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First published on June 5, 2007; DOI: 10.1124/mol.107.034215

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Received for publication February 22, 2007.
Revised June 5, 2007.
Accepted for publication June 5, 2007.

Signaling pathways involved in cyclooxygenase-2 induction by hepatocyte growth factor in non-small cell lung cancer

Jill M. Siegfried 1*, Christopher T. Gubish 2, Mary E. Rothstein 1, Pierre E. Queiroz De Oliveira 1, Laura P. Stabile 1

1 University of Pittsburgh 2 Univeristy of Pittsburgh

* Address correspondence to: E-mail: siegfrie{at}server.pharm.pitt.edu

Abstract

Many studies have suggested a role for the hepatocyte growth factor (HGF)/c-Met pathway in tumorigenesis. Some actions of HGF are thought to be mediated by cyclooxygenase-2 (COX-2), resulting in the production of prostaglandin E2 (PGE2). We examined four c-Met positive 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 Erk1/2 and p38 pathways. HGF treatment caused activation of the AP-1, c/ebp and CREB 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. 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 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 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.


Key words: Cyclooxygenases, Oncogenes


This article has been cited by other articles:


Home page
 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
Y. H. Lee, Y. J. Suzuki, A. J. Griffin, and R. M. Day
Hepatocyte growth factor regulates cyclooxygenase-2 expression via {beta}-catenin, Akt, and p42/p44 MAPK in human bronchial epithelial cells
Am J Physiol Lung Cell Mol Physiol, April 1, 2008; 294(4): L778 - L786.
[Abstract] [Full Text] [PDF]


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