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: Yuya Yoshimoto, Masaya Imoto
• Journal: Experimental cell research (Exp Cell Res) Vol. 279 Issue 1 Pg. 118-27 (Sep 10 2002) ISSN: 0014-4827 [Print] United States
• PMID: 12213220 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Bacterial Agents
• Antineoplastic Agents
• Depsipeptides
• Enzyme Inhibitors
• FASLG protein, human
• Fas Ligand Protein
• Fungal Proteins
• Macrolides
• Membrane Glycoproteins
• Peptides, Cyclic
• fas Receptor
• Epidermal Growth Factor
• concanamycin B
• ErbB Receptors
• Vacuolar Proton-Translocating ATPases
• destruxin E

Topics

• Anti-Bacterial Agents (isolation & purification, pharmacology)
• Antineoplastic Agents (isolation & purification, pharmacology)
• Apoptosis
• Carcinoma (enzymology, pathology, ultrastructure)
• Cell Nucleus (ultrastructure)
• Cell Survival (drug effects)
• Colonic Neoplasms (enzymology, pathology)
• Depsipeptides
• Dose-Response Relationship, Drug
• Enzyme Inhibitors (isolation & purification, pharmacology)
• Epidermal Growth Factor (antagonists & inhibitors)
• ErbB Receptors (metabolism)
• Fas Ligand Protein
• Fungal Proteins
• Humans
• Macrolides
• Membrane Glycoproteins (physiology)
• Peptides, Cyclic (isolation & purification, pharmacology)
• Tumor Cells, Cultured
• Vacuolar Proton-Translocating ATPases (antagonists & inhibitors)
• fas Receptor (physiology)