Insulin-dependent GLUT4 is a risk factor for cancer in the prostate

Abstract

Abstract Background: Diabetic men are less likely to suffer prostate cancer, and insulin signalling through insulin receptors has been long considered. However, the role of insulin-dependent glucose transporters has yet to be elucidated. The unique metabolic properties of prostate cancer are attributed to the central role of androgens. Androgen-sensitive tumour cells have higher mitochondrial activity, while castration-resistant cells exhibit aerobic glycolysis. In addition, to glycolysis, one of the hallmarks of cancer metabolism is increased glucose uptake. However, the prostate's oncogenic value of glucose transporters (GLUTs) needs to be better characterized. This research aims to discover the relevance of insulin-dependent glucose transporters to cancer progression and their importance in the protective role of diabetes in prostate cancer. Methods: Androgen-sensitive LNCaP and androgen-insensitive PC-3 cells were used in vitro. Castration-resistant LNCaP-R cells and cells overexpressing GLUT1 or GLUT4 were established from LNCaP cell line. In addition, TRAMP (Transgenic Adenocarcinoma of Mouse Prostate) mice and prostatic samples from patients were employed. Results: We found that androgens stimulate insulin-independent glucose transporters, while androgen independence is associated with GLUT4 overexpression. The ectopic overexpression of GLUT4 promotes the characteristics of a castration-resistant phenotype. Metabolomics confirmed that hormone-resistant prostate cancer cells show an oxidative metabolism with a clear enrichment in amino acid metabolism. Diabetic TRAMP mice showed total tumour regression, while insulin administration restored proliferation and recovered GLUT4 levels. The levels of GLUT4 increase along with tumour progression in TRAMP mice, and it is reduced by castration and streptozotocin-induced diabetes. Finally, the levels of GLUT4 accumulation in tumour tissues compared to normal epithelial in patients' samples showed a clear co-location with nuclear AR. Conclusion: Here it is confirmed the relevance of insulin-mediated glucose uptake through GLUT4 with prostate cancer progression and its relation to the reduced occurrence of prostate cancer in diabetic men.