The Antioxidant Quercetin Inhibits Cellular Proliferation via HIF-1-Dependent Induction of p21WAF

Abstract

Flavonoids are dietary antioxidants that may play a role as adjunct nutritional supplements in cancer or during inflammatory disorders. Hypoxia and the transcription factor hypoxia-inducible factor-1α also appear to play a key role in many human cancers. In this study, we investigated the role of quercetin in the hypoxia-dependent HIF-1α induction. It was shown that quercetin induced HIF-1α expression and HIF-1 activity under normoxia and hypoxia in human HepG2 hepatoma cells. By using actinomycin D and cycloheximide, we showed that quercetin acted post-transcriptionally by prolonging the HIF-1α protein half-life. Thereby quercetin interfered with the proline hydroxylation-dependent HIF-1α protein destabilization in the N-terminal HIF-1α transactivation domain. Experiments with quercetin analogues revealed that a flavonol structure and the presence of hydroxyl groups at position 3′ and 4′ are a prerequisite for the HIF-1α stabilizing effects. Further, quercetin inhibited cell proliferation and induced expression of the cell cycle inhibitor p21WAF and knocking-down HIF-1α disrupted these effects. These results provide evidence that quercetin inhibits the cell cycle and that induction of the HIF-system contributes to these effects of quercetin. Antioxid. Redox Signal. 13, 437–448.