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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Apoptosis / drug effects*
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Apoptosis / physiology
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Apoptosis Regulatory Proteins
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Brain Neoplasms / drug therapy*
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Brain Neoplasms / metabolism*
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Brain Neoplasms / physiopathology
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Caspase 8
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Caspase 9
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Caspase Inhibitors
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Caspases / metabolism
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Cell Survival / drug effects
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Cell Survival / physiology
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Coumarins / pharmacology
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Cycloheximide / pharmacology
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Dose-Response Relationship, Drug
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Enzyme Inhibitors / pharmacology
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ErbB Receptors / antagonists & inhibitors*
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ErbB Receptors / genetics
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ErbB Receptors / metabolism
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Fas Ligand Protein
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Fluorescent Dyes / pharmacology
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Gene Expression Regulation, Neoplastic / drug effects
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Gene Expression Regulation, Neoplastic / physiology
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Glioma / drug therapy*
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Glioma / metabolism*
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Glioma / physiopathology
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Humans
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Membrane Glycoproteins / metabolism*
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Membrane Glycoproteins / pharmacology
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Oligopeptides / pharmacology
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Proto-Oncogene Proteins c-bcl-2 / drug effects
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Quinazolines
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Serpins / pharmacology
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Signal Transduction / drug effects
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Signal Transduction / physiology
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TNF-Related Apoptosis-Inducing Ligand
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Tumor Cells, Cultured
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Tumor Necrosis Factor-alpha / metabolism*
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Tumor Necrosis Factor-alpha / pharmacology
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Tyrphostins / pharmacology
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Viral Proteins*
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bcl-X Protein
Substances
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Apoptosis Regulatory Proteins
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BCL2L1 protein, human
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Caspase Inhibitors
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Coumarins
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Enzyme Inhibitors
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FASLG protein, human
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Fas Ligand Protein
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Fluorescent Dyes
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Membrane Glycoproteins
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Oligopeptides
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Proto-Oncogene Proteins c-bcl-2
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Quinazolines
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Serpins
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TNF-Related Apoptosis-Inducing Ligand
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TNFSF10 protein, human
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Tumor Necrosis Factor-alpha
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Tyrphostins
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Viral Proteins
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acetyl-aspartyl-glutamyl-valyl-aspartyl-amino-4-methylcoumarin
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bcl-X Protein
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RTKI cpd
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interleukin-1beta-converting enzyme inhibitor
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Cycloheximide
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ErbB Receptors
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CASP8 protein, human
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CASP9 protein, human
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Caspase 8
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Caspase 9
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Caspases