Constitutive expression of c-FLIP in Hodgkin and Reed-Sternberg cells.
Crosslinking of the transmembrane receptor CD95/Fas leads to activation of a signaling cascade resulting in apoptosis. c-FLIP is a recently described protein that potently inhibits Fas-mediated apoptosis and has been shown to be a key factor in germinal center B cell survival. Because Hodgkin and Reed-Sternberg cells in classical Hodgkin's disease (cHD) are also resistant to Fas-mediated apoptosis we studied the role of c-FLIP in classical HD. High levels of c-FLIP protein were identified in two Fas-resistant Hodgkin-derived cell lines. In contrast to other tumor cells, inhibition of protein synthesis by cycloheximide did not lead to down-regulation of c-FLIP protein in these HD cell lines. Furthermore, Fas-mediated apoptosis was only partially restored suggesting that normal regulation of c-FLIP was disrupted. The in vivo relevance of these findings was supported by demonstration of significant c-FLIP expression by immunohistochemistry in 18 of 19 evaluable cases of primary HD. Taken together, c-FLIP is constitutively expressed in HD and may therefore be a major mechanism responsible for Fas-resistance in HD.
Thomas
Roman Kurt
RK
Department of Internal Medicine I, University of Cologne, Cologne, Germany.
Kallenborn
Anne
A
Wickenhauser
Claudia
C
Schultze
Joachim Ludwig
JL
Draube
Andreas
A
Vockerodt
Martina
M
Re
Daniel
D
Diehl
Volker
V
Wolf
Jürgen
J
D000293:Adolescent; D000328:Adult; D000368:Aged; D017209:Apoptosis / Q000502:physiology; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D003513:Cycloheximide / Q000494:pharmacology; D015536:Down-Regulation; D006689:Hodgkin Disease / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008875:Middle Aged; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D016539:Reed-Sternberg Cells / Q000378:metabolism* / Q000502:physiology; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000502:physiology
D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D019014:fas Receptor; D003513:Cycloheximide