Activation of the CD95 (APO-1/Fas) pathway in drug- and γ-irradiation-induced apoptosis of brain tumor cells

Simone Fulda, Carsten Scaffidi, Torsten Pietsch, Peter H. Krammer, Marcus E. Peter, Klaus Michael Debatin*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

114 Scopus citations

Abstract

Chemotherapeutic agents and γ-irradiation used in the treatment of brain tumors, the most common solid tumors of childhood, have been shown to act primarily by inducing apoptosis. Here, we report that activation of the CD95 pathway was involved in drug- and γ-irradiation-induced apoptosis of medulloblastoma and glioblastoma cells. Upon treatment CD95 ligand (CD95-L) was induced that stimulated the CD95 pathway by crosslinking CD95 via an autocrine/paracrine loop. Blocking CD95-L/receptor interaction using F(ab')2 anti-CD95 antibody fragments strongly reduced apoptosis. Apoptosis depended on activation of caspases (interleukin 1β-converting enzyme/Ced-3 like proteases) as it was almost completely abrograted by the broad range caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone. Apoptosis was mediated by cleavage of the receptor proximal caspase FLICE/MACH (caspase-8) and the downstream caspase CPP32 (caspase-3, Apopain) resulting in cleavage of the prototype caspase substrate PARP. Moreover, CD95 was upregulated in wild-type p53 cells thereby increasing responsiveness towards CD95 triggering. Since activation of the CD95 system upon treatment was also found in primary medulloblastoma cells ex vivo, these findings may have implications to define chemosensitivity and to develop novel therapeutic strategies in the management of malignant brain tumors.

Original languageEnglish (US)
Pages (from-to)884-893
Number of pages10
JournalCell Death and Differentiation
Volume5
Issue number10
DOIs
StatePublished - Oct 1998

Keywords

  • Apoptosis
  • Brain tumors
  • CD95 (APO-1/Fas)
  • Drugs
  • γ-irradiation

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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