Resveratrol inhibits hypoxia-induced accumulation of hypoxia-inducible factor-1alpha and VEGF expression in human tongue squamous cell carcinoma and hepatoma cells.
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.
Zhang
Qunzhou
Q
Center for Craniofacial Molecular Biology, University of Southern California, School of Dentistry, Los Angeles 90033, USA.
Tang
Xudong
X
Lu
Qing Yi
QY
Zhang
Zuo Feng
ZF
Brown
Jimmy
J
Le
Anh D
AD
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D015687:Cell Hypoxia / Q000502:physiology; D045744:Cell Line, Tumor; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009361:Neoplasm Invasiveness; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*; D014062:Tongue Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D015533:Transcriptional Activation / Q000187:drug effects; D042442:Vascular Endothelial Growth Factors / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics
D000972:Antineoplastic Agents, Phytogenic; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; D000077185:Resveratrol; D013267:Stilbenes; D042442:Vascular Endothelial Growth Factors; C497442:HIF1A protein, human