Co-inhibition of epidermal growth factor receptor and type 1 insulin-like growth factor receptor synergistically sensitizes human malignant glioma cells to CD95L-induced apoptosis.
Inhibition of epidermal growth factor receptor (EGFR) signaling sensitizes human malignant glioma cells to death ligand-induced apoptosis. However, tumor cells may compensate the loss of EGFR signaling by activation of the type 1 insulin-like growth factor receptor (IGF-1R). We here report that antagonism of the IGF-1R with the small-molecule inhibitor AG1024 in combination with inhibitors of the EGFR synergistically sensitizes human malignant glioma cells to CD95L-induced apoptosis. This cell death is p53-independent, but requires caspase 8 activity. The levels of the receptor, CD95, are not altered by the inhibitors alone or in combination. Analysis of the downstream signaling pathways reveals synergistic inhibition of ribosomal protein S6 phosphorylation by inhibitor co-treatment, suggesting an involvement of the mammalian target of rapamycin pathway. These findings suggest that adding inhibitors of IGF-1R may be a strategy to overcome escape from the anti-apoptotic effects of EGFR inhibition in malignant gliomas.
Steinbach
Joachim P
JP
Laboratory of Molecular Neuro-Oncology, Department of Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, School of Medicine, Hoppe-Seylerstr. 3, 72076 Tuebingen, Germany. joachim.steinbach@uni-tuebingen.de
Eisenmann
Christine
C
Klumpp
Andrea
A
Weller
Michael
M
D017209:Apoptosis; D001932:Brain Neoplasms / Q000378:metabolism*; D053181:Caspase 8; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000378:metabolism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D053222:Fas Ligand Protein; D005910:Glioma / Q000378:metabolism*; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism*; D011799:Quinazolines / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D038601:Ribosomal Protein S6 / Q000378:metabolism; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D020032:Tyrphostins / Q000494:pharmacology
D004791:Enzyme Inhibitors; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D011799:Quinazolines; D038601:Ribosomal Protein S6; D016159:Tumor Suppressor Protein p53; D020032:Tyrphostins; C447031:tyrphostin AG 1024; D066246:ErbB Receptors; D017526:Receptor, IGF Type 1; C505530:CASP8 protein, human; D053181:Caspase 8; D020169:Caspases; C088860:4-((3-bromophenyl)amino)-6,7-dimethoxyquinazoline