communication, thus influencing physiological and pathological processes, including cancer. Nanovesicles have also been found in edible-plants and have shown therapeutic activity in inflammatory bowel diseases; however information on their role in affecting cancer progression is missing.Our study identify for the first time a fraction of vesicles from lemon juice (Citrus limon L.), obtained as a result of different ultracentrifugation, with density ranging from 1,15 to 1,19 g/ml and specific proteomic profile. By using an in vitro approach, we show that isolated nanovesicles inhibit cancer cell proliferation in different tumor cell lines, by activating a TRAIL-mediated apoptotic cell death. Furthermore, we demonstrate that lemon nanovesicles suppress CML tumor growth in vivo by specifically reaching tumor site and by activating TRAIL-mediated apoptotic cell processes. Overall, this study suggests the possible use of plant-edible nanovesicles as a feasible approach in cancer treatment. PMID:26098775

  20. Growth delay of human bladder cancer cells by Prostate Stem Cell Antigen downregulation is associated with activation of immune signaling pathways

    International Nuclear Information System (INIS)

    Prostate stem cell antigen (PSCA) is a glycosylphosphatidylinositol (GPI) anchored protein expressed not only in prostate but also in pancreas and bladder cancer as shown by immunohistochemistry and mRNA analysis. It has been targeted by monoclonal antibodies in preclinical animal models and more recently in a clinical trial in prostate cancer patients. The biological role played in tumor growth is presently unknown. In this report we have characterized the contribution of PSCA expression to tumor growth. A bladder cell line was engineered to express a doxycycline (dox) regulated shRNA against PSCA. To shed light on the PSCA biological role in tumor growth, microarray analysis was carried out as a function of PSCA expression. Expression of gene set of interest was further analyzed by qPCR Down regulation of the PSCA expression was associated with reduced cell proliferation in vitro and in vivo. Mice bearing subcutaneous tumors showed a reduced tumor growth upon treatment with dox, which effectively induced shRNA against PSCA as revealed by GFP expression. Pathway analysis of deregulated genes suggests a statistical significant association between PSCA downregulation and activation of genes downstream of the IFNα/β receptor. These experiments established for the first time a correlation between the level of PSCA expression and tumor growth and suggest a role of PSCA in counteracting the natural immune response

  1. Synergistic growth inhibitory effects of the dual endothelin-1 receptor antagonist bosentan on pancreatic stellate and cancer cells.

    Science.gov (United States)

    Fitzner, Brit; Brock, Peter; Holzhüter, Stephanie-Anna; Nizze, Horst; Sparmann, Gisela; Emmrich, Jörg; Liebe, Stefan; Jaster, Robert

    2009-02-01

    Pancreatic stellate cells (PSC) play a key role in pancreatic fibrosis. Activation of PSC occurs in response to pro-fibrogenic stimuli and is maintained by autocrine loops of mediators, such as endothelin (ET)-1. Here, we have evaluated effects of the dual ET receptor antagonist bosentan in models of pancreatic fibrogenesis and cancer. Cell culture studies revealed that PSC and DSL6A pancreatic cancer cells expressed both ET-1 and ET receptors. Bosentan efficiently inhibited proliferation of both cell types and collagen synthesis in PSC. Expression of the myofibroblastic marker alpha-smooth muscle actin, connective tissue growth factor, and ET-1 itself in PSC was reduced, while expression of matrix metalloproteinase-9 was enhanced. Like PSC, DSL6A cells secrete less ET-1 when cultured with bosentan. In a rat model of pancreatic fibrosis, chronic pancreatitis induced by dibutyltin dichloride, a tendency towards a diminished disease progression was observed in a subgroup of rats with less severe disease. Together, our results indicate that bosentan exerts antifibrotic and antitumor effects in vitro. Its efficiency in vivo warrants further investigation. PMID:18612819

  2. Aurora kinase inhibitors attached to iron oxide nanoparticles enhances inhibition of the growth of liver cancer cells

    International Nuclear Information System (INIS)

    We have developed a novel Aurora kinase inhibitor (AKI) AM-005, an analogue of pan-AKI AT-9283. To improve the intracellular efficacy of AM-005 and AT-9283, we utilized magnetite nanoparticles (NPs) to deliver AM-005 and AT-9283 into human SMMC-7721 and HepG2 liver cancer cells. The drug-loaded NPs were prepared through quasi-emulsion solvent diffusion of magnetite NPs with AM-005 or AT-9283. The encapsulated drugs were readily released from NPs, preferentially at low pHs. Upon exposure, cancer cells effectively internalized drug-loaded NPs into lysosome-like vesicles, which triggered a series of cellular changes, including the formation of enlarged cytoplasm, the significant increase of membrane permeability, and the generation of reactive oxygen species (ROS). The increased ROS synthesis sustained over 72 h, whereas that in the cells treated with free-form drugs declined rapidly after 48 h. However, chemical sequestration of the iron core of NPs had a minor influence on the generation of intracellular ROS. On the other hand, uncoupling of AM-005 uptake with NP internalization into cells failed to induce ROS synthesis. Overall, our approach achieved two-fold increase in suppressing the viability of tumor cells in vitro and the growth of tumors in vivo. We conclude that magnetite NPs can be used as pH responsive nanocarriers that are able to improve the efficacy of AKIs

  3. Aurora kinase inhibitors attached to iron oxide nanoparticles enhances inhibition of the growth of liver cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Xiquan [Southeast University, State Key Laboratory of Bioelectronics and Jiangsu Key Laboratory for Biomaterials and Devices, School of Biological Science & Medical Engineering (China); Xie, Li [Southeast University, Zhongda Hospital, School of Medicine (China); Zheng, Ming; Yao, Juan [Jiangsu Chai Tai Tianqing Pharmaceutical Co. Ltd. (China); Song, Lina [Southeast University, State Key Laboratory of Bioelectronics and Jiangsu Key Laboratory for Biomaterials and Devices, School of Biological Science & Medical Engineering (China); Chang, Weiwei [Jiangsu Chai Tai Tianqing Pharmaceutical Co. Ltd. (China); Zhang, Yu; Ji, Min, E-mail: minji888@hotmail.com; Gu, Ning, E-mail: guning@seu.edu.cn [Southeast University, State Key Laboratory of Bioelectronics and Jiangsu Key Laboratory for Biomaterials and Devices, School of Biological Science & Medical Engineering (China); Zhan, Xi, E-mail: zhan01@gmail.com [University of Maryland School of Medicine, The Center of Vascular and Inflammatory Diseases, The Department of Pathology (United States)

    2015-06-15

    We have developed a novel Aurora kinase inhibitor (AKI) AM-005, an analogue of pan-AKI AT-9283. To improve the intracellular efficacy of AM-005 and AT-9283, we utilized magnetite nanoparticles (NPs) to deliver AM-005 and AT-9283 into human SMMC-7721 and HepG2 liver cancer cells. The drug-loaded NPs were prepared through quasi-emulsion solvent diffusion of magnetite NPs with AM-005 or AT-9283. The encapsulated drugs were readily released from NPs, preferentially at low pHs. Upon exposure, cancer cells effectively internalized drug-loaded NPs into lysosome-like vesicles, which triggered a series of cellular changes, including the formation of enlarged cytoplasm, the significant increase of membrane permeability, and the generation of reactive oxygen species (ROS). The increased ROS synthesis sustained over 72 h, whereas that in the cells treated with free-form drugs declined rapidly after 48 h. However, chemical sequestration of the iron core of NPs had a minor influence on the generation of intracellular ROS. On the other hand, uncoupling of AM-005 uptake with NP internalization into cells failed to induce ROS synthesis. Overall, our approach achieved two-fold increase in suppressing the viability of tumor cells in vitro and the growth of tumors in vivo. We conclude that magnetite NPs can be used as pH responsive nanocarriers that are able to improve the efficacy of AKIs.

  4. Enrichment of breast cancer stem-like cells by growth on electrospun polycaprolactone-chitosan nanofiber scaffolds

    OpenAIRE

    Sims-Mourtada J; Niamat RA; Samuel S; Eskridge C; Kmiec EB

    2014-01-01

    Jennifer Sims-Mourtada,1 Rohina A Niamat,2 Shani Samuel,2 Chris Eskridge,2 Eric B Kmiec1,2 1Center for Translational Cancer Research, Helen F Graham Cancer Center and Research Institute, Christiana Care Health Services, Inc, Newark, 2Department of Chemistry, Delaware State University, Dover, DE, USA Abstract: A small population of highly tumorigenic breast cancer cells has recently been identified. These cells, known as breast-cancer stem-like cells (BCSC), express markers similar to mammary...

  5. Ormeloxifene efficiently inhibits ovarian cancer growth

    Science.gov (United States)

    Maher, Diane M.; Khan, Sheema; Nordquist, Jordan; Ebeling, Mara C.; Bauer, Nichole A.; Kopel, Lucas; Singh, Man Mohan; Halaweish, Fathi; Bell, Maria C.; Jaggi, Meena; Chauhan, Subhash C.

    2014-01-01

    Ovarian cancer continues to be a leading cause of cancer related deaths for women. Anticancer agents effective against chemo-resistant cells are greatly needed for ovarian cancer treatment. Repurposing drugs currently in human use is an attractive strategy for developing novel cancer treatments with expedited translation into clinical trials. Therefore, we examined whether ormeloxifene (ORM), a non-steroidal Selective Estrogen Receptor Modulator (SERM) currently used for contraception, is therapeutically effective at inhibiting ovarian cancer growth. We report that ORM treatment inhibits cell growth and induces apoptosis in ovarian cancer cell lines, including cell lines resistant to cisplatin. Furthermore, ORM treatment decreases Akt phosphorylation, increases p53 phosphorylation, and modulates the expression and localization patterns of