Abstract
Type 2 diabetes has been associated with decreased risk of prostate cancer in observational studies, and this inverse association has been recently confirmed in several large cohort studies. However the mechanisms involved in this protective effect remain to be elucidated. The aim of the present study was to explore whether different features of type 2 diabetes (hyperinsulinemia, hyperglycemia and tumor necrosis factor alpha [TNF-α]) protect against the development of prostate cancer. For this purpose LNCaP cells were used for in vitro experiments and nude mice in which PAC120 (hormone-dependent human prostate cancer) xenografts had been implanted were used for in vivo examinations. We provide evidence that increasing glucose concentrations downregulate androgen receptor (AR) mRNA and protein levels through NF-κB activation in LNCaP cells. Moreover, there was a synergic effect of glucose and TNFα in downregulating the AR in LNCaP cells. By contrast, insulin had no effect on AR regulation. In vivo experiments showed that streptozotocin-induced diabetes (STZ-DM) produces tumor growth retardation and a significant reduction in AR expression in PAC120 prostate cancer mice. In conclusion, our results suggest that hyperglycemia and TNF-α play an important role in protecting against prostate cancer by reducing androgen receptor levels via NF-κB.
Highlights
Type 2 diabetes (T2D) and prostate cancer (PCa) are two major, growing health problems that affect millions of men worldwide
The results showed that insulin treatments did not change androgen receptor (AR) mRNA levels when compared with untreated LNCaP cells (Figure 1A)
T2D has been associated with a low risk of developing PCa and this has been recently confirmed in a meta-analysis which included 29 cohort and 16 case-control studies involving 8.1 million participants and 132,331 PCa cases [34]
Summary
Type 2 diabetes (T2D) and prostate cancer (PCa) are two major, growing health problems that affect millions of men worldwide. T2D has been recognized as a key factor contributing to the development of solid organ malignancies including liver, pancreas, colorectal, breast, endometrial, uterine, and bladder [2,3] several large cohort studies have demonstrated a significant decreased risk of PCa in T2D [4,5,6,7]. Long-standing diabetes protects against PCa development, there is evidence that diabetic men may have a worse outcome because they have hystologically more aggressive PCa in comparison with nondiabetic patients [9,10,11]. One of the reasons for this feature could be the lower serum levels of prostate-specific antigen (PSA) that type 2 diabetic patients present in comparison with nondiabetic subjects [5,12,13]. It should be noted that the protective effect of diabetes on PCa is not a consequence of detection bias from delayed diagnosis due to lower PSA levels [5,14,15]
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