Activation of the cd95 (apo-1/fas) pathway in drug- and γ-irradiation-induced apoptosis of brain tumor cells

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. SIMILAR CONTENT BEING VIEWED BY OTHERS BH3 MIMETIC DRUGS COOPERATE WITH TEMOZOLOMIDE, JQ1 AND INDUCERS OF

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PHARMACOLOGICAL TARGETING OF C-FLIPL AND BCL-2 FAMILY MEMBERS PROMOTES APOPTOSIS IN CD95L-RESISTANT CELLS Article Open access 30 November 2020 ARTICLE PDF AUTHOR INFORMATION AUTHORS AND

AFFILIATIONS * University Children's Hospital, Prittwitzstr. 43, Ulm, D-89075, Germany Simone Fulda & Klaus-Michael Debatin * Division of Immunogenetics, German Cancer Research

Center, Im Neuenheimer Feld 280, Heidelberg, D-69120, Germany Carsten Scaffidi, Peter H Krammer & Marcus E Peter * Department of Neuropathology, University of Bonn Medical Center, Bonn,

D-53105, Germany Torsten Pietsch Authors * Simone Fulda View author publications You can also search for this author inPubMed Google Scholar * Carsten Scaffidi View author publications You

can also search for this author inPubMed Google Scholar * Torsten Pietsch View author publications You can also search for this author inPubMed Google Scholar * Peter H Krammer View author

publications You can also search for this author inPubMed Google Scholar * Marcus E Peter View author publications You can also search for this author inPubMed Google Scholar * Klaus-Michael

Debatin View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to Klaus-Michael Debatin. ADDITIONAL INFORMATION Edited by

M. Piacentini RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Fulda, S., Scaffidi, C., Pietsch, T. _et al._ Activation of the CD95 (APO-1/Fas) pathway in

drug- and γ-irradiation-induced apoptosis of brain tumor cells. _Cell Death Differ_ 5, 884–893 (1998). https://doi.org/10.1038/sj.cdd.4400419 Download citation * Received: 08 April 1998 *

Revised: 07 May 1998 * Accepted: 15 May 1998 * Published: 22 October 1998 * Issue Date: 01 October 1998 * DOI: https://doi.org/10.1038/sj.cdd.4400419 SHARE THIS ARTICLE Anyone you share the

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Nature SharedIt content-sharing initiative KEYWORDS * apoptosis * brain tumors * drugs * γ-irradiation * CD95 (APO-1/Fas)