Quercetin suppresses hypoxia-induced accumulation of hypoxia-inducible factor-1α (HIF-1α) through inhibiting protein synthesis

被引:68
作者
Lee, Dae-Hee [1 ]
Lee, Yong J. [1 ]
机构
[1] Univ Pittsburgh, Sch Med, Dept Surg & Pharmacol, Pittsburgh, PA 15213 USA
关键词
quercetin; hypoxia; hypoxia-inducible factor-1 alpha; VEGF; protein synthesis; pVHL;
D O I
10.1002/jcb.21851
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Quercetin, a ubiquitous bioactive plant flavonoid, has been shown to inhibit. the proliferation of cancer cells and induce the accumulation of hypoxia-inducible factor-1 alpha (HIF-1 alpha) in normoxia. In this study, under hypoxic conditions (1% O(2)), we examined the effect of quercetin on the intracellular level of HIF-1 alpha and extracellular level of vascular endothelial growth factor (VEGF) in a variety of human cancer cell lines. Surprisingly, we observed that quercetin suppressed the HIF-1 alpha accumulation during hypoxia in human prostate cancer LNCaP, colon cancer CX-1, and breast cancer SkBr3 cells. Quercetin treatment also significantly reduced hypoxia-induced secretion of VEGF. Suppression of HIF-1 alpha accumulation during treatment with quercetin in hypoxia was not prevented by treatment with 26S proteasome inhibitor MG132 or PI3K inhibitor LY294002. Interestingly, hypoxia (1% O(2)) in the presence of 100 mu M quercetin inhibited protein synthesis by 94% during incubation for 8 h. Significant quercetin concentration-dependent inhibition of protein synthesis and suppression of HIF-1 alpha accumulation were observed under hypoxic conditions. Treatment with 100 mu M cycloheximide, a protein synthesis inhibitor, replicated the effect of quercetin by inhibiting HIF-1 alpha accumulation during hypoxia. These results suggest that suppression of HIF-1 alpha accumulation during treatment with quercetin under hypoxic conditions is due to inhibition of protein synthesis.
引用
收藏
页码:546 / 553
页数:8
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