Flavonoids induce HIF-1 alpha but impair its nuclear accumulation and activity

Abstract

Hypoxia-inducible factor-1 alpha (HIF-1 alpha) is the regulatory subunit of the transcription factor HIF-1, which is highly involved in the pathology of diseases associated with tissue hypoxia. In this study we investigated the ability of plant flavonoids to induce HIF-1 alpha and regulate HIF-1 transcriptional activity in HeLa cells. We demonstrate for the first time that the flavonoids baicalein, luteolin and fisetin, as well as the previously investigated quercetin, induce HIF-1 alpha under normal oxygen pressure, whereas kaempferol, taxifolin, and rutin are inactive. We further reveal that the capability of flavonoids to bind efficiently intracellular iron and their lipophilicity are essential for HIF-1 alpha induction. Despite the ability of flavonoids to stabilize HIF-1 alpha, the transcriptional activity of HIF-1 induced by flavonoids was significantly; lower than that observed with the iron chelator and known HIF-1 inducer, desferrioxamine (DFO). Furthermore, when cells in which HIF-1 had been induced by DFO were also treated with flavonoids, the transcriptional activity of HIF-1 was strongly impaired without simultaneous reduction in HIF-1 a protein levels. Localization of HIF-1 alpha by immuno- and direct fluorescence microscopy and in vitro phosphorylation assays suggest that flavonoids inhibit HIF-1 activity by impairing the MAPK-dependent phosphorylation of HIF-1 alpha, thereby decreasing its nuclear accumulation. (c) 2007 Elsevier Inc. All rights reserved.