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Carcinogenesis Advance Access published online on January 8, 2009
Carcinogenesis, doi:10.1093/carcin/bgp009
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© The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Grape seed extract inhibits VEGF expression via reducing HIF-1{alpha} protein expression

Jianming Lu1, Keqiang Zhang1, Shiuan Chen2 and Wei Wen1

1 Division of Molecular Medicine
2 Department of Surgical Research, Beckman Research Institute of the City of Hope, Duarte, CA 91010

Request for reprints: Wei Wen, Division of Molecular Medicine, Beckman Research Institute of the City of Hope, 1500 East Duarte Road, Duarte, CA 91010, Tel: 626-256-4673, ext: 65275. E-mail: wwen{at}coh.org

Grape Seed Extract (GSE) is a widely consumed dietary supplement that has anti-tumor activity. Here we have investigated the inhibitory effect of GSE on the expression of vascular endothelial growth factor (VEGF) and the mechanism underlying this action. We found that GSE inhibited VEGF mRNA and protein expression in U251 human glioma cells and MDA-MB-231 human breast cancer cells. GSE inhibited transcriptional activation of the VEGF gene through reducing protein but not mRNA expression of hypoxia-inducible factor 1{alpha} (HIF-1{alpha}). The inhibitory effect of GSE on HIF-1{alpha} expression was mainly through inhibiting HIF-1{alpha} protein synthesis rather than promoting protein degradation. Consistent with this result, GSE suppressed phosphorylation of several important components involved in HIF-1{alpha} protein synthesis, such as Akt, S6 kinase and S6 protein. Furthermore, in the MDA-MB-231 tumor, we found that GSE treatment inhibited the expression of VEGF and HIF-1{alpha} and the phosphorylation of S6 kinase without altering the subcellular localization of HIF-1{alpha}, correlating with reduced vessel density and tumor size. Depletion of polyphenol with polyvinylpyrrolidone (PVPP) abolished the inhibitory activity of GSE, suggesting a water soluble fraction of polyphenol in GSE is responsible for the inhibitory activity. Taken together, our results indicate that GSE inhibits VEGF expression by reducing HIF-1{alpha} protein synthesis through blocking Akt activation. This finding provides new insight into the mechanisms of anti-cancer activity of GSE and reveals a novel molecular mechanism underlying the anti-angiogenic action of GSE.

Received October 29, 2008; revised December 18, 2008; accepted December 29, 2008.


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