title: Insulin increases de novo steroidogenesis in prostate cancer cells.
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.
authors: Australian Prostate Cancer Research Centre, Queensland University of Technology, Brisbane, Queensland, Australia.
authors: Amy A
authors: AA
authors: Lubik
authors: Jennifer H
authors: JH
authors: Gunter
authors: Stephen C
authors: SC
authors: Hendy
authors: Jennifer A
authors: JA
authors: Locke
authors: Hans H
authors: HH
authors: Adomat
authors: Vanessa
authors: V
authors: Thompson
authors: Adrian
authors: A
authors: Herington
authors: Martin E
authors: ME
authors: Gleave
authors: Michael
authors: M
authors: Pollak
authors: Colleen C
authors: CC
authors: Nelson
mesh_terms: D000429:Alcohol Oxidoreductases / Q000096:biosynthesis / Q000235:genetics; D000728:Androgens / Q000096:biosynthesis; D000818:Animals; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D012739:Gonadal Steroid Hormones / Q000096:biosynthesis*; D006801:Humans; D007328:Insulin / Q000494:pharmacology / Q000502:physiology*; D055504:Insulin Receptor Substrate Proteins / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D051379:Mice; D017430:Prostate-Specific Antigen / Q000096:biosynthesis / Q000235:genetics; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D014176:Protein Biosynthesis / Q000187:drug effects / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D023041:Xenograft Model Antitumor Assays
chemical_list: D000728:Androgens; D012739:Gonadal Steroid Hormones; C526297:IRS2 protein, human; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D012333:RNA, Messenger; D000429:Alcohol Oxidoreductases; C105846:retinol dehydrogenase 5; D017430:Prostate-Specific Antigen