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Flavonoids induce HIF-1alpha but impair its nuclear accumulation and activity.
Free Radic Biol Med. 2008 Feb 15; 44(4):657-70.FR

Abstract

Hypoxia-inducible factor-1alpha (HIF-1alpha) 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-1alpha 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-1alpha 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-1alpha induction. Despite the ability of flavonoids to stabilize HIF-1alpha, 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-1alpha protein levels. Localization of HIF-1alpha 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-1alpha, thereby decreasing its nuclear accumulation.

Authors+Show Affiliations

Department of Medicine, School of Health Sciences, University of Thessaly, 22 Papakyriazi Street, 41222 Larissa, Greece.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18061585

Citation

Triantafyllou, Anastasia, et al. "Flavonoids Induce HIF-1alpha but Impair Its Nuclear Accumulation and Activity." Free Radical Biology & Medicine, vol. 44, no. 4, 2008, pp. 657-70.
Triantafyllou A, Mylonis I, Simos G, et al. Flavonoids induce HIF-1alpha but impair its nuclear accumulation and activity. Free Radic Biol Med. 2008;44(4):657-70.
Triantafyllou, A., Mylonis, I., Simos, G., Bonanou, S., & Tsakalof, A. (2008). Flavonoids induce HIF-1alpha but impair its nuclear accumulation and activity. Free Radical Biology & Medicine, 44(4), 657-70.
Triantafyllou A, et al. Flavonoids Induce HIF-1alpha but Impair Its Nuclear Accumulation and Activity. Free Radic Biol Med. 2008 Feb 15;44(4):657-70. PubMed PMID: 18061585.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Flavonoids induce HIF-1alpha but impair its nuclear accumulation and activity. AU - Triantafyllou,Anastasia, AU - Mylonis,Ilias, AU - Simos,George, AU - Bonanou,Sophia, AU - Tsakalof,Andreas, Y1 - 2007/11/07/ PY - 2007/05/05/received PY - 2007/09/28/revised PY - 2007/10/29/accepted PY - 2007/12/7/pubmed PY - 2008/3/7/medline PY - 2007/12/7/entrez SP - 657 EP - 70 JF - Free radical biology & medicine JO - Free Radic Biol Med VL - 44 IS - 4 N2 - Hypoxia-inducible factor-1alpha (HIF-1alpha) 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-1alpha 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-1alpha 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-1alpha induction. Despite the ability of flavonoids to stabilize HIF-1alpha, 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-1alpha protein levels. Localization of HIF-1alpha 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-1alpha, thereby decreasing its nuclear accumulation. SN - 0891-5849 UR - https://www.unboundmedicine.com/medline/citation/18061585/Flavonoids_induce_HIF_1alpha_but_impair_its_nuclear_accumulation_and_activity_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0891-5849(07)00729-0 DB - PRIME DP - Unbound Medicine ER -