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.
Li
Zhao-Dong
ZD
Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
Liu
Ling-Zhi
LZ
Shi
Xianglin
X
Fang
Jing
J
Jiang
Bing-Hua
BH
D000230:Adenocarcinoma / Q000378:metabolism*; D001580:Benzopyrenes / Q000008:administration & dosage*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
D001580:Benzopyrenes; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A; D046988:Proteasome Endopeptidase Complex