The antioxidant quercetin inhibits cellular proliferation via HIF-1-dependent induction of p21WAF.
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-1alpha 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-1alpha induction. It was shown that quercetin induced HIF-1alpha 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-1alpha protein half-life. Thereby quercetin interfered with the proline hydroxylation-dependent HIF-1alpha protein destabilization in the N-terminal HIF-1alpha 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-1alpha stabilizing effects. Further, quercetin inhibited cell proliferation and induced expression of the cell cycle inhibitor p21WAF and knocking-down HIF-1alpha 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.
Bach
Aline
A
Department of Chemistry, University of Kaiserslautern , Kaiserslautern, Germany.
Bender-Sigel
Julia
J
Schrenk
Dieter
D
Flügel
Daniela
D
Kietzmann
Thomas
T
D000975:Antioxidants / Q000494:pharmacology*; D015152:Blotting, Northern; D015153:Blotting, Western; D000001:Calcimycin / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002614:Chelating Agents / Q000494:pharmacology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D044950:Flavanones / Q000494:pharmacology; D047309:Flavones / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D044948:Flavonols / Q000494:pharmacology; D019073:HT29 Cells; D056945:Hep G2 Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D047311:Luteolin / Q000494:pharmacology; D011393:Procollagen-Proline Dioxygenase / Q000378:metabolism; D055550:Protein Stability / Q000187:drug effects; D011794:Quercetin / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism
D000975:Antioxidants; D002614:Chelating Agents; D050759:Cyclin-Dependent Kinase Inhibitor p21; D044950:Flavanones; D047309:Flavones; D005419:Flavonoids; D044948:Flavonols; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017382:Reactive Oxygen Species; C070379:1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester; D000001:Calcimycin; D004533:Egtazic Acid; C040015:myricetin; D011794:Quercetin; D011393:Procollagen-Proline Dioxygenase; D047311:Luteolin