Radiation-induced caspase-8 mediates p53-independent apoptosis in glioma cells.
Malignant gliomas are almost uniformly fatal and display exquisite radiation resistance. Glioma cells lacking wild-type (WT) p53 function are more susceptible to radiation-induced apoptosis than their isogenic counterparts expressing WT p53. We explored the mechanisms of such apoptosis and found that, in the absence of WT p53, radiation increases caspase-8 expression and activity. Inhibition of caspase-8 expression using caspase-8 antisense or small interfering RNA (siRNA) oligonucleotides partially blocks radiation-induced apoptosis. In contrast, inhibition of the mitochondrial death pathway by expression of Bcl-2 has no effect on radiation-induced caspase-8 activity or apoptosis. Our data indicate that, in contrast to commonly accepted models of p53-dependent radiation-induced apoptosis, in our cell system, radiation relies on caspase-8 activity to help mediate p53-independent cell death. In a system of inducible E2F1 activity, E2F1 activated caspase-8 and, accordingly, decreased cellular viability, effects that were abolished by caspase-8 siRNA. In this model, in the absence of WT p53, p21Cip1 is not induced, and E2F1 activity is sustained and allows transcription and activation of caspase-8. This model may explain why p53 mutations in adult gliomas paradoxically correlate with improved survival and enhanced response to radiation.
Afshar
Golnar
G
Department of Radiation Oncology, University of California at San Francisco, 94143-1708, USA.
Jelluma
Nannette
N
Yang
Xiaodong
X
Basila
Daniel
D
Arvold
Nils D
ND
Karlsson
Amelia
A
Yount
Garret L
GL
Dansen
Tobias B
TB
Koller
Erich
E
Haas-Kogan
Daphne A
DA
D017209:Apoptosis / Q000502:physiology / Q000528:radiation effects*; D053181:Caspase 8; D020169:Caspases / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology* / Q000528:radiation effects; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D050687:E2F1 Transcription Factor / Q000378:metabolism; D004790:Enzyme Induction / Q000528:radiation effects; D005910:Glioma / Q000201:enzymology* / Q000473:pathology / Q000532:radiotherapy; D006801:Humans; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D014158:Transcription, Genetic / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000502:physiology
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C505530:CASP8 protein, human; D053181:Caspase 8; D020169:Caspases