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J. Biol. Chem., Vol. 281, Issue 45, 33982-33996, November 10, 2006

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A Novel Positive Feedback Loop between Peroxisome Proliferator-activated Receptor- and Prostaglandin E₂ Signaling Pathways for Human Cholangiocarcinoma Cell Growth^*

From the Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213

Peroxisome proliferator-activated receptor- (PPAR) is a nuclear receptor implicated in lipid oxidation and the pathogenesis of obesity and diabetes. This study was designed to examine the potential effect of PPAR on human cholangiocarcinoma cell growth and its mechanism of actions. Overexpression of PPAR or activation of PPAR by its pharmacological ligand, GW501516, at low doses (0.5–50 nM) promoted the growth of three human cholangiocarcinoma cell lines (CCLP1, HuCCT1, and SG231). This effect was mediated by induction of cyclooxygenase-2 (COX-2) gene expression and production of prostaglandin E₂ (PGE₂) that in turn transactivated epidermal growth factor receptor (EGFR) and Akt. In support of this, inhibition of COX-2, EGFR, and Akt prevented the PPAR-induced cell growth. Furthermore, PPAR activation or PGE₂ treatment induced the phosphorylation of cytosolic phospholipase A₂ (cPLA₂), a key enzyme that releases arachidonic acid (AA) substrate for PG production via COX. Overexpression or activation of cPLA₂ enhanced PPAR binding to PPAR response element (DRE) and increased PPAR reporter activity, indicating a novel role of cPLA₂ for PPAR activation. Consistent with this, AA enhanced the binding of PPAR to DRE, in vitro, suggesting a direct role of AA for PPAR activation. In contrast, although PGE₂ treatment increased the DRE reporter activity in intact cells, it failed to induce PPAR binding to DRE in cell-free system, suggesting that cPLA₂-mediated AA release is required for PGE₂-induced PPAR activation. Taken together, these observations reveal that PPAR induces COX-2 expression in human cholangiocarcinoma cells and that the COX-2-derived PGE₂ further activates PPAR through phosphorylation of cPLA₂. This positive feedback loop plays an important role for cholangiocarcinoma cell growth and may be targeted for chemoprevention and treatment.

Received for publication, January 5, 2006 , and in revised form, August 24, 2006.

^* This work was supported by National Institutes of Health R01 Grants CA102325 and CA106280 (to T. W.). 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 Pathology, University of Pittsburgh School of Medicine, MUH E-740, 200 Lothrop St., Pittsburgh, PA 15213. Tel.: 412-647-9504; Fax: 412-647-5237; E-mail: wut{at}upmc.edu.

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