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Insulin Increases De Novo Steroidogenesis in Prostate Cancer Cells
- Source :
- Cancer Research. 71:5754-5764
- Publication Year :
- 2011
- Publisher :
- American Association for Cancer Research (AACR), 2011.
-
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. Cancer Res; 71(17); 5754–64. ©2011 AACR.
- Subjects :
- 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
Subjects
Details
- ISSN :
- 15387445 and 00085472
- Volume :
- 71
- Database :
- OpenAIRE
- Journal :
- Cancer Research
- Accession number :
- edsair.doi.dedup.....304e7bec095d4adcbd9745e6bf8ab74d