Signaling Pathways Involved in Cyclooxygenase-2 Induction by Hepatocyte Growth Factor in NonâSmall-Cell Lung Cancer
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 (PGE 2 ). We examined four c-Met-positive nonâsmall-cell lung cance...
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Published in | Molecular pharmacology Vol. 72; no. 3; p. 769 |
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Main Authors | , , , , |
Format | Journal Article |
Language | English |
Published |
American Society for Pharmacology and Experimental Therapeutics
01.09.2007
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Online Access | Get full text |
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Summary: | 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 (PGE 2 ). We examined four c-Met-positive nonâsmall-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 PGE 2 secretion, and treatment of NSCLC cells with exogenous PGE 2 significantly increased cell proliferation. The addition of PGE 2 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 PGE 2 . This suggests that secretion of PGE 2 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 PGE 2 each significantly stimulated invasion in NSCLC cells. Cells transiently transfected with c-Met antisense plasmid showed
a significant decrease in HGF- or PGE 2 -induced invasion. PGE 2 -induced invasion was EGFR-dependent, confirming a link between PGE 2 , EGFR, and c-Met. Targeting of both the HGF/c-Met and PGE 2 pathways with a neutralizing antibody to HGF and celecoxib resulted in enhanced anti-invasion effects in response to HGF. |
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ISSN: | 0026-895X 1521-0111 |
DOI: | 10.1124/mol.107.034215 |