Dibenzoylmethane, a natural dietary compound, induces HIF-1 alpha and increases expression of VEGF

Biochem Biophys Res Commun. 2003 Mar 28;303(1):279-86. doi: 10.1016/s0006-291x(03)00336-x.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Benzoates / pharmacology*
  • Blotting, Western
  • Chalcones*
  • Chelating Agents / pharmacology
  • Dimerization
  • Dose-Response Relationship, Drug
  • Endothelial Growth Factors / biosynthesis*
  • Enzyme-Linked Immunosorbent Assay
  • Genes, Reporter
  • Humans
  • Hypoxia
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Intercellular Signaling Peptides and Proteins / biosynthesis*
  • Iron / metabolism
  • Lymphokines / biosynthesis*
  • Time Factors
  • Transcription Factors / biosynthesis*
  • Transcription, Genetic
  • Transcriptional Activation
  • Transfection
  • Tumor Cells, Cultured
  • Ubiquitin / metabolism
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors

Substances

  • Benzoates
  • Chalcones
  • Chelating Agents
  • Endothelial Growth Factors
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Intercellular Signaling Peptides and Proteins
  • Lymphokines
  • Transcription Factors
  • Ubiquitin
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors
  • dibenzoylmethane
  • Iron