Australian Prostate Cancer Research Centre Queensland, Queensland University of Technology, Level 1, Building 33, Princess Alexandra Hospital, Ipswich Rd Brisbane, Qld, 4102, Australia.
Androgen-dependent pathways regulate maintenance and growth of normal and malignant prostate tissue. 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). While ADT generates a therapeutic response, it is also associated with a pattern of metabolic alterations consistent with metabolic syndrome including elevated circulating insulin. Since 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 nM insulin increased mRNA and protein expression of steroidogenesis enzymes and upregulated the insulin receptor substrate IRS2. 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 DHT, insulin treatment resulted in increased mRNA expression of the prostate specific antigen PSA. CRPC progression also correlated with increased expression of IRS2 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.
Lubik AA, Gunter JH, Hendy SC, Locke JA, Adomat HH, Thompson V, Herington A, Gleave ME, Pollak M, Nelson CC. Are you the author?
Reference: Cancer Res. 2011 Jul 14. Epub ahead of print.