TY - JOUR
T1 - trans-3,4,5′-Trihydroxystibene inhibits hypoxia-inducible factor 1α and vascular endothelial growth factor expression in human ovarian cancer cells
AU - Cao, Zongxian
AU - Fang, Jing
AU - Xia, Chang
AU - Shi, Xianglin
AU - Jiang, Bing Hua
PY - 2004/8/1
Y1 - 2004/8/1
N2 - trans-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 1α (HIF-1α) 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-1α mRNA levels, it did dramatically inhibit both basal-level and growth factor-induced HIF-1α protein expression in the cells. Resveratrol also greatly inhibited VEGF expression. Mechanistically, we demonstrated that resveratrol inhibited HIF-1α 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-1α expression. Second, resveratrol inhibited insulin-like growth factor 1-induced HIF-1α expression through the inhibition of protein translational regulators, including Mr 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-1α protein degradation through the proteasome pathway. Our data suggested that resveratrol may inhibit human ovarian cancer progression and angiogenesis by inhibiting HIF-1α and VEGF expression and thus provide a novel potential mechanism for the anticancer action of resveratrol.
AB - trans-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 1α (HIF-1α) 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-1α mRNA levels, it did dramatically inhibit both basal-level and growth factor-induced HIF-1α protein expression in the cells. Resveratrol also greatly inhibited VEGF expression. Mechanistically, we demonstrated that resveratrol inhibited HIF-1α 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-1α expression. Second, resveratrol inhibited insulin-like growth factor 1-induced HIF-1α expression through the inhibition of protein translational regulators, including Mr 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-1α protein degradation through the proteasome pathway. Our data suggested that resveratrol may inhibit human ovarian cancer progression and angiogenesis by inhibiting HIF-1α and VEGF expression and thus provide a novel potential mechanism for the anticancer action of resveratrol.
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U2 - 10.1158/1078-0432.CCR-03-0588
DO - 10.1158/1078-0432.CCR-03-0588
M3 - Article
C2 - 15297429
AN - SCOPUS:4143140856
SN - 1078-0432
VL - 10
SP - 5253
EP - 5263
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 15
ER -