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Insulin increases De Novo Steroidogenesis in prostate cancer cells

Lubik, Amy, Gunter, Jennifer, Hendy, Stephen, Locke, Jennifer, Adomat, Hans, Thompson, Vanessa, Herington, Adrian, Gleave, Martin, Pollak, Michael, & Nelson, Colleen (2011) Insulin increases De Novo Steroidogenesis in prostate cancer cells. Cancer Research, 71(17), pp. 5754-5764.

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    Abstract

    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.

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    38 citations in Scopus
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    33 citations in Web of Science®

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    ID Code: 52340
    Item Type: Journal Article
    DOI: 10.1158/0008-5472.CAN-10-2470
    ISSN: 0008-5472
    Subjects: Australian and New Zealand Standard Research Classification > MEDICAL AND HEALTH SCIENCES (110000) > ONCOLOGY AND CARCINOGENESIS (111200)
    Divisions: Current > QUT Faculties and Divisions > Faculty of Health
    Current > Institutes > Institute of Health and Biomedical Innovation
    Copyright Owner: Copyright 2011 American Association for Cancer Research.
    Deposited On: 19 Jul 2012 16:29
    Last Modified: 04 Feb 2014 10:04

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