Peroxisomal proliferator-activated receptor-alpha-dependent inhibition of endothelial cell proliferation and tumorigenesis.
The peroxisomal proliferator-activated nuclear receptor-alpha (PPARalpha), the target for most hypolipidemic drugs in current clinical use, regulates the transcription of genes involved in lipid metabolism and transport, and energy homeostasis. More recently, PPARalpha and its ligands have been implicated in inflammatory responses and the regulation of cell proliferation. PPARalpha also regulates the expression of Cyp4a fatty acid omega-hydroxylases and Cyp2c arachidonic acid epoxygenase genes. To study the role of the PPARalpha receptor and of its Cyp2c epoxygenase gene target in tumorigenesis, we treated mice injected with tumor cells with Wy-14,643, a PPARalpha-selective ligand. Compared with untreated controls, Wy-14643-treated animals showed marked reductions in tumor growth and vascularization, which were accompanied by decreases in the plasma levels of pro-angiogenic epoxygenase metabolites (EETs), hepatic EET biosynthesis, and Cyp2c epoxygenase expression. All these Wy-14643-induced responses were absent in PPARalpha(-/-) mice and are thus PPARalpha-mediated. Primary cultures of mouse lung endothelial cells treated with Wy-14643 showed reductions in cell proliferation and in the formation of capillary-like structures. These effects were absent in cells obtained from PPRAalpha(-/-) mice and reversed by the addition of EETs. These results identify important anti-angiogenic and anti-tumorigenic roles for PPARalpha, characterize the contribution of its Cyp2c epoxygenases gene target to these responses, and suggest potential anti-cancer roles for this nuclear receptor and its ligands.
Pozzi
Ambra
A
Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
Ibanez
Maria Raquel
MR
Gatica
Arnaldo E
AE
Yang
Shilin
S
Wei
Shouzuo
S
Mei
Shaojun
S
Falck
John R
JR
Capdevila
Jorge H
JH
D000818:Animals; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D015777:Eicosanoids / Q000737:chemistry / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000502:physiology*; D008099:Liver / Q000201:enzymology; D008168:Lung / Q000166:cytology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism*; D011743:Pyrimidines / Q000378:metabolism
D015777:Eicosanoids; D047493:PPAR alpha; D011743:Pyrimidines; C400322:cytochrome P-450 CYP2C subfamily; C006253:pirinixic acid; D003577:Cytochrome P-450 Enzyme System