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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

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

T Wieder, F Essmann, A Prokop, K Schmelz, K Schulze-Osthoff, R Beyaert, B Dörken, P T Daniel

Blood. 2001 Mar 1;97(5):1378-87.

PMID: 11222383

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR42415431	Caspase-8 Inhibitor I, Cell-Permeable			Price

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