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Research Articles: Therapeutics, Targets, and Development

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

¹ The Institute for Nutritional Sciences, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, Shanghai, China and ² MBR Cancer Center, West Virginia University, Morgantown, West Virginia

Requests for reprints: Jing Fang, The Institute for Nutritional Sciences, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China. Phone: 86-21-54920241; Fax: 86-21-54920291. E-mail: jfang{at}sibs.ac.cn

Abstract

Chrysin is a natural flavonoid and has been shown recently to have anticancer effects. However, the mechanisms that chrysin inhibits cancers are not well known. In this study, we investigated the effects of chrysin on expression of hypoxia-inducible factor-1 (HIF-1) and vascular endothelial growth factor in human prostate cancer DU145 cells. Chrysin inhibited insulin-induced expression of HIF-1 by reducing its stability. Chrysin increases ubiquitination and degradation of HIF-1 by increasing its prolyl hydroxylation. In addition, chrysin interfered with interaction between HIF-1 and heat shock protein 90. Chrysin was also found to inhibit HIF-1 expression through AKT signaling. Inhibition of HIF-1 by chrysin resulted in abrogation of vascular endothelial growth factor expression. Finally, we showed that chrysin inhibited DU145 xenograft-induced angiogenesis in nude mice. Taken together, these results suggest that chrysin is a potent inhibitor of HIF-1 and provide a new sight into the mechanisms of chrysin against cancers. [Mol Cancer Ther 2007;6(1):220–6]

Grant support: Shanghai Municipal Commission of Science and Technology grants 05DJ14009 and 04DZ14007 and National Nature Science Foundation of China grants 30470361 and 30570962.

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Received 8/28/06; revised 10/ 9/06; accepted 11/20/06.