Capsaicin regulates vascular endothelial cell growth factor expression by modulation of hypoxia inducing factor-lα in human malignant melanoma cells

Purpose: Capsaicin (8-Methyl-N-Vanillyl-6-nonenamide), a known natural dietary chernopreventive agent, inhibits malignant melanoma cell proliferation. In the present study, we examined the effect of capsaicin on constitutive and induced vascular endothelial cell growth factor (VEGF) expression in malignant melanoma cells. Results: Capsaicin treatment resulted in enhanced VEGF protein secretion in malignant melanoma cells independent of IL-lbeta and TNF-alpha. The observed up-regulation of VEGF production by capsaicin was concentration- and duration-dependent and was inversely associated with inhibition of melanoma cell proliferation. We observed an increase in hypoxia-inducible factor (HIF)-lalpha and VEGF mRNA expression in capsaicin-treated melanoma cells. Further, an electrophoretic mobility shift assay (EMSA) from nuclear extracts from melanoma cells showed a decrease in constitutive activation of NF-B-K and enhanced HIF-lalpha binding activity to hypoxia response element (HRE) in melanoma cells treated with different concentrations of capsaicin. Conclusions: These data suggest that inhibition of cellular proliferation by capsaicin follows enhanced VEGF production by remaining melanoma cells by enhancing HIF-1alpha expression and binding to HRE.