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J. Biol. Chem., Vol. 282, Issue 24, 17685-17695, June 15, 2007

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Peroxisomal Proliferator-activated Receptor--dependent Inhibition of Endothelial Cell Proliferation and Tumorigenesis^*

Ambra Pozzi^¶, Maria Raquel Ibanez, Arnaldo E. Gatica, Shilin Yang, Shouzuo Wei, Shaojun Mei, John R. Falck^||, and Jorge H. Capdevila^**1

From the Departments of Medicine, Cancer Biology, and ^**Biochemistry, Vanderbilt University Medical Center, Nashville, Tennessee 37232, the ^¶Veterans Affairs Hospital, Nashville, Tennessee 37212, and the ^||Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390

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

Received for publication, February 16, 2007 , and in revised form, March 26, 2007.

^* This work was supported by National Institutes of Health Grants R01-CA94849 (to A. P.), R01-DK74359 (to A. P.), R01-GM37922 (to J. H. C.), R01-GM31278 (to J. R. F.), P01-DK38226 (to J. C. H. and J. R. F.), the Robert A. Welch Foundation (to J. R. F.), and by Vanderbilt University Mass Spectrometry Center, supported in part by Cancer Center Grant CA-68485. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Medicine, Vanderbilt University Medical School, Medical Center North S-3223, Nashville, TN 37232. Tel.: 615-322-4968; Fax: 615-343-4704; E-mail: jorge.capdevila{at}vanderbilt.edu.

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