Abstract
Hypoxia-inducible factor-1alpha (HIF-1alpha) 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-1alpha 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-1alpha protein accumulation in cancer cells, but did not affect HIF-1alpha 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-1alpha accumulation seems to involve a gradually shortened half-life of HIF-1alpha 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-1alpha 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-1alpha/VEGF could be a promising drug target for resveratrol in the development of an effective chemopreventive and anticancer therapy in human cancers.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Antineoplastic Agents, Phytogenic / pharmacology*
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Carcinoma, Hepatocellular / drug therapy
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Carcinoma, Hepatocellular / metabolism*
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Carcinoma, Hepatocellular / pathology
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Carcinoma, Squamous Cell / drug therapy
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Carcinoma, Squamous Cell / metabolism*
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Carcinoma, Squamous Cell / pathology
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Cell Hypoxia / physiology
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Cell Line, Tumor
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Humans
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Hypoxia-Inducible Factor 1, alpha Subunit / antagonists & inhibitors*
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Hypoxia-Inducible Factor 1, alpha Subunit / genetics
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Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
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Liver Neoplasms / drug therapy
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Liver Neoplasms / metabolism*
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Liver Neoplasms / pathology
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MAP Kinase Signaling System / drug effects
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Mitogen-Activated Protein Kinases / antagonists & inhibitors
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Mitogen-Activated Protein Kinases / metabolism
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Neoplasm Invasiveness
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoinositide-3 Kinase Inhibitors
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Proto-Oncogene Proteins c-akt / antagonists & inhibitors
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Proto-Oncogene Proteins c-akt / metabolism
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RNA, Messenger / biosynthesis
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RNA, Messenger / genetics
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Resveratrol
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Stilbenes / pharmacology*
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Tongue Neoplasms / drug therapy
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Tongue Neoplasms / metabolism*
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Tongue Neoplasms / pathology
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Transcriptional Activation / drug effects
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Vascular Endothelial Growth Factors / antagonists & inhibitors
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Vascular Endothelial Growth Factors / biosynthesis*
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Vascular Endothelial Growth Factors / genetics
Substances
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Antineoplastic Agents, Phytogenic
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HIF1A protein, human
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Hypoxia-Inducible Factor 1, alpha Subunit
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Phosphoinositide-3 Kinase Inhibitors
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RNA, Messenger
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Stilbenes
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Vascular Endothelial Growth Factors
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Proto-Oncogene Proteins c-akt
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Mitogen-Activated Protein Kinases
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Resveratrol