trans- 3,4,5′-Trihydroxystibene Inhibits Hypoxia-Inducible Factor 1α and Vascular Endothelial Growth Factor Expression in Human Ovarian Cancer Cells
Open Access
- 1 August 2004
- journal article
- Published by American Association for Cancer Research (AACR) in Clinical Cancer Research
- Vol. 10 (15), 5253-5263
- https://doi.org/10.1158/1078-0432.ccr-03-0588
Abstract
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.Keywords
This publication has 36 references indexed in Scilit:
- The subtle side to hypoxia inducible factor (HIFα) regulationEuropean Journal of Biochemistry, 2003
- Cellular adaptation to hypoxia: O2‐sensing protein hydroxylases, hypoxia‐inducible transcription factors, and O2‐regulated gene expressionThe FASEB Journal, 2002
- Cancer Statistics, 2001CA: A Cancer Journal for Clinicians, 2001
- Cellular function of p70S6K: A role in regulating cell motilityImmunology & Cell Biology, 2000
- Resveratrol, a Natural Product Present in Wine, Decreases Tumour Growth in a Rat Tumour ModelBiochemical and Biophysical Research Communications, 1999
- Cancer Chemopreventive Activity of Resveratrol, a Natural Product Derived from GrapesScience, 1997
- Cyclophosphamide and Cisplatin Compared with Paclitaxel and Cisplatin in Patients with Stage III and Stage IV Ovarian CancerNew England Journal of Medicine, 1996
- Expression of Vascular Endothelial Growt Factor and Its Receptors fit and KDR in Ovarian CarcinomaJNCI Journal of the National Cancer Institute, 1995
- What Is the Evidence That Tumors Are Angiogenesis Dependent?JNCI Journal of the National Cancer Institute, 1990
- The production of resveratrol by Vitis vinifera and other members of the Vitaceae as a response to infection or injuryPhysiological Plant Pathology, 1976