title: Epidermal growth factor competes with EGF receptor inhibitors to induce cell death in EGFR-overexpressing tumor cells.
abstract: Epidermal growth factor receptor (EGFR) signaling plays an important role in cell growth and differentiation. Mutations in the EGFR gene and EGFR gene amplifications have been associated with increased responsiveness to selective EGFR tyrosine kinase inhibitors (EGFR-TKIs). By contrast, EGF may also stimulate apoptosis in tumor cells, depending on EGFR and Her2 (erbB-2) expression levels. In the present study, we investigated cellular responses after EGFR activation by EGF, or inhibition by cetuximab and gefitinib. EGF treatment induced a near-immediate increase in p38 MAPK phosphorylation together with inactivation of ERK1/2. In contrast, gefitinib- and cetuximab-induced phosphorylation of p38 MAPK was much delayed, and gefitinib also induced a delayed activation of ERK1/2. EGF induced progressive cell death of A431 cells with prolonged treatment, whereas cetuximab- or gefitinib-treated cells showed temporary growth arrest and subsequent re-growth. Moreover, in combination treatment experiments, cetuximab or gefitinib competitively inhibited EGF-induced cell death. Normal WI38-VA13 cells did not display any noticeable changes in cell proliferation in response to EGF, gefitinib or cetuximab. EGF-induced death signaling is apparently irreversible: EGF induced significant EGFR phosphorylation/internalization and activated caspase-3, -8 and -9, effects that were not observed in cetuximab- or gefitinib-treated cells. Collectively, these results indicate that EGF may be a more potent cytotoxic agent than EGFR blockers in EGFR-overexpressing cancer cells.
authors.affiliation: Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea.
authors.forename: Ji-Young
authors.initials: JY
authors.lastname: Song
authors.forename: Sang-Wook
authors.initials: SW
authors.lastname: Lee
authors.forename: Joon Pio
authors.initials: JP
authors.lastname: Hong
authors.forename: Sung Eun
authors.initials: SE
authors.lastname: Chang
authors.forename: Han
authors.initials: H
authors.lastname: Choe
authors.forename: Jene
authors.initials: J
authors.lastname: Choi
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D000068818:Cetuximab; D004789:Enzyme Activation / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000378:metabolism / Q000494:pharmacology*; D066246:ErbB Receptors / Q000187:drug effects / Q000378:metabolism*; D005434:Flow Cytometry; D000077156:Gefitinib; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D011799:Quinazolines; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; D000068818:Cetuximab; D000077156:Gefitinib