title: Induction of EGF-dependent apoptosis by vacuolar-type H(+)-ATPase inhibitors in A431 cells overexpressing the EGF receptor.
abstract: The stimulation of human tumor cells overexpressing epidermal growth factor receptor (EGFR) with EGF enhances tumor development and malignancy. Therefore, compounds that modulate the EGF-mediated signal inducing apoptosis in EGFR-overexpressing cells would represent a new class of antitumor drug and might be useful in the treatment of a subset of human tumors. In the course of screening for compounds that induce apoptosis in EGFR-overexpressing human epidermal carcinoma A431 cells from secondary metabolites of microorganisms, we found that vacuolar-type H(+)-ATPase (V-ATPase) inhibitors, such as concanamycin B and destruxin E, induced apoptosis only when the cells were stimulated with EGF. The EGF-dependent apoptosis by V-ATPase inhibitors was not observed in other types of human tumor cells which do not overexpress EGFR. The apoptosis in A431 cells was inhibited by anti-FasL antibody which neutralized the cytotoxic effect of FasL, indicating that the Fas/FasL system was involved. The expression of cell surface FasL was upregulated by stimulation with EGF and increased further by V-ATPase inhibitors. Moreover, EGF inhibited cytotoxic Fas antibody-induced apoptosis, whereas V-ATPase inhibitors disrupted the protective effect of EGF on apoptosis in A431 cells. Taken together, these results suggested that V-ATPase inhibitors induced EGF-dependent apoptosis in A431 cells, possibly through both the enhancement of EGF-induced cell surface expression of FasL and the disruption of an EGF-induced survival signal.
authors.affiliation: Department of Bioscience and Informatics, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama, 223-8522, Japan.
authors.forename: Yuya
authors.initials: Y
authors.lastname: Yoshimoto
authors.forename: Masaya
authors.initials: M
authors.lastname: Imoto
mesh_terms: D000900:Anti-Bacterial Agents / Q000302:isolation & purification / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000302:isolation & purification / Q000494:pharmacology*; D017209:Apoptosis; D002277:Carcinoma / Q000201:enzymology / Q000473:pathology* / Q000648:ultrastructure; D002467:Cell Nucleus / Q000648:ultrastructure; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000201:enzymology / Q000473:pathology; D047630:Depsipeptides; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000302:isolation & purification / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000037:antagonists & inhibitors*; D066246:ErbB Receptors / Q000378:metabolism; D053222:Fas Ligand Protein; D005656:Fungal Proteins; D006801:Humans; D018942:Macrolides; D008562:Membrane Glycoproteins / Q000502:physiology; D010456:Peptides, Cyclic / Q000302:isolation & purification / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D025262:Vacuolar Proton-Translocating ATPases / Q000037:antagonists & inhibitors*; D019014:fas Receptor / Q000502:physiology
chemical_list: D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; D047630:Depsipeptides; D004791:Enzyme Inhibitors; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D005656:Fungal Proteins; D018942:Macrolides; D008562:Membrane Glycoproteins; D010456:Peptides, Cyclic; D019014:fas Receptor; D004815:Epidermal Growth Factor; C036979:concanamycin B; D066246:ErbB Receptors; D025262:Vacuolar Proton-Translocating ATPases; C040425:destruxin E