Dibenzoylmethane, a natural dietary compound, induces HIF-1 alpha and increases expression of VEGF.
Hypoxia-inducible factor 1 (HIF-1) is the major transcription factor activated during hypoxia. It is composed of HIF-1 alpha and HIF-1 beta subunits. While HIF-1 beta is constitutively expressed, HIF-1 alpha is targeted to proteasome degradation under normoxic conditions. Under hypoxia, HIF-1 alpha is stabilized and heterodimerizes with HIF-1 beta. Iron chelators have also been reported to stabilize HIF-1 alpha protein and activate HIF-1. In this study, we investigated the effects of dibenzoylmethane (DBM), a natural dietary compound and an iron chelator, on HIF-1 pathway. We found that DBM increases HIF-1 alpha protein levels in a dose- and time-dependent manner. This induction was accompanied with activation of HIF-1, measured by reporter gene assay and increased production of its downstream target, the vascular endothelial growth factor. Mechanistically, HIF-1 alpha was stabilized by DBM at a step prior to ubiquitination. The effect of DBM on HIF-1 and its low toxicity profile might be therapeutically beneficial in ischemic diseases.
Mabjeesh
Nicola J
NJ
Department of Hematology and Oncology, Winship Cancer Institute, Emory University School of Medicine, 1365-B Clifton Road, Atlanta, GA 30322, USA.
Willard
Margaret T
MT
Harris
Wayne B
WB
Sun
He-Ying
HY
Wang
Ruoxiang
R
Zhong
Hua
H
Umbreit
Jay N
JN
Simons
Jonathan W
JW
D001565:Benzoates / Q000494:pharmacology*; D015153:Blotting, Western; D047188:Chalcones; D002614:Chelating Agents / Q000494:pharmacology; D019281:Dimerization; D004305:Dose-Response Relationship, Drug; D016228:Endothelial Growth Factors / Q000096:biosynthesis*; D004797:Enzyme-Linked Immunosorbent Assay; D017930:Genes, Reporter; D006801:Humans; D000860:Hypoxia; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis*; D007501:Iron / Q000378:metabolism; D008222:Lymphokines / Q000096:biosynthesis*; D013997:Time Factors; D014157:Transcription Factors / Q000096:biosynthesis*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D014407:Tumor Cells, Cultured; D025801:Ubiquitin / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D001565:Benzoates; D047188:Chalcones; D002614:Chelating Agents; D016228:Endothelial Growth Factors; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D014157:Transcription Factors; D025801:Ubiquitin; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C061481:dibenzoylmethane; D007501:Iron