Green tea extract and (-)-epigallocatechin-3-gallate inhibit hypoxia- and serum-induced HIF-1α protein accumulation and VEGF expression in human cervical carcinoma and hepatoma cells

Green tea extract and its major component (-)-epigallo-catechin-3-gallate (EGCG) exhibit antiangiogenic activities in various experimental tumor models. A growing body of evidence has established that hypoxia-inducible factor-1 alpha (HIF-1 alpha) and its downstream target, vascular endothelial growth factor (VEGF), play a critical role in tumor angiogenesis. In this study, we investigated the effect of green tea extract and EGCG on HIF-1 alpha and VEGF expression in human cervical carcinoma (HeLa) and hepatoma (HepG2) cells. Our results showed that green tea extract and EGCG significantly inhibited hypoxia- and serum-induced HIF-1 alpha protein accumulation in these cancer cells but had no effects on HIF-1 alpha mRNA expression. Suppression of HIF-1 alpha protein by green tea extract and EGCG also resulted in a drastic decrease in VEGF expression at both mRNA and protein levels. The mechanisms of green tea extract and EGCG inhibition of hypoxia-induced HIF-1 alpha protein accumulation seem to involve the blocking of both phosphatidylinositol 3-kinase/ Akt and extracellular signal-regulated kinase 1/2 signaling pathways and the enhancing of HIF-1 alpha protein degradation through the proteasome system. In addition, green tea extract and EGCG inhibited serum-induced HIF-1 alpha protein and VEGF expression by interfering with the phosphatidy-linositol 3-kinase/Akt/mammalian target of rapamycin signaling pathways, which play a crucial role in the protein translational machinery cascade. Functionally, green tea extract and EGCG abolished both chemoattractant- and hypoxia-stimulated HeLa cell migration. Our data suggested that HIF-1 alpha/VEGF function as therapeutic target for green tea extract and EGCG in the context of cancer chemoprevention and anticancer therapy.