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J. Biol. Chem., Vol. 279, Issue 43, 44344-44354, October 22, 2004

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Transforming Growth Factor- (TGF-) Activates Cytosolic Phospholipase A₂ (cPLA₂)-mediated Prostaglandin E₂ (PGE)₂/EP₁ and Peroxisome Proliferator-activated Receptor- (PPAR-)/Smad Signaling Pathways in Human Liver Cancer Cells

A NOVEL MECHANISM FOR SUBVERSION OF TGF--INDUCED MITOINHIBITION^*

Chang Han, A. Jake Demetris, Youhua Liu, James H. Shelhamer, and Tong Wu¶

From the Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213 and the Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland 20892

Transforming growth factor- (TGF-) potently inhibits the growth of human epithelial cells. However, neoplastic epithelial cells become resistant to TGF--mediated mitoinhibition, and the mechanisms for this alteration during tumorigenesis are not fully understood. This study was designed to determine whether there is an association between the cytosolic phospholipase A₂ (cPLA₂)-controlled eicosanoid metabolism and the growth response to TGF- in human liver cancer cells. TGF- treatment induced simultaneous Smad-mediated gene transcription and phosphorylation of cPLA₂. Whereas Smad activation inhibited tumor cell growth, phosphorylation of cPLA₂ promoted growth and counteracted Smad-mediated mitoinhibition. TGF-1 failed to prevent the growth of cells with high basal expression of cPLA₂, but inhibition of cPLA₂ , cyclooxygenase-2 (COX-2), or EP₁ receptor restored mi-toinhibition by TGF-1 in these cells. These results suggest that resistance of tumor cells to TGF--mediated mitoinhibition involves activation of cPLA₂ /COX-2/EP₁ signaling. Furthermore, the TGF-1-induced Smad transcriptional activity and mitoinhibition were blocked by overexpression of cPLA₂ or peroxisome proliferator-activated receptor- (PPAR-) but enhanced by depletion of cPLA₂ or PPAR-. These findings, along with the observations that cPLA₂ activates PPAR- and that PPAR- binds Smad3, illustrate novel cPLA₂/COX-2/EP₁ and cPLA₂/PPAR-/Smad signaling pathways that counteract the mitoinhibition by TGF- in human cancer cells.

Received for publication, April 30, 2004 , and in revised form, August 2, 2004.

^* This work was supported by grants from the American Liver Foundation and the Cancer Research Foundation of America and by Grant DK49615 from the National Institutes of Health. 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.

^¶ To whom correspondence should be addressed: Dept. of Pathology, University of Pittsburgh School of Medicine, Presbyterian University Hospital C902, 200 Lothrop St., Pittsburgh, PA 15213. Tel.: 412-647-9504; Fax: 412-647-5237; E-mail: wut{at}upmc.edu.

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