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

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-1A (HIF-1A) and vascular endothelial growth factor in human prostate cancer DU145 cells. Chrysin inhibited insulin-induced expression of HIF-1A by reducing its stability. Chrysin increases ubiquitination and degradation of HIF-1A by increasing its prolyl hydroxylation. In addition, chrysin interfered with interaction between HIF-1A and heat shock protein 90. Chrysin was also found to inhibit HIF-1A expression through AKT signaling. Inhibition of HIF-1A 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-1A and provide a new sight into the mechanisms of chrysin against cancers. [Mol Cancer Ther 2007;6(1):220 -6]

A flavonoid chrysin suppresses hypoxic survival and metastatic growth of mouse breast cancer cells

“…In a previous study, STAT3 signaling was not investigated, and the inhibitory effect of chrysin on Akt-modulated HIF-1α protein stability was shown only in the insulin-stimulated normoxic cells, but the mechanism was not tested in hypoxic cells (16). In 4T1 cells, the inhibition of hypoxia-induced VEGF expression and STAT3 activation by chrysin were observed at a concentration lower than that affecting Akt phosphorylation ( Fig.…”

“…Our results clearly show that chrysin, as well as a STAT3 inhibitor, could abrogate hypoxia-induced VEGF gene expression of 4T1 cells, through inhibition of STAT3 tyrosine phosphorylation, without decreasing HIF-1α protein levels. Chrysin has been shown to decrease HIF-1α protein levels in hypoxic DU145 human prostate cancer cells, thus abrogating insulin-induced HIF-1α protein stabilization in normoxic DU145 cells, via inhibition of Akt phosphorylation (16).…”

“…Inhibition of subcutaneous tumor growth by chrysin has recently been demonstrated in mouse models of breast cancer and hepatoma (14,15). Chrysin has also been shown to suppress hypoxia-induced VEGF expression in human prostate cancer cells in vitro (16), and abrogates tumor-induced angiogenesis in vivo (15,16). However, until now, there has been no report on the effect of chrysin on hypoxic survival and metastatic progression of cancer cells.…”

Chrysin Inhibits Lymphangiogenesis <i>in Vitro</i>

“…9,11,12) In addition, chrysin inhibits angiogenesis by suppression of endothelial cell proliferation and migration in human umbilical vascular endothelial cells (HUVEC). [18][19][20][21] However, the potency of chrysin on lymphangiogenesis is not currently available. The chrysin at non-toxic concentration 25 μM (Fig.…”

Anti-asthmatic potential of chrysin on ovalbumin-induced bronchoalveolar hyperresponsiveness in rats

“…Anti-asthmatic potential of chrysin on ovalbumin-induced bronchoalveolar hyperresponsiveness in rats (Caprifoliaceae) (Rahman Kang, 2009), Cyclanthera pedata Scrabs (Caigua) (Montoro et al, 2005), and bee propolis (Burdock, 1998), was reported to possess inhibition of IgE and Th2 cytokine (Yano et al, 2007), inhibition of cyclooxygenase (COX), inducible nitric oxide synthase (iNOS) (Liang et al, 2001;Cho et al, 2004;Hougee et al, 2005;Woo et al, 2005;Comalada et al, 2006;Harris et al, 2006), and hypoxia-inducible factor-1 expression (Fu et al, 2007).…”