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J. Biol. Chem., Vol. 281, Issue 34, 24831-24846, August 25, 2006

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Modulation of Stat3 Activation by the Cytosolic Phospholipase A₂ and Cyclooxygenase-2-controlled Prostaglandin E₂ Signaling Pathway^*

Chang Han¹, A. Jake Demetris, Donna B. Stolz, Lihong Xu, Kyu Lim, and Tong Wu²

From the Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania 15213 and the Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, Pennsylvania 15261

A variety of human cancers show constitutive activation of signal transducer and activator of transcription-3 (Stat3) and overexpression of cyclooxygenase-2 (COX-2). This study describes a novel cross-talk between the COX-2-controlled prostaglandin E₂ (PGE₂) and Stat3 signaling pathways that coordinately regulate human cancer cell growth. COX-2-derived PGE₂ induces interleukin-6 production through activation of EP₄ receptor and subsequent phosphorylation of gp130/Stat3 in human cholangiocarcinoma cells. In parallel, activation of COX-2/PGE₂ signaling also enhances Stat3 phosphorylation and reporter activity through EP₁ receptor-induced activation of c-Src and EGFR in these cells. Moreover, the observations that EP₁ receptor is detected in the nucleus as well as in the Stat3·DNA binding complex and that activation of EP₁ receptor in the nuclei enhances Stat3 activation depicts a previously undescribed G protein-coupled receptor in the nucleus for Stat3 activation and tumor cell growth.

Received for publication, March 8, 2006 , and in revised form, June 14, 2006.

^* This work was supported by the Cancer Research and Prevention Foundation grant (to C. H.) and the National Institutes of Health R01 Grants DK49615 (to A. J. D.), CA 76541 (to D. B. S.), and 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 may be addressed: Dept. of Pathology, University of Pittsburgh School of Medicine, BST E1514, Pittsburgh, PA 15261. Tel.: 412-648-1474; Fax: 412-647-5237; E-mail: changhan+{at}pitt.edu.

² To whom correspondence may 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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