Benzo[a]pyrene-3,6-dione inhibited VEGF expression through inducing HIF-1alpha degradation.
Vascular endothelial growth factor (VEGF) is a potent angiogenesis inducer for tumor growth and angiogenesis. Benzo[a]pyrene (BaP) belongs to polycyclic aromatic hydrocarbons (PAHs) and is known to cause carcinogenesis. But the effects of BaP and its metabolites on VEGF and HIF-1 expression remain to be elucidated. In this study, we ... found benzo[a]pyrene-3,6-dione (BPQ), but not BaP and benzo[a]pyrene-7,8-diol-9,10-epoxide (BPDE) inhibited VEGF expression in a dose-dependent manner. BPQ inhibited VEGF transcriptional activation through hypoxia-inducible factor 1 (HIF-1) binding site. BPQ specifically decreased HIF-1alpha, but not HIF-1beta subunit expression in A549 cells. We found that BPQ did not inhibit HIF-1alpha mRNA level, but inhibited its protein expression in a proteasome-dependent manner. To further clarify the mechanism of BPQ in regulating HIF-1alpha stability, we found that BPQ inhibited HIF-1alpha protein expression by the increase of the proteasome-dependent degradation, and by the disruption of HIF-1alpha and Hsp90 association.
Mesh Terms:
Adenocarcinoma, Benzopyrenes, Cell Line, Dose-Response Relationship, Drug, Gene Expression, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, Kidney, Proteasome Endopeptidase Complex, Signal Transduction, Vascular Endothelial Growth Factor A
Adenocarcinoma, Benzopyrenes, Cell Line, Dose-Response Relationship, Drug, Gene Expression, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, Kidney, Proteasome Endopeptidase Complex, Signal Transduction, Vascular Endothelial Growth Factor A
Biochem. Biophys. Res. Commun.
Date: Jun. 01, 2007
PubMed ID: 17442277
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