Modulation of Stat3 activation by the cytosolic phospholipase A2alpha 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 E(2) (PGE(2)) and Stat3 signaling pathways that coordinately regulate human cancer cell growth. COX-2-derived PGE(2) induces interleukin-6 production through activation of EP(4) receptor and subsequent phosphorylation of gp130/Stat3 in human cholangiocarcinoma cells. In parallel, activation of COX-2/PGE(2) signaling also enhances Stat3 phosphorylation and reporter activity through EP(1) receptor-induced activation of c-Src and EGFR in these cells. Moreover, the observations that EP(1) receptor is detected in the nucleus as well as in the Stat3.DNA binding complex and that activation of EP(1) 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.

• Authors: Chang Han, A Jake Demetris, Donna B Stolz, Lihong Xu, Kyu Lim, Tong Wu
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 281 Issue 34 Pg. 24831-46 (Aug 25 2006) ISSN: 0021-9258 [Print] United States
• PMID: 16790433 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Retracted Publication)

Chemical References

• Interleukin-6
• Isoenzymes
• PTGER1 protein, human
• Receptors, G-Protein-Coupled
• Receptors, Prostaglandin E
• Receptors, Prostaglandin E, EP1 Subtype
• STAT3 Transcription Factor
• Cyclooxygenase 2
• Phospholipases A
• Group IV Phospholipases A2
• Dinoprostone

Topics

• Cell Line, Tumor
• Cell Nucleus (metabolism)
• Cell Proliferation
• Cyclooxygenase 2 (metabolism)
• Cytosol (metabolism)
• Dinoprostone (metabolism)
• Enzyme Activation
• Gene Expression Regulation, Neoplastic
• Group IV Phospholipases A2
• Humans
• Interleukin-6 (biosynthesis)
• Isoenzymes (metabolism)
• Phospholipases A (metabolism)
• Receptor Cross-Talk
• Receptors, G-Protein-Coupled (metabolism)
• Receptors, Prostaglandin E (metabolism)
• Receptors, Prostaglandin E, EP1 Subtype
• STAT3 Transcription Factor (genetics, metabolism)
• Signal Transduction