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Paclitaxel-induced apoptosis in BJAB cells proceeds via a death receptor-independent, caspases-3/-8-driven mitochondrial amplification loop.
Oncogene. 2003 Apr 17; 22(15):2236-47.O

Abstract

Caspase-8 is a key effector of death-receptor-triggered apoptosis. In a previous study, we demonstrated, however, that caspase-8 can also be activated in a death receptor-independent manner via the mitochondrial apoptosis pathway, downstream of caspase-3. Here, we show that caspases-3 and -8 mediate a mitochondrial amplification loop that is required for the optimal release of cytochrome c, mitochondrial permeability shift transition, and cell death during apoptosis induced by treatment with the microtubule-damaging agent paclitaxel (Taxol). In contrast, Smac release from mitochondria followed a different pattern, and therefore seems to be regulated independently from cytochrome c release. Taxol-induced cell death was inhibited by the use of synthetic, cell-permeable caspase-3- (zDEVD-fmk) or caspase-8-specific (zIETD-fmk) inhibitors. Apoptosis signaling was not affected by a dominant-negative FADD mutant (FADD-DN), thereby excluding a role of death receptor signaling in the amplification loop and drug-induced apoptosis. The inhibitor experiments were corroborated by the use of BJAB cells overexpressing the natural serpin protease inhibitor, cytokine response modifier A. These data demonstrate that the complete activation of mitochondria, release of cytochrome c, and execution of drug-induced apoptosis require a mitochondrial amplification loop that depends on caspases-3 and -8 activation. In addition, this is the first report to demonstrate death receptor-independent caspase-8 autoprocessing in vivo.

Authors+Show Affiliations

Department of Hematology, Oncology and Tumor Immunology, University Medical Center Charité, University of Berlin, Germany.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

12700660

Citation

von Haefen, Clarissa, et al. "Paclitaxel-induced Apoptosis in BJAB Cells Proceeds Via a Death Receptor-independent, Caspases-3/-8-driven Mitochondrial Amplification Loop." Oncogene, vol. 22, no. 15, 2003, pp. 2236-47.
von Haefen C, Wieder T, Essmann F, et al. Paclitaxel-induced apoptosis in BJAB cells proceeds via a death receptor-independent, caspases-3/-8-driven mitochondrial amplification loop. Oncogene. 2003;22(15):2236-47.
von Haefen, C., Wieder, T., Essmann, F., Schulze-Osthoff, K., Dörken, B., & Daniel, P. T. (2003). Paclitaxel-induced apoptosis in BJAB cells proceeds via a death receptor-independent, caspases-3/-8-driven mitochondrial amplification loop. Oncogene, 22(15), 2236-47.
von Haefen C, et al. Paclitaxel-induced Apoptosis in BJAB Cells Proceeds Via a Death Receptor-independent, Caspases-3/-8-driven Mitochondrial Amplification Loop. Oncogene. 2003 Apr 17;22(15):2236-47. PubMed PMID: 12700660.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Paclitaxel-induced apoptosis in BJAB cells proceeds via a death receptor-independent, caspases-3/-8-driven mitochondrial amplification loop. AU - von Haefen,Clarissa, AU - Wieder,Thomas, AU - Essmann,Frank, AU - Schulze-Osthoff,Klaus, AU - Dörken,Bernd, AU - Daniel,Peter T, PY - 2003/4/18/pubmed PY - 2003/5/15/medline PY - 2003/4/18/entrez SP - 2236 EP - 47 JF - Oncogene JO - Oncogene VL - 22 IS - 15 N2 - Caspase-8 is a key effector of death-receptor-triggered apoptosis. In a previous study, we demonstrated, however, that caspase-8 can also be activated in a death receptor-independent manner via the mitochondrial apoptosis pathway, downstream of caspase-3. Here, we show that caspases-3 and -8 mediate a mitochondrial amplification loop that is required for the optimal release of cytochrome c, mitochondrial permeability shift transition, and cell death during apoptosis induced by treatment with the microtubule-damaging agent paclitaxel (Taxol). In contrast, Smac release from mitochondria followed a different pattern, and therefore seems to be regulated independently from cytochrome c release. Taxol-induced cell death was inhibited by the use of synthetic, cell-permeable caspase-3- (zDEVD-fmk) or caspase-8-specific (zIETD-fmk) inhibitors. Apoptosis signaling was not affected by a dominant-negative FADD mutant (FADD-DN), thereby excluding a role of death receptor signaling in the amplification loop and drug-induced apoptosis. The inhibitor experiments were corroborated by the use of BJAB cells overexpressing the natural serpin protease inhibitor, cytokine response modifier A. These data demonstrate that the complete activation of mitochondria, release of cytochrome c, and execution of drug-induced apoptosis require a mitochondrial amplification loop that depends on caspases-3 and -8 activation. In addition, this is the first report to demonstrate death receptor-independent caspase-8 autoprocessing in vivo. SN - 0950-9232 UR - https://www.unboundmedicine.com/medline/citation/12700660/Paclitaxel_induced_apoptosis_in_BJAB_cells_proceeds_via_a_death_receptor_independent_caspases_3/_8_driven_mitochondrial_amplification_loop_ L2 - https://doi.org/10.1038/sj.onc.1206280 DB - PRIME DP - Unbound Medicine ER -