[Show abstract][Hide abstract] 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 H2O2 production and p70S6K1 activation in PC-3 prostate cancer cells. The inhibition of H2O2 production by catalase abolished insulin-induced p70S6K1 activation. H2O2 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 H2O2 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.
[Show abstract][Hide abstract] ABSTRACT: Chrysin is a natural flavonoid and has been shown recently to have anticancer effects. However, the mechanisms that chrysin inhibits cancers are not well known. In this study, we investigated the effects of chrysin on expression of hypoxia-inducible factor-1alpha (HIF-1alpha) and vascular endothelial growth factor in human prostate cancer DU145 cells. Chrysin inhibited insulin-induced expression of HIF-1alpha by reducing its stability. Chrysin increases ubiquitination and degradation of HIF-1alpha by increasing its prolyl hydroxylation. In addition, chrysin interfered with interaction between HIF-1alpha and heat shock protein 90. Chrysin was also found to inhibit HIF-1alpha expression through AKT signaling. Inhibition of HIF-1alpha by chrysin resulted in abrogation of vascular endothelial growth factor expression. Finally, we showed that chrysin inhibited DU145 xenograft-induced angiogenesis in nude mice. Taken together, these results suggest that chrysin is a potent inhibitor of HIF-1alpha and provide a new sight into the mechanisms of chrysin against cancers.
Molecular Cancer Therapeutics 02/2007; 6(1):220-6. DOI:10.1158/1535-7163.MCT-06-0526 · 5.68 Impact Factor