期刊
TOXICOLOGY AND APPLIED PHARMACOLOGY
卷 271, 期 2, 页码 144-155出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.taap.2013.04.031
关键词
Hypoxia-inducible factor-1 alpha (HIF-1 alpha); Angiogenesis; Degradation; Wogonin
资金
- National Natural Science Foundation of China [30973556, 81001452]
- Program for Changjiang Scholars and Innovative Research Team in University [IRT1193]
- State Key Laboratory of Natural Medicines, China Pharmaceutical University [JKGZ201101]
- Fundamental Research Funds for the Central Universities [JKP2011003]
- National Science & Technology Major Project [2012ZX09304-001]
- Natural Science Foundation of Jiangsu Province [BK2009297, BK2010432]
Wogonin, a plant-derived flavone, has been shown recently to have antitumor effects. However, the mechanisms that wogonin inhibits tumor angiogenesis are not well known. In this study, we investigated the effects of wogonin on expression of hypoxia-inducible factor-1 alpha (HIF-1 alpha) and secretion of vascular endothelial growth factor (VEGF) in tumor cells. We found that wogonin decreased the expression of HIF-1 alpha by affecting its stability and reduced the secretion of VEGF, which suppressed angiogenesis in cancer. Wogonin promoted the degradation of HIF-1 alpha by increasing its prolyl hydroxylation, which depended on prolyl hydroxylase (PHD) and the von Hippel-Lindau tumor suppressor (VHL). Intriguingly, wogonin impeded the binding between heat-shock protein 90 (Hsp90) and HIF-1 alpha. In addition, wogonin down-regulated the Hsp90 client proteins EGFR, Cdk4 and survivin, but did not affect the level of Hsp90. Wogonin also increased ubiquitination of HIF-1 alpha and promoted its degradation in proteasome. We also found that wogonin could inhibit nuclear translocation of HIF-1 alpha. Electrophoresis mobility shift assay (EMSA) showed that wogonin decreased the binding activity of exogenous consensus DNA oligonucleotide with HIF-1 alpha in nuclear extracts from MCF-7 cells. Chromatin immunoprecipitation (ChIP) assay also revealed that HIF-1 alpha directly binded to endogenous hypoxia-responsive element (HRE) and this binding was significantly decreased in MCF-7 cells treated with wogonin. Preliminary results indicated in vivo activity of wogonin against xenograft-induced angiogenesis in nude mice. Taken together, the results suggested that wogonin was a potent inhibitor of HIF-1 alpha and provided a new insight into the mechanisms of wogonin against cancers. (C) 2013 Elsevier Inc. All rights reserved.
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