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

Abstract

ABSTRACTtrans-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.

Statin and resveratrol in combination induces cardioprotection against myocardial infarction in hypercholesterolemic rat

“…From the literature β-catenin is found to be a critical mediator during development and angiogenesis [24], which is phosphorylated in a cytosolic multiprotein complex containing adenomatous polyposis coli protein (APC), Axin and GSK-3β [24][25][26][27]. When phosphorylation of β-catenin is blocked, this allows β-catenin to accumulate and translocate into nucleus, where it forms a complex with T-cell transcription factors/lymphoid-enhancer binding factor (TCF/LEF) family of transcription factors and is able to activate or repress several important target genes, such as c-Myc, cyclin D1, fibronectin, VEGF, Bcl-2 and survivin [28][29][30][31]. VEGF expression was found to be increased in HC (1.15 fold), HCR (1.86 fold), HCS (1.3 fold), HCRS (1.5 fold) when compared to control group.…”

Chrysin inhibits expression of hypoxia-inducible factor-1α through reducing hypoxia-inducible factor-1α stability and inhibiting its protein synthesis

“…Thus, it is conceivable that chrysin may also inhibit HIF-1a via AKT signaling. It was reported that flavonoids or related compounds, such as apigenin (28,46), resveratrol (47), and (À)-epigallocatechin-3-gallate (48), inhibited expression of HIF-1a through multiple pathways, including protein synthesis and protein degradation. Consistent with previous reports, we show here that chrysin is also multifunctioning in HIF-1a pathway.…”

Resveratrol Exerts Differential Effects in Vitro and in Vivo against Ovarian Cancer Cells

“…Further, alterations in the angiogenic characteristics of ovarian surface epithelium may play an important role in the etiology of ovarian cancer (Schumacher et al, 2007). Human ovarian cancer progression and angiogenesis were reduced by resveratrol through suppression of hypoxia-inducible factor 1α (HIF-1α) and vascular endothelial growth factor (VEGF) as observed (Cao et al, 2004). Thus, the potential array of therapeutic targets for this remarkable natural compound implicates the novel rationale for resveratrol as an extremely attractive candidate in the treatment of ovarian cancer.…”