Constitutive Expression of c-FLIP in Hodgkin and Reed-Sternberg Cells

Am J Pathol. 2002 Apr;160(4):1521-8. doi: 10.1016/S0002-9440(10)62578-3.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Apoptosis / physiology
  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cycloheximide / pharmacology
  • Down-Regulation
  • Hodgkin Disease / metabolism*
  • Hodgkin Disease / pathology*
  • Hodgkin Disease / physiopathology
  • Humans
  • Intracellular Signaling Peptides and Proteins*
  • Middle Aged
  • Protein Synthesis Inhibitors / pharmacology
  • RNA, Messenger / metabolism
  • Reed-Sternberg Cells / metabolism*
  • Reed-Sternberg Cells / physiology
  • Tumor Cells, Cultured
  • fas Receptor / physiology

Substances

  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • CFLAR protein, human
  • Carrier Proteins
  • Intracellular Signaling Peptides and Proteins
  • Protein Synthesis Inhibitors
  • RNA, Messenger
  • fas Receptor
  • Cycloheximide