Insulin Increases De Novo Steroidogenesis in Prostate Cancer Cells
| Autor: | Adrian C. Herington, Amy A. Lubik, Jennifer A. Locke, Martin E. Gleave, Colleen C. Nelson, Hans Adomat, Stephen C. Hendy, Vanessa C. Thompson, Jennifer H. Gunter, Michael Pollak |
|---|---|
| Rok vydání: | 2011 |
| Předmět: |
Male
Cancer Research medicine.medical_specialty medicine.medical_treatment Biology urologic and male genital diseases Gene Expression Regulation Enzymologic Androgen deprivation therapy Mice Prostate cancer Downregulation and upregulation Internal medicine Insulin receptor substrate medicine Animals Humans Insulin RNA Messenger Gonadal Steroid Hormones Prostatic Neoplasms Prostate-Specific Antigen medicine.disease Xenograft Model Antitumor Assays IRS2 Gene Expression Regulation Neoplastic Alcohol Oxidoreductases Insulin receptor Endocrinology Oncology Protein Biosynthesis Dihydrotestosterone Androgens Insulin Receptor Substrate Proteins biology.protein medicine.drug |
| Zdroj: | Cancer Research. 71:5754-5764 |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/0008-5472.can-10-2470 |
| Popis: | Androgen-dependent pathways regulate maintenance and growth of normal and malignant prostate tissues. Androgen deprivation therapy (ADT) exploits this dependence and is used to treat metastatic prostate cancer; however, regression initially seen with ADT gives way to development of incurable castration-resistant prostate cancer (CRPC). Although ADT generates a therapeutic response, it is also associated with a pattern of metabolic alterations consistent with metabolic syndrome including elevated circulating insulin. Because CRPC cells are capable of synthesizing androgens de novo, we hypothesized that insulin may also influence steroidogenesis in CRPC. In this study, we examined this hypothesis by evaluating the effect of insulin on steroid synthesis in prostate cancer cell lines. Treatment with 10 nmol/L insulin increased mRNA and protein expression of steroidogenesis enzymes and upregulated the insulin receptor substrate insulin receptor substrate 2 (IRS-2). Similarly, insulin treatment upregulated intracellular testosterone levels and secreted androgens, with the concentrations of steroids observed similar to the levels reported in prostate cancer patients. With similar potency to dihydrotestosterone, insulin treatment resulted in increased mRNA expression of prostate-specific antigen. CRPC progression also correlated with increased expression of IRS-2 and insulin receptor in vivo. Taken together, our findings support the hypothesis that the elevated insulin levels associated with therapeutic castration may exacerbate progression of prostate cancer to incurable CRPC in part by enhancing steroidogenesis. Cancer Res; 71(17); 5754–64. ©2011 AACR. |
| Databáze: | OpenAIRE |
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