Abstract

The peroxisomal proliferator-activated nuclear receptor-alpha (PPAR alpha), 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, PPAR alpha and its ligands have been implicated in inflammatory responses and the regulation of cell proliferation. PPAR alpha also regulates the expression of Cyp4a fatty acid omega-hydroxylases and Cyp2c arachidonic acid epoxygenase genes. To study the role of the PPAR alpha receptor and of its Cyp2c epoxygenase gene target in tumorigenesis, we treated mice injected with tumor cells with Wy-14,643, a PPAR alpha-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 PPAR alpha(-/-) mice and are thus PPAR alpha-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 PPRA alpha(-/-) mice and reversed by the addition of EETs. These results identify important anti- angiogenic and anti- tumorigenic roles for PPAR alpha, 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.