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Molecular Pharmacology

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Research ArticleArticle

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

Jill M. Siegfried, Christopher T. Gubish, Mary E. Rothstein, Pierre E. Queiroz de Oliveira and Laura P. Stabile
Molecular Pharmacology September 2007, 72 (3) 769-779; DOI: https://doi.org/10.1124/mol.107.034215
Jill M. Siegfried
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Christopher T. Gubish
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Mary E. Rothstein
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Pierre E. Queiroz de Oliveira
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Laura P. Stabile
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Abstract

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.

Footnotes

  • This work was supported by National Institutes of Health grant R01-CA79882 (to J.M.S.).

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

  • doi:10.1124/mol.107.034215.

  • ABBREVIATIONS: EGFR, epidermal growth factor receptor; COX-2, cyclooxygenase-2; HGF, hepatocyte growth factor; NSCLC, non–small-cell lung cancer; ELISA, enzyme-linked immunosorbent assay; PGE2, prostaglandin E2; TGFα, transforming growth factor α; AS, antisense; NA, neutralizing antibody; AP-1, activator protein-1; CREB, cAMP response element-binding protein; MEK, mitogen-activated protein kinase kinase; PI3K, phosphoinositide-3 kinase; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; PP2, 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine; MAPK, mitogen-activated protein kinase; C/EBP, CCAAT/enhancer-binding protein; U0126, 1,4-diamino-2,3-dicyano-1,4-bis(methylthio)butadiene; LY294002, 2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride; SB202190, 4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)-1H-imidazole.

  • ↵ Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

    • Received February 21, 2007.
    • Accepted June 5, 2007.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 72 (3)
Molecular Pharmacology
Vol. 72, Issue 3
1 Sep 2007
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Research ArticleArticle

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

Jill M. Siegfried, Christopher T. Gubish, Mary E. Rothstein, Pierre E. Queiroz de Oliveira and Laura P. Stabile
Molecular Pharmacology September 1, 2007, 72 (3) 769-779; DOI: https://doi.org/10.1124/mol.107.034215

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Research ArticleArticle

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

Jill M. Siegfried, Christopher T. Gubish, Mary E. Rothstein, Pierre E. Queiroz de Oliveira and Laura P. Stabile
Molecular Pharmacology September 1, 2007, 72 (3) 769-779; DOI: https://doi.org/10.1124/mol.107.034215
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