The Journal of Experimental Medicine
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Published online 12 April 2004 doi:10.1084/jem.20031080
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 199, Number 8, 1041-1052
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c-FLIP Mediates Resistance of Hodgkin/Reed-Sternberg Cells to Death Receptor–induced Apoptosis

Stephan Mathas1,2, Andreas Lietz2, Ioannis Anagnostopoulos3, Franziska Hummel2, Burkhard Wiesner4, Martin Janz2, Franziska Jundt2, Burkhard Hirsch3, Korinna Jöhrens-Leder3, Hans-Peter Vornlocher5, Kurt Bommert2, Harald Stein3, and Bernd Dörken1,2

1 Max-Delbrück-Center for Molecular Medicine, 13125 Berlin, Germany
2 Humboldt-University, Charité, Robert-Rössle-Klinik, 13125 Berlin, Germany
3 Universitätsklinikum Benjamin Franklin, Institute for Pathology, Free University, 12200 Berlin, Germany
4 Institute of Molecular Pharmacology, 13125 Berlin, Germany
5 Ribopharma AG, 95326 Kulmbach, Germany

Address correspondence to Stephan Mathas, Max-Delbrück-Center for Molecular Medicine, FG Dörken, D-13125 Berlin, Germany. Phone: 49-30-94062720; Fax: 49-30-94063124; email: mathas{at}rrk-berlin.de

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 1ß–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)-{kappa}B. Despite expression of other NF-{kappa}B–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.

Key Words: lymphoma • CD95 antigen • TRAIL protein • NF-{kappa}B • siRNA

S. Mathas and A. Lietz contributed equally to this work.

The online version of this article contains supplemental material.

Abbreviations used in this paper: ALPS, autoimmune lymphoproliferative syndrome; AP-1, activator protein 1; C-8, caspase-8; C-10, caspase-10; c-FLIP, cellular FLICE-inhibitory protein; c-FLIPL, c-FLIP long; c-FLIPS, c-FLIP short; cHL, classical Hodgkin's lymphoma; CHX, cycloheximide; DISC, death-inducing signaling complex; FADD, Fas-associated death domain–containing protein; FLIP, FLICE-inhibitory protein; GC, germinal center; GFP, green fluorescent protein; HRS, Hodgkin/Reed-Sternberg; NF, nuclear factor; rhTRAIL, recombinant human TNF-related apoptosis-inducing ligand; siFLIP, c-FLIPS/L–specific small interfering RNA oligoribonucleotide; siRNA, small interfering RNA oligoribonucleotide; TRAIL, TNF-related apoptosis-inducing ligand.


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