Abstract
Cyclooxygenase-2 (COX-2)-mediated prostaglandin synthesis has recently been implicated in human cholangiocarcinogenesis. This study was designed to examine the mechanisms by which COX-2-derived prostaglandin E2 (PGE2) regulates cholangiocarcinoma cell growth and invasion. Immunohistochemical analysis revealed elevated expression of COX-2 and the epidermal growth factor (EGF) receptor (EGFR) in human cholangiocarcinoma tissues. Overexpression of COX-2 in a human cholangiocarcinoma cell line (CCLP1) increased tumor cell growth and invasion in vitro and in severe combined immunodeficient mice. Overexpression of COX-2 or treatment with PGE2 or the EP1 receptor agonist ONO-DI-004 induced phosphorylation of EGFR and enhanced tumor cell proliferation and invasion, which were inhibited by the EP1 receptor small interfering RNA or antagonist ONO-8711. Treatment of CCLP1 cells with PGE2 or ONO-DI-004 enhanced binding of EGFR to the EP1 receptor and c-Src. Furthermore, PGE2 or ONO-DI-004 treatment also increased Akt phosphorylation, which was blocked by the EGFR tyrosine kinase inhibitors AG 1478 and PD 153035. These findings reveal that the EP1 receptor transactivated EGFR, thus activating Akt. On the other hand, activation of EGFR by its cognate ligand (EGF) increased COX-2 expression and PGE2 production, whereas blocking PGE2 synthesis or the EP1 receptor inhibited EGF-induced EGFR phosphorylation. This study reveals a novel cross-talk between the EP1 receptor and EGFR signaling that synergistically promotes cancer cell growth and invasion.
Highlights
Treatment for patients with the advanced disease or any effective therapy for its chemoprevention
COX-2-derived prostaglandin E2 (PGE2) Induces EGFR Phosphorylation in Cholangiocarcinoma Cells—Increased expression of COX-2 and EGFR in human cholangiocarcinoma cells suggests a possible interconnection between these two signaling pathways during cholangiocarcinogenesis
Given that COX-2-derived prostaglandins mediate effects primarily through specific plasma membrane receptors that are coupled with G-proteins and that certain G-protein-coupled receptor (GPCR) are known to activate EGFR (24 –26), we postulated that COX-2 may promote tumor growth through activation of EGFR
Summary
Immunohistochemical analysis revealed elevated expression of COX-2 and the epidermal growth factor (EGF) receptor (EGFR) in human cholangiocarcinoma tissues. Overexpression of COX-2 or treatment with PGE2 or the EP1 receptor agonist ONO-DI-004 induced phosphorylation of EGFR and enhanced tumor cell proliferation and invasion, which were inhibited by the EP1 receptor small interfering RNA or antagonist ONO-8711. Overexpression of COX-2 in cultured cholangiocarcinoma cells enhances PGE2 production and promotes tumor growth (12). In light of recent evidence showing activation of EGFR by GPCRs (24 –26) and enhanced EGFR activation in cholangiocarcinoma cells (27, 28), this study was designed to evaluate our hypothesis that the G-protein-coupled EP receptor may transactivate EGFR and that this mechanism may be important in cholangiocarcinogenesis. Our findings reveal a novel interaction between COX-2-derived PGE2 and EGFR signaling that synergistically promotes cancer cell growth and invasion
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