Abstract |
Grape seed extract (GSE) is a widely consumed dietary supplement that has antitumor 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 messenger RNA ( 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 (HIF) 1alpha. The inhibitory effect of GSE on HIF-1alpha expression was mainly through inhibiting HIF-1alpha protein synthesis rather than promoting protein degradation. Consistent with this result, GSE-suppressed phosphorylation of several important components involved in HIF-1alpha 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-1alpha and the phosphorylation of S6 kinase without altering the subcellular localization of HIF-1alpha, correlating with reduced vessel density and tumor size. Depletion of polyphenol with polyvinylpyrrolidone 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-1alpha protein synthesis through blocking Akt activation. This finding provides new insight into the mechanisms of anticancer activity of GSE and reveals a novel molecular mechanism underlying the antiangiogenic action of GSE.
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Authors | Jianming Lu, Keqiang Zhang, Shiuan Chen, Wei Wen |
Journal | Carcinogenesis
(Carcinogenesis)
Vol. 30
Issue 4
Pg. 636-44
(Apr 2009)
ISSN: 1460-2180 [Electronic] England |
PMID | 19131542
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- Culture Media, Conditioned
- Grape Seed Extract
- Grape Seed Proanthocyanidins
- HIF1A protein, human
- Hypoxia-Inducible Factor 1, alpha Subunit
- Plant Extracts
- Proanthocyanidins
- RNA, Messenger
- VEGFA protein, human
- Vascular Endothelial Growth Factor A
- Luciferases
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Topics |
- Breast Neoplasms
(drug therapy, metabolism)
- Cell Movement
(drug effects)
- Culture Media, Conditioned
(pharmacology)
- Glioma
(drug therapy, metabolism)
- Grape Seed Extract
- Humans
- Hypoxia-Inducible Factor 1, alpha Subunit
(antagonists & inhibitors, genetics, metabolism)
- Immunoblotting
- Immunoenzyme Techniques
- Luciferases
- Plant Extracts
(pharmacology)
- Proanthocyanidins
(pharmacology)
- Promoter Regions, Genetic
- RNA, Messenger
(genetics, metabolism)
- Reverse Transcriptase Polymerase Chain Reaction
- Tumor Cells, Cultured
- Vascular Endothelial Growth Factor A
(antagonists & inhibitors)
- Vitis
(chemistry)
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