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¹ Center for Craniofacial Molecular Biology, University of Southern California, School of Dentistry; ² Center for Human Nutrition and ³ School of Public Health, University of California; and ⁴ Department of Head and Neck Surgery, Charles R. Drew University of Medicine and Science, 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

Hypoxia-inducible factor-1 (HIF-1) is overexpressed in many human tumors and their metastases, and is closely associated with a more aggressive tumor phenotype. In this study, we investigated the effect of resveratrol, a natural product commonly found in grapes and various other fruits, on hypoxia-induced HIF-1 protein accumulation and vascular endothelial growth factor (VEGF) expression in human tongue squamous cell carcinomas and hepatoma cells. Our results showed that resveratrol significantly inhibited both basal level and hypoxia-induced HIF-1 protein accumulation in cancer cells, but did not affect HIF-1 mRNA levels. Pretreatment of cells with resveratrol significantly reduced hypoxia-induced VEGF promoter activities and VEGF expression at both mRNA and protein levels. The mechanism of resveratrol inhibition of hypoxia-induced HIF-1 accumulation seems to involve a gradually shortened half-life of HIF-1 protein caused by an enhanced protein degradation through the 26S proteasome system. In addition, resveratrol remarkably inhibited hypoxia-mediated activation of extracellular signal-regulated kinase 1/2 and Akt, leading to a marked decrease in hypoxia-induced HIF-1 protein accumulation and VEGF transcriptional activation. Functionally, we observed that resveratrol also significantly inhibited the hypoxia-stimulated invasiveness of cancer cells. These data suggested that HIF-1/VEGF could be a promising drug target for resveratrol in the development of an effective chemopreventive and anticancer therapy in human cancers.

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Received 6/16/05; revised 7/21/05; accepted 8/11/05.