Vitamin C supplementation prevents testosterone-induced hyperplasia of rat prostate by down-regulating HIF-1alpha.
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-1alpha 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-1alpha expression in several malignant tumors, we examined its therapeutic potential in BPH. HIF-1alpha was noticeably induced by testosterone in prostate cells, and this HIF-1alpha 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-1alpha suppression by vitamin C was rescued by knocking down HIF-prolyl hydroxylase-2, suggesting that vitamin C destabilizes HIF-1alpha 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-1alpha expression and by so doing effectively prevents prostate hyperplasia. In male rats, testosterone treatment for 4 weeks induced prostate hyperplasia. Furthermore, HIF-1alpha and VEGF levels were significantly elevated in hyperplasic prostates. In vitamin C-treated rats, however, most prostate hyperplasia parameters and prostrate HIF-1alpha/VEGF levels were markedly reduced. Accordingly, our findings indicate that vitamin C could be further developed clinically for use as an anti-BPH agent.
Li
Shan-Hua
SH
Department of Pharmacology, Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, South Korea.
Ryu
Ji-Hye
JH
Park
Sook-Eun
SE
Cho
Young-Suk
YS
Park
Jong-Wan
JW
Lee
Wang-Jae
WJ
Chun
Yang-Sook
YS
D000818:Animals; D001205:Ascorbic Acid / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D008297:Male; D011467:Prostate / Q000187:drug effects / Q000378:metabolism; D011470:Prostatic Hyperplasia / Q000188:drug therapy* / Q000517:prevention & control; D051381:Rats; D017207:Rats, Sprague-Dawley; D013739:Testosterone / Q000037:antagonists & inhibitors / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A; D013739:Testosterone; D001205:Ascorbic Acid