This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Cao, Z. Articles by Jiang, B.-H. Search for Related Content PubMed PubMed Citation Articles by Cao, Z. Articles by Jiang, B.-H.

trans-3,4,5'-Trihydroxystibene Inhibits Hypoxia-Inducible Factor 1 and Vascular Endothelial Growth Factor Expression in Human Ovarian Cancer Cells

¹ Department of Microbiology, Immunology and Cell Biology, Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, West Virginia, and ² Institute for Nutritional Sciences, Chinese Academy of Sciences, Shanghai, China.

trans-3,4,5'-Trihydroxystibene (resveratrol) is a natural product commonly found in the human diet and has been shown recently to have anticancer effects on various human cancer cells. However, the molecular basis for its anticancer action remains to be elucidated. In this study, we investigated the effect of resveratrol on hypoxia-inducible factor 1 (HIF-1) and vascular endothelial growth factor (VEGF) expression in human ovarian cancer cells A2780/CP70 and OVCAR-3. We found that although resveratrol did not affect HIF-1 mRNA levels, it did dramatically inhibit both basal-level and growth factor-induced HIF-1 protein expression in the cells. Resveratrol also greatly inhibited VEGF expression. Mechanistically, we demonstrated that resveratrol inhibited HIF-1 and VEGF expression through multiple mechanisms. First, resveratrol inhibited AKT and mitogen-activated protein kinase activation, which played a partial role in the down-regulation of HIF-1 expression. Second, resveratrol inhibited insulin-like growth factor 1-induced HIF-1 expression through the inhibition of protein translational regulators, including M_r 70,000 ribosomal protein S6 kinase 1, S6 ribosomal protein, eukaryotic initiation factor 4E-binding protein 1, and eukaryotic initiation factor 4E. Finally, we showed that resveratrol substantially induced HIF-1 protein degradation through the proteasome pathway. Our data suggested that resveratrol may inhibit human ovarian cancer progression and angiogenesis by inhibiting HIF-1 and VEGF expression and thus provide a novel potential mechanism for the anticancer action of resveratrol.

This article has been cited by other articles:

				N. F. Trincheri, G. Nicotra, C. Follo, R. Castino, and C. Isidoro Resveratrol induces cell death in colorectal cancer cells by a novel pathway involving lysosomal cathepsin D Carcinogenesis, May 1, 2007; 28(5): 922 - 931. [Abstract] [Full Text] [PDF]

				X. Tang, Q. Zhang, J. Nishitani, J. Brown, S. Shi, and A. D. Le Overexpression of Human Papillomavirus Type 16 Oncoproteins Enhances Hypoxia-Inducible Factor 1{alpha} Protein Accumulation and Vascular Endothelial Growth Factor Expression in Human Cervical Carcinoma Cells Clin. Cancer Res., May 1, 2007; 13(9): 2568 - 2576. [Abstract] [Full Text] [PDF]

				B. Fu, J. Xue, Z. Li, X. Shi, B.-H. Jiang, and J. Fang Chrysin inhibits expression of hypoxia-inducible factor-1{alpha} through reducing hypoxia-inducible factor-1{alpha} stability and inhibiting its protein synthesis Mol. Cancer Ther., January 1, 2007; 6(1): 220 - 226. [Abstract] [Full Text] [PDF]

				Q. Zhang, X. Tang, Q. Lu, Z. Zhang, J. Rao, and A. D. Le Green tea extract and (-)-epigallocatechin-3-gallate inhibit hypoxia- and serum-induced HIF-1{alpha} protein accumulation and VEGF expression in human cervical carcinoma and hepatoma cells Mol. Cancer Ther., May 1, 2006; 5(5): 1227 - 1238. [Abstract] [Full Text] [PDF]

				P. Marambaud, H. Zhao, and P. Davies Resveratrol Promotes Clearance of Alzheimer's Disease Amyloid-{beta} Peptides J. Biol. Chem., November 11, 2005; 280(45): 37377 - 37382. [Abstract] [Full Text] [PDF]

				Q. Zhang, X. Tang, Q. Y. Lu, Z. F. Zhang, J. Brown, and A. D. Le Resveratrol inhibits hypoxia-induced accumulation of hypoxia-inducible factor-1{alpha} and VEGF expression in human tongue squamous cell carcinoma and hepatoma cells Mol. Cancer Ther., October 1, 2005; 4(10): 1465 - 1474. [Abstract] [Full Text] [PDF]