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

Item Type:	Article
Title:	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
Creators Name:	Wieder, T. and Essmann, F. and Prokop, A. and Schmelz, K. and Schulze-Osthoff, K. and Beyaert, R. and Doerken, B. and Daniel, P.T.
Abstract:	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 downstream 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.
Keywords:	Antineoplastic Agents, Antineoplastic Antibiotics, Apoptosis, B-Cell Lymphoma, Bone Marrow, CD95 Antigens, Carrier Proteins, Caspase 3, Caspase 8, Caspase 9, Caspases, Cultured Tumor Cells, Epirubicin, Fas Ligand Protein, Fas-Associated Death Domain Protein, Immunoblotting, Membrane Glycoproteins, Paclitaxel, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Signal Transducing Adaptor Proteins, Transfection
Source:	Blood
ISSN:	0006-4971
Publisher:	American Society of Hematology
Volume:	97
Number:	5
Page Range:	1378-1387
Date:	1 March 2001
Official Publication:	https://doi.org/10.1182/blood.V97.5.1378
PubMed:	View item in PubMed

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