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PMID: 15078899 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

c-FLIP mediates resistance of Hodgkin/Reed-Sternberg cells to death receptor-induced apoptosis.

The Journal of experimental medicine ·Vol. 199 ·No. 8 ·2004-04-19 ·Pages 1041-52

Mathas S, Lietz A, Anagnostopoulos I, Hummel F, Wiesner B, Janz M, Jundt F, Hirsch B, Jöhrens-Leder K, Vornlocher HP, Bommert K, Stein H, Dörken B

Abstract

Resistance to death receptor-mediated apoptosis is supposed to be important for the deregulated growth of B cell lymphoma. Hodgkin/Reed-Sternberg (HRS) cells, the malignant cells of classical Hodgkin's lymphoma (cHL), resist CD95-induced apoptosis. Therefore, we analyzed death receptor signaling, in particular the CD95 pathway, in these cells. High level CD95 expression allowed a rapid formation of the death-inducing signaling complex (DISC) containing Fas-associated death domain-containing protein (FADD), caspase-8, caspase-10, and most importantly, cellular FADD-like interleukin 1beta-converting enzyme-inhibitory protein (c-FLIP). The immunohistochemical analysis of the DISC members revealed a strong expression of CD95 and c-FLIP overexpression in 55 out of 59 cases of cHL. FADD overexpression was detectable in several cases. Triggering of the CD95 pathway in HRS cells is indicated by the presence of CD95L in cells surrounding them as well as confocal microscopy showing c-FLIP predominantly localized at the cell membrane. Elevated c-FLIP expression in HRS cells depends on nuclear factor (NF)-kappaB. Despite expression of other NF-kappaB-dependent antiapoptotic proteins, the selective down-regulation of c-FLIP by small interfering RNA oligoribonucleotides was sufficient to sensitize HRS cells to CD95 and tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis. Therefore, c-FLIP is a key regulator of death receptor resistance in HRS cells.

MeSH Terms
Adaptor Proteins, Signal Transducing Apoptosis/drug effects,physiology Apoptosis Regulatory Proteins Base Sequence CASP8 and FADD-Like Apoptosis Regulating Protein Carrier Proteins/genetics,metabolism,physiology Caspase 10 Caspase 8 Caspases/metabolism Cell Line, Tumor Cycloheximide/pharmacology Fas-Associated Death Domain Protein Hodgkin Disease/pathology,physiopathology Humans Intracellular Signaling Peptides and Proteins Membrane Glycoproteins/physiology NF-kappa B/metabolism RNA, Small Interfering/genetics Reed-Sternberg Cells/drug effects,pathology,physiology TNF-Related Apoptosis-Inducing Ligand Tumor Necrosis Factor-alpha/physiology fas Receptor/physiology
Chemicals
Adaptor Proteins, Signal Transducing Apoptosis Regulatory Proteins CASP8 and FADD-Like Apoptosis Regulating Protein CFLAR protein, human Carrier Proteins FADD protein, human Fas-Associated Death Domain Protein Intracellular Signaling Peptides and Proteins Membrane Glycoproteins NF-kappa B RNA, Small Interfering TNF-Related Apoptosis-Inducing Ligand TNFSF10 protein, human Tumor Necrosis Factor-alpha fas Receptor Cycloheximide CASP8 protein, human Caspase 10 Caspase 8 Caspases CASP10 protein, human
Authors & Affiliations
13 authors, click to expand affiliations / ORCID
Mathas Stephan
Max-Delbrück-Center for Molecular Medicine, FG Dörken, D-13125 Berlin, Germany. mathas@rrk-berlin.de
Lietz Andreas
Anagnostopoulos Ioannis
Hummel Franziska
Wiesner Burkhard
Janz Martin
Jundt Franziska
Hirsch Burkhard
Jöhrens-Leder Korinna
Vornlocher Hans-Peter
Bommert Kurt
Stein Harald
Dörken Bernd
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Article Info
Journal
The Journal of experimental medicine
Abbr.
J Exp Med
ISSN
0022-1007
DOI
10.1084/jem.20031080
Email
mathas@rrk-berlin.de
Published
2004-04-19
Epub
2004-00-12
Pages
1041-52
Language
English
Region
United States
NLM ID
2985109R
PMCID
PMC2211891
Subset
IM
External Links
PubMed source DOI: 10.1084/jem.20031080 PMC Full Text View journal details
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