The flavonoid quercetin induces hypoxia-inducible factor-1alpha (HIF-1alpha) and inhibits cell proliferation by depleting intracellular iron.
Quercetin, a flavonoid with anti-oxidant, metal chelating, kinase modulating and anti-proliferative properties, can induce hypoxia-inducible factor-1alpha (HIF-1alpha) in normoxia, but its mechanism of action has not been determined. In this study we characterized the induction of HIF-1alpha and the inhibition of cell proliferation caused by quercetin in HeLa and ASM (airway smooth muscle) cells and examined the effect of iron on these processes. Furthermore, we investigated the relevance of the intracellular levels of quercetin to HIF-1alpha expression and cell proliferation. Our data demonstrate that quercetin depletes intracellular calcein-chelatable iron and that supplying additional iron from extracellular or intracellular pools abrogates the induction of HIF-1alpha by quercetin. Moreover, addition of iron reverses the quercetin-induced inhibition of DNA synthesis, cell proliferation and cycle progression, but to different extents, depending on cell type. We propose that quercetin stabilises HIF-1alpha and inhibits cell proliferation predominantly by decreasing the concentration of intracellular iron through chelation.
Triantafyllou
Anastasia
A
Laboratory of Biochemistry, Department of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece.
Liakos
Panagiotis
P
Tsakalof
Andreas
A
Chachami
Georgia
G
Paraskeva
Efrosyni
E
Molyvdas
Pashalis-Adam
PA
Georgatsou
Elena
E
Simos
George
G
Bonanou
Sophia
S
D000975:Antioxidants / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects*; D002614:Chelating Agents / Q000737:chemistry; D005290:Ferric Compounds / Q000494:pharmacology; D005419:Flavonoids / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D005452:Fluoresceins / Q000032:analysis; D015870:Gene Expression / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007501:Iron / Q000032:analysis; D000090463:Iron Deficiencies; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011794:Quercetin / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects; D015854:Up-Regulation
D000975:Antioxidants; D002614:Chelating Agents; D005290:Ferric Compounds; D005419:Flavonoids; D005452:Fluoresceins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007501:Iron; D020929:Mitogen-Activated Protein Kinase Kinases; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011794:Quercetin; C025314:ferric citrate; C007740:fluorexon