Open AccessCD95‐mediated Apoptosis of Human Glioma Cells: Modulation by Epidermal Growth Factor Receptor Activity
Author(s) -
Steinbach Joachim P.,
Supra Petra,
Huang H.J. Su,
Cavenee Webster K.,
Weller Michael
Publication year - 2002
Publication title -
brain pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.986
H-Index - 132
eISSN - 1750-3639
pISSN - 1015-6305
DOI - 10.1111/j.1750-3639.2002.tb00418.x
Subject(s) - fas receptor , apoptosis , programmed cell death , cancer research , epidermal growth factor receptor , glioma , caspase , egfr inhibitors , in vivo , cytotoxic t cell , biology , chemistry , receptor , in vitro , biochemistry , microbiology and biotechnology
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.