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-α 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 μM, 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.
Bibliographical noteFunding Information:
Address all correspondence to: Jill M. Siegfried, PhD, Department of Pharmacology, University of Pittsburgh, E1340, 200 Lothrop Street, Pittsburgh, PA 15213. E-mail: firstname.lastname@example.org 1This work was supported by a grant (U01 CA84968) from the Early Detection Research Network (J.R.G. and J.M.S.), a grant (P50 CA90440) from the Specialized Program of Research Excellence (J.M.S.), and a National Institutes of Health grant (1 R01 CA 098372-01). S.M.T. and V.Y.W.L. were supported by Career Development Awards from the University of Pittsburgh Lung Cancer SPORE. Received 30 June 2004; Revised 1 November 2004; Accepted 3 November 2004.
- Non-small cell lung cancer
- Signal transduction