HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

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

This Article Full Text Full Text (PDF) All Versions of this Article: 282/24/17685    most recent M701429200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Pozzi, A. Articles by Capdevila, J. H. Search for Related Content PubMed PubMed Citation Articles by Pozzi, A. Articles by Capdevila, J. H. Social Bookmarking                      What's this?

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.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				P. J. H. Smeets, H. M. de Vogel-van den Bosch, P. H. M. Willemsen, A. P. Stassen, T. Ayoubi, G. J. van der Vusse, and M. van Bilsen Transcriptomic analysis of PPAR{alpha}-dependent alterations during cardiac hypertrophy Physiol Genomics, December 12, 2008; 36(1): 15 - 23. [Abstract] [Full Text] [PDF]

				J. Ma and D. J. Waxman Combination of antiangiogenesis with chemotherapy for more effective cancer treatment Mol. Cancer Ther., December 1, 2008; 7(12): 3670 - 3684. [Abstract] [Full Text] [PDF]

				S. Y. Cheranov, M. Karpurapu, D. Wang, B. Zhang, R. C. Venema, and G. N. Rao An essential role for SRC-activated STAT-3 in 14,15-EET-induced VEGF expression and angiogenesis Blood, June 15, 2008; 111(12): 5581 - 5591. [Abstract] [Full Text] [PDF]

				D. Panigrahy, A. Kaipainen, S. Huang, C. E. Butterfield, C. M. Barnes, M. Fannon, A. M. Laforme, D. M. Chaponis, J. Folkman, and M. W. Kieran PPAR{alpha} agonist fenofibrate suppresses tumor growth through direct and indirect angiogenesis inhibition PNAS, January 22, 2008; 105(3): 985 - 990. [Abstract] [Full Text] [PDF]