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Radiation-Induced Caspase-8 Mediates p53-Independent Apoptosis in Glioma Cells

¹ Departments of Radiation Oncology and ² Comprehensive Cancer Center, University of California at San Francisco; ³ California Pacific Medical Center Research Institute, San Francisco, California; and ⁴ Functional Genomics, Isis Pharmaceuticals, Inc., Carlsbad, California

Requests for reprints: Daphne A. Haas-Kogan, Department of Radiation Oncology, University of California at San Francisco, 1600 Divisadero Street, Suite H1031, San Francisco, CA 94143-1708. Phone: 415-353-7175; Fax: 415-353-9883; E-mail: hkogan{at}Radonc17.ucsf.edu.

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, p21^Cip1 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. (Cancer Res 2006; 66(8): 4223-32)