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.