Flavonoids-induced accumulation of hypoxia-inducible factor (HIF)-1α/2α is mediated through chelation of iron

✍ Scribed by Sung-Soo Park; Insoo Bae; Yong J. Lee

• Publisher: John Wiley and Sons
• Year: 2008
• Tongue: English
• Weight: 286 KB
• Volume: 103
• Category: Article
• ISSN: 0730-2312
• DOI: 10.1002/jcb.21588

✦ Synopsis

Abstract

Hypoxia‐inducible factor‐1 alpha (HIF‐1α) is the regulatory subunit of the heterodimeric transcription factor HIF‐1 that is the key regulator of cellular response to low oxygen tension. Under normoxic conditions, HIF‐1α is continuously degraded by the ubiquitin‐proteasome pathway through pVHL (von Hippel–Lindau tumor suppressor protein). Under hypoxic conditions, HIF‐1α is stabilized and induces the transcription of HIF‐1 target genes. Quercetin, a flavonoid with anti‐oxidant, anti‐inflammatory, and kinase modulating properties, has been found to induce HIF‐1α accumulation and VEGF secretion in normoxia. In this study, the molecular mechanisms of quercetin‐mediated HIF‐1α accumulation were investigated. Previous studies have shown that, in addition to being induced by hypoxia, HIF‐1α can be induced through the phosphatidylinositol 3‐kinase (PI3K)/Akt and p53 signaling pathways. But our study revealed, through p53 mutant‐type as well as p53 null cell lines, that neither the PI3K/Akt nor the p53 signaling pathway is required for quercetin‐induced HIF‐1α accumulation. And we observed that HIF‐1α accumulated by quercetin is not ubiquitinated and the interaction of HIF‐1α with pVHL is reduced, compared with HIF‐1α accumulated by the proteasome inhibitor MG132. The use of quercetin's analogues showed that only quercetin and galangin induce HIF‐1/2α accumulation and this effect is completely reversed by additional iron ions. This is because quercetin and galangin are able to chelate cellular iron ions that are cofactors of HIF‐1/2α proline hydroxylase (PHD). These data suggest that quercetin inhibits the ubiquitination of HIF‐1/2α in normoxia by hindering PHD through chelating iron ions. J. Cell. Biochem. 103: 1989–1998, 2007. © 2007 Wiley‐Liss, Inc.