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| 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., Essmann, F., Prokop, A., Schmelz, K., Schulze-Osthoff, K., Beyaert, R., 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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