Reactive oxygen species regulate insulin-induced VEGF and HIF-1 expression through the activation of p70S6K1 in human prostate cancer cells

Abstract

Vascular endothelial growth factor (VEGF) and hypoxia-inducible factor 1 (HIF-1) are important regulators of angiogenesis. HIF-1 is composed of HIF-1α and HIF-1β subunits, and regulates VEGF expression at transcriptional level. In this study, we demonstrated that insulin induced H ₂ O ₂ production and p70S6K1 activation in PC-3 prostate cancer cells. The inhibition of H ₂ O ₂ production by catalase abolished insulin-induced p70S6K1 activation. H ₂ O ₂ production is also required for insulin-induced VEGF and HIF-1α expression in the cells. Over-expression of p70S6K1 or HIF-1α reversed catalase- and rapamycin-inhibited VEGF transcriptional activation. These results suggest that insulin induced HIF-1α and VEGF expression through H ₂ O ₂ production and p70S6K1 activation in prostate cancer cells. In addition, we found that inhibition of p70S6K1 by rapamycin decreased prostate tumor angiogenesis, suggesting that p70S6K1 plays an important role in tumor angiogenesis. These results provide some useful information for prostate cancer therapy in the future.