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Research Articles: Therapeutics

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

¹ Center for Craniofacial Molecular Biology, University of Southern California School of Dentistry; ² Center for Human Nutrition, ³ Department of Epidemiology, School of Public Health; and ⁴ School of Medicine, University of California, Los Angeles, California

Requests for reprints: Anh D. Le, Division of Surgical, Therapeutic and Bioengineering Sciences, Center for Craniofacial Molecular Biology, University of Southern California School of Dentistry, Health Sciences Campus, 2250 Alcazar Street, CSA103, Los Angeles, CA 90033. Phone: 323-442-2556; Fax: 323-442-2981. E-mail: anhle{at}usc.edu

Green tea extract and its major component (–)-epigallocatechin-3-gallate (EGCG) exhibit antiangiogenic activities in various experimental tumor models. A growing body of evidence has established that hypoxia-inducible factor-1 (HIF-1) 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 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 protein accumulation in these cancer cells but had no effects on HIF-1 mRNA expression. Suppression of HIF-1 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 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 protein degradation through the proteasome system. In addition, green tea extract and EGCG inhibited serum-induced HIF-1 protein and VEGF expression by interfering with the phosphatidylinositol 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/VEGF function as therapeutic target for green tea extract and EGCG in the context of cancer chemoprevention and anticancer therapy. [Mol Cancer Ther 2006;5(5):1227–38]

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Note: Q. Zhang and X. Tang contributed equally to this work.

Received 11/28/05; revised 2/ 1/06; accepted 3/ 9/06.