title: Activation of peroxisome proliferator-activated receptor α (PPARα) suppresses hypoxia-inducible factor-1α (HIF-1α) signaling in cancer cells.
abstract: Activation of peroxisome proliferator-activated receptor α (PPARα) has been demonstrated to inhibit tumor growth and angiogenesis, yet the mechanisms behind these actions remain to be characterized. In this study, we examined the effects of PPARα activation on the hypoxia-inducible factor-1α (HIF-1α) signaling pathway in human breast (MCF-7) and ovarian (A2780) cancer cells under hypoxia. Incubation of cancer cells under 1% oxygen for 16 h significantly induced HIF-1α expression and activity as assayed by Western blotting and reporter gene analysis. Treatment of the cells with PPARα agonists, but not a PPARγ agonist, prior to hypoxia diminished hypoxia-induced HIF-1α expression and activity, and addition of a PPARα antagonist attenuated the suppression of HIF-1α signaling. Activation of PPARα attenuated hypoxia-induced HA-tagged HIF-1α protein expression without affecting the HA-tagged HIF-1α mutant protein level, indicating that PPARα activation promotes HIF-1α degradation in these cells. This was further confirmed using proteasome inhibitors, which reversed PPARα-mediated suppression of HIF-1α expression under hypoxia. Using the co-immunoprecipitation technique, we found that activation of PPARα enhances the binding of HIF-1α to von Hippel-Lindau tumor suppressor (pVHL), a protein known to mediate HIF-1α degradation through the ubiquitin-proteasome pathway. Following PPARα-mediated suppression of HIF-1α signaling, VEGF secretion from the cancer cells was significantly reduced, and tube formation by endothelial cells was dramatically impaired. Taken together, these findings demonstrate for the first time that activation of PPARα suppresses hypoxia-induced HIF-1α signaling in cancer cells, providing novel insight into the anticancer properties of PPARα agonists.
authors.affiliation: Department of Radio-Oncology, Nanjing Medical University Affiliated Suzhou Hospital; Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104.
authors.forename: Jundong
authors.initials: J
authors.lastname: Zhou
authors.affiliation: School of Radiation Medicine and Protection, Soochow University, Suzhou 205123, China; Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104.
authors.forename: Shuyu
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Radio-Oncology, Nanjing Medical University Affiliated Suzhou Hospital; Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104.
authors.forename: Jing
authors.initials: J
authors.lastname: Xue
authors.affiliation: Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104.
authors.forename: Jori
authors.initials: J
authors.lastname: Avery
authors.affiliation: Department of Radio-Oncology, Nanjing Medical University Affiliated Suzhou Hospital.
authors.forename: Jinchang
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Pathology and Medicine, University of Colorado Denver, Denver, Colorado 80217.
authors.forename: Stuart E
authors.initials: SE
authors.lastname: Lind
authors.affiliation: Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104. Electronic address: weiqun-ding@ouhsc.edu.
authors.forename: Wei-Qun
authors.initials: WQ
authors.lastname: Ding
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis* / Q000235:genetics; D009154:Mutation; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D047493:PPAR alpha / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000494:pharmacology; D059748:Proteolysis; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics / Q000378:metabolism
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D047493:PPAR alpha; D061988:Proteasome Inhibitors; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D046988:Proteasome Endopeptidase Complex; C497446:VHL protein, human