title: CD95-mediated apoptosis of human glioma cells: modulation by epidermal growth factor receptor activity.
abstract: The death ligands CD95L and Apo2L/TRAIL are promising investigational agents for the treatment of malignant glioma. EGFR is overexpressed in a significant proportion of malignant gliomas in vivo. Here, we report that CD95L-induced cell death is enhanced by EGFR inhibition using tyrphostine AG1478 in 7 of 12 human malignant glioma cell lines. Conversely, CD95-mediated and Apo2L-induced cell death are both inhibited by overexpression of EGFR in LN-229 cells. CD95L-induced cell death augmented by AG1478 is accompanied by enhanced processing of caspase 8. LN-229 cells overexpressing the viral caspase inhibitor, crm-A, are not sensitized to CD95L-induced cell death by AG1478, indicating that EGFR exerts its antiapoptotic properties through a caspase 8-dependent pathway. These data define a modulatory effect of EGFR-activity on death ligand-induced apoptosis and indicate that EGFR inhibition is likely to improve the efficacy of death ligand-based cancer therapies. Furthermore, it is tempting to speculate that EGFR amplification protects tumor cells from death ligand-mediated host immune responses in vivo and that EGFR's effects on death receptor-mediated apoptosis may explain the anti-tumor effects of non-cytotoxic, unarmed anti-EGFR family antibodies.
authors.affiliation: Department of Neurology, University of Tübingen, School of Medicine, Germany. joachim.steinbach@uni-tuebingen.de
authors.forename: Joachim P
authors.initials: JP
authors.lastname: Steinbach
authors.forename: Petra
authors.initials: P
authors.lastname: Supra
authors.forename: H-J Su
authors.initials: HJ
authors.lastname: Huang
authors.forename: Webster K
authors.initials: WK
authors.lastname: Cavenee
authors.forename: Michael
authors.initials: M
authors.lastname: Weller
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D051017:Apoptosis Regulatory Proteins; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000503:physiopathology; D053181:Caspase 8; D053453:Caspase 9; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D003374:Coumarins / Q000494:pharmacology; D003513:Cycloheximide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D053222:Fas Ligand Protein; D005456:Fluorescent Dyes / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism* / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects / Q000378:metabolism; D011799:Quinazolines; D015843:Serpins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D053221:TNF-Related Apoptosis-Inducing Ligand; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000494:pharmacology; D020032:Tyrphostins / Q000494:pharmacology; D014764:Viral Proteins; D051020:bcl-X Protein
chemical_list: D051017:Apoptosis Regulatory Proteins; C494811:BCL2L1 protein, human; D061945:Caspase Inhibitors; D003374:Coumarins; D004791:Enzyme Inhibitors; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D005456:Fluorescent Dyes; D008562:Membrane Glycoproteins; D009842:Oligopeptides; D019253:Proto-Oncogene Proteins c-bcl-2; D011799:Quinazolines; D015843:Serpins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D020032:Tyrphostins; D014764:Viral Proteins; C102580:acetyl-aspartyl-glutamyl-valyl-aspartyl-amino-4-methylcoumarin; D051020:bcl-X Protein; C101044:RTKI cpd; C074641:interleukin-1beta-converting enzyme inhibitor; D003513:Cycloheximide; D066246:ErbB Receptors; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases