Gastrin-releasing peptide receptor mediates activation of the epidermal growth factor receptor in lung cancer cells.
Gastrin-releasing peptide receptor (GRPR) and the epidermal growth factor receptor (EGFR) are expressed in several cancers including non-small cell lung cancer (NSCLC). Here we demonstrate the activation of EGFR by the GRPR ligand, gastrin-releasing peptide (GRP), in NSCLC cells. GRP induced rapid activation of p44/42 MAPK in lung cancer cells through EGFR. GRP-mediated activation of MAPK in NSCLC cells was abrogated by pretreatment with the anti-EGFR-neutralizing antibody, C225. Pretreatment of NSCLC cells with neutralizing antibodies to the EGFR ligands, TGF-A or HB-EGF, also decreased GRP-mediated MAPK activation. On matrix metalloproteinase (MMP) inhibition, GRP failed to activate MAPK in NSCLC cells. EGF and GRP both stimulated NSCLC proliferation, and inhibition of either EGFR or GRPR resulted in cell death. Combining a GRPR antagonist with the EGFR tyrosine kinase inhibitor, gefitinib, resulted in additive cytotoxic effects. Additive effects were seen at gefitinib concentrations from 1 to 18 microM, encompassing the ID50 values of both gefitinib-sensitive and gefitinib-resistant NSCLC cell lines. Because a major effect of GRPR appears to be promoting the release of EGFR ligand, this study suggests that a greater inhibition of cell proliferation may occur by abrogating EGFR ligand release in consort with inhibition of EGFR.
Thomas
Sufi Mary
SM
Department of Otolaryngology, University of Pittsburgh Medical Center and University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA.
Grandis
Jennifer Rubin
JR
Wentzel
Abbey L
AL
Gooding
William E
WE
Lui
Vivian Wai Yan
VW
Siegfried
Jill M
JM
D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism; D016923:Cell Death; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000378:metabolism*; D000077156:Gefitinib; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D008024:Ligands; D008175:Lung Neoplasms / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation; D011799:Quinazolines / Q000494:pharmacology; D018004:Receptors, Bombesin / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction; D016211:Transforming Growth Factor alpha / Q000378:metabolism
D008024:Ligands; D011799:Quinazolines; D018004:Receptors, Bombesin; D016211:Transforming Growth Factor alpha; D066246:ErbB Receptors; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D000077156:Gefitinib