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

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.