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Signaling Pathways Involved in Cyclooxygenase-2 Induction by Hepatocyte Growth Factor in Non–Small-Cell Lung Cancer

Department of Pharmacology, University of Pittsburgh (J.M.S., C.T.G., M.E.R., P.E.Q., L.P.S.), and the University of Pittsburgh Cancer Institute (J.M.S., L.P.S.), Pittsburgh, Pennsylvania

Many studies have suggested a role for the hepatocyte growth factor (HGF)/c-Met pathway in tumorigenesis. Some actions of HGF are believed to be mediated by cyclooxygenase-2 (COX-2), resulting in the production of prostaglandin E2 (PGE₂). We examined four c-Met-positive non–small-cell lung cancer (NSCLC) cell lines for effects of HGF on COX-2. HGF increased COX-2 protein expression 3-fold over basal levels. Induction of COX-2 occurred through both the extracellular signal-regulated kinase 1/2 and p38 pathways. HGF treatment caused activation of the activator protein-1, CCAAT/enhancer-binding protein, and cAMP response element-binding protein transcription factors, and COX-2 induction was blocked by actinomycin D. The half-life of COX-2 mRNA was also increased by HGF. HGF stimulation resulted in a 4-fold increase in PGE₂ secretion, and treatment of NSCLC cells with exogenous PGE₂ significantly increased cell proliferation. The addition of PGE₂ to NSCLC cells also led to rapid phosphorylation of c-Met in the absence of HGF, which was blocked by epidermal growth factor receptor (EGFR) inhibition. EGFR ligands were released in response to PGE₂. This suggests that secretion of PGE₂ induced by HGF/c-Met pathway activation can further activate the c-Met pathway via EGFR in a reinforcing loop that is independent of HGF. HGF and PGE₂ each significantly stimulated invasion in NSCLC cells. Cells transiently transfected with c-Met antisense plasmid showed a significant decrease in HGF- or PGE₂-induced invasion. PGE₂-induced invasion was EGFR-dependent, confirming a link between PGE₂, EGFR, and c-Met. Targeting of both the HGF/c-Met and PGE₂ pathways with a neutralizing antibody to HGF and celecoxib resulted in enhanced anti-invasion effects in response to HGF.

Address correspondence to: Dr. Jill M. Siegfried, Department of Pharmacology, E1352 Biomedical Science Tower, University of Pittsburgh, Pittsburgh, PA 15261. E-mail: siegfrie{at}server.pharm.pitt.edu

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