Induction of apoptosis in glioblastoma cells by an atypical protein kinase C pseudosubstrate peptide.
BACKGROUND
Glioblastoma responds poorly to standard chemotherapy agents. The expression of a mutant, constitutively-active EGF receptor (EGFRvIII) is common in glioblastoma and contributes to chemotherapy resistance. We have assessed the cytotoxicity of an inhibitor of atypical protein kinase C on glioblastoma cells expressing EGFRvIII.


METHODS
Glioblastoma cells were treated with a peptide-based atypical protein kinase C inhibitor. Apoptosis was assessed by morphological criteria, TUNEL assays, annexin V staining, Hoechst staining and colorimetric assays for cell viability.


RESULTS
The atypical protein kinase C inhibitor induced rapid apoptosis in glioblastoma cells expressing EGFRvIII and killed these cells with an IC50 of 16 microM. Glioblastoma cells which do not express EGFRvIII were less sensitive. Apoptosis was not affected by caspase inhibitors and occurred without detectable caspase activation.


CONCLUSIONS
An atypical protein kinase C inhibitor induces rapid apoptosis in glioblastoma cells by a caspase-independent mechanism that is enhanced, rather than inhibited, by EGFRvIII.
Lorimer
Ian A J
IA
Ottawa Regional Cancer Centre, Centre for Cancer Therapeutics, Ontario, Canada. Ian.Lorimer@orcc.on.ca
Parolin
Doris A E
DA
Lavictoire
Sylvie J
SJ
D017209:Apoptosis / Q000187:drug effects*; D061945:Caspase Inhibitors; D020169:Caspases / Q000502:physiology; D002467:Cell Nucleus / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D066246:ErbB Receptors / Q000502:physiology; D005909:Glioblastoma / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D006801:Humans; D009226:Myristates / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology*; D010718:Phosphatidylserines / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013379:Substrate Specificity; D014407:Tumor Cells, Cultured
D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D009226:Myristates; D010446:Peptide Fragments; D010718:Phosphatidylserines; C410723:epidermal growth factor receptor VIII; D066246:ErbB Receptors; D011493:Protein Kinase C; D020169:Caspases