Activation of caspase-8 in drug-induced apoptosis of B-lymphoid cells is independent of CD95/Fas receptor-ligand interaction and occurs downstream of caspase-3

被引:219
作者
Wieder, T
Essmann, F
Prokop, A
Schmelz, K
Schulze-Osthoff, K
Beyaert, R
Dörken, B
Daniel, PT
机构
[1] Humboldt Univ, Univ Med Ctr Charite, Dept Hematol Oncol & Tumor Immunol, D-13125 Berlin, Germany
[2] Humboldt Univ, Univ Med Ctr Charite, Dept Pediat Hematol Oncol, D-13125 Berlin, Germany
[3] Univ Munster, Dept Immunol & Cell Biol, D-4400 Munster, Germany
[4] Univ Ghent, Ghent, Belgium
关键词
D O I
10.1182/blood.V97.5.1378
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
The activation of caspase-8, a crucial upstream mediator of death receptor signaling, was investigated in epirubicin- and Taxol-induced apoptosis of B-lymphoma cells. This study was performed because the CD95/Fas receptor-ligand interaction, recruitment of the Fas-associated death domain (FADD) adaptor protein, and subsequent activation of procaspase-8 have been implicated in the execution of drug-induced apoptosis in other cell types, indeed, active caspase-8 was readily detected after treatment of mature and immature B-lymphoid cells with epirubicin or Taxol. However, neither constitutive nor drug-induced expression of the CD95/Fas ligand was detectable in B-lymphoma cells. Furthermore, overexpression of a dominant-negative FADD mutant (FADDdn) did not block caspase-8 processing and subsequent DNA fragmentation, indicating that drug-induced caspase-8 activation was mediated by a CD95/Fas-independent mechanism. Instead, caspase-8 cleavage was slightly preceded by activation of caspase-3, suggesting that drug-induced caspase-8 activation in B-lymphoma cells is a down-stream event mediated by other caspases. This assumption was confirmed in 2 experimental systems-zDEVD-fmk, a cell-permeable inhibitor of caspase-3-like activity, blocked drug-induced caspase-8 cleavage, and depletion of caspase-3 from cell extracts impaired caspase-8 cleavage after in vitro activation with dATP and cytochrome c. Thus, these data indicate that drug-induced caspase-8 activation in B-lymphoma cells is independent of death receptor signaling and is mediated by postmitochondrial caspase-3 activation. (Blood, 2001;97: 1378-1387) (C) 2001 by The American Society of Hematology.
引用
收藏
页码:1378 / 1387
页数:10
相关论文
共 51 条
  • [1] Bantel H, 1999, CANCER RES, V59, P2083
  • [2] BENE MC, 1995, LEUKEMIA, V9, P1783
  • [3] Involvement of MACH, a novel MORT1/FADD-interacting protease, in Fas/APO-1- and TNF receptor-induced cell death
    Boldin, MP
    Goncharov, TM
    Goltsev, YV
    Wallach, D
    [J]. CELL, 1996, 85 (06) : 803 - 815
  • [4] Bouchon A, 2000, EUR J IMMUNOL, V30, P69, DOI 10.1002/1521-4141(200001)30:1<69::AID-IMMU69>3.0.CO
  • [5] 2-#
  • [6] Chinnaiyan AM, 1996, J BIOL CHEM, V271, P4961
  • [7] Liposomal ET-18-OCH3 induces cytochrome c-mediated apoptosis independently of CD95 (APO-1/Fas) signaling
    Cuvillier, O
    Mayhew, E
    Janoff, AS
    Spiegel, S
    [J]. BLOOD, 1999, 94 (10) : 3583 - 3592
  • [8] DANIEL PT, 1994, J IMMUNOL, V152, P5624
  • [9] Activation and activation-induced death of human tonsillar B cells and Burkitt lymphoma cells: Lack of CD95 (Fas/APO-1) ligand expression and function
    Daniel, PT
    Oettinger, U
    Mapara, MY
    Bommert, K
    Bargou, R
    Dorken, B
    [J]. EUROPEAN JOURNAL OF IMMUNOLOGY, 1997, 27 (04) : 1029 - 1034
  • [10] DHEIN J, 1992, J IMMUNOL, V149, P3166