Modulation of Stat3 activation by the cytosolic phospholipase A 2α and cyclooxygenase-2-controlled prostaglandin E2 signaling pathway

Abstract

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. © 2006 by The American Society for Biochemistry and Molecular Biology, Inc.