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Paclitaxel-induced apoptosis in BJAB cells proceeds via a death receptor-independent, caspases-3/-8-driven mitochondrial amplification loop

Oncogene volume 22, pages 2236–2247 (2003)Cite this article

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.

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Acknowledgements

The technical assistance of Antje Richter is gratefully acknowledged. We thank AM Chinnaiyan and VM Dixit (Ann Arbor, MI, USA) for providing the dominant-negative FADD (FADD-DN) construct. BJAB Bcl-xL and vector controls were kindly provided by S Fulda, University of Ulm, Germany. This work was supported by grants from the Deutsche Forschungsgemeinschaft (SFB 506 and Da238/4-1), the European Union TMR program, and the Deutsche José Carreras Leukämie-Stiftung e. V. (DJCLS-R01/02).

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Author notes

  1. Clarissa von Haefen, Thomas Wieder and Frank Essmann: These authors contributed equally to the present study

Authors and Affiliations

  1. Department of Hematology, Oncology and Tumor Immunology, University Medical Center Charité, Campus Berlin-Buch, Humboldt University of Berlin, Germany

    Clarissa von Haefen, Thomas Wieder, Frank Essmann, Bernd Dörken & Peter T Daniel

  2. Institute for Molecular Medicine, University of Düsseldorf, Germany

    Klaus Schulze-Osthoff

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  1. Clarissa von Haefen
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Correspondence to Peter T Daniel.

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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 22, 2236–2247 (2003). https://doi.org/10.1038/sj.onc.1206280

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