Insulin directly increases de novo steroidogenesis in prostate cancer cells

Amy Lubik, Jennifer Gunter, Stephen Hendy, Jennifer Locke, Adomat Hans, Vanessa Thompson, Adrian Herington, Martin Gleave, Michael Pollak, Colleen Nelson

    Research output: Contribution to journalArticle

    83 Citations (Scopus)

    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.

    Original languageEnglish
    Pages (from-to)5754-5764
    Number of pages11
    JournalCancer Research
    Volume71
    Issue number17
    DOIs
    Publication statusPublished - 2011

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  • Cite this

    Lubik, A., Gunter, J., Hendy, S., Locke, J., Hans, A., Thompson, V., Herington, A., Gleave, M., Pollak, M., & Nelson, C. (2011). Insulin directly increases de novo steroidogenesis in prostate cancer cells. Cancer Research, 71(17), 5754-5764. https://doi.org/10.1158/0008-5472.CAN-10-2470