Vitamin C supplementation prevents testosterone-induced hyperplasia of rat prostate by down-regulating HIF-1α

Benign prostatic hyperplasia (BPH) is a disease that impairs the well-being of many aged men To alleviate BPH symptoms or to find a cure for this disease, key molecules should be identified that control prostate cell proliferation. Recently, HIF-1 alpha has attracted attention in this context, because it is highly expressed in hyperplasic prostates and prevents prostate cell death. Thus, given that vitamin C inhibits HIF-1 alpha expression in several malignant tumors, we examined its therapeutic potential in BPH HIF-1 alpha was noticeably induced by testosterone in prostate cells, and this HIF-1 alpha induction was abolished by vitamin C. Vascular endothelial growth factor (VEGF) promoter activity reporter assays and semi-quantitative RT-PCR revealed that vitamin C inhibited HIF-1-dependent VEGF expression Furthermore. HIF-1 alpha suppression by vitamin C was rescued by knocking down HIF-prolyl hydroxylase-2, suggesting that vitamin C destabilizes HIF-1 alpha via prolyl hydroxylation Moreover, vitamin C treatment abolished cell proliferation induced by testosterone treatment to the control level These results suggest that vitamin C inhibits testosterone-induced HIF-1 alpha expression and by so doing effectively prevents prostate hyperplasia. In male rats, testosterone treatment for 4 weeks induced prostate hyperplasia. Furthermore, HIF-1 alpha and VEGF levels were significantly elevated in hyperplasic prostates In vitamin C-treated rats, however, most prostate hyperplasia parameters and prostrate HIF-1 alpha/VEGF levels were markedly reduced. Accordingly, our findings indicate that vitamin C cot Id be further developed clinically for use as an anti-BPH agent. (C) 2010 Elsevier Inc. All rights reserved.