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Caspase-8/FLICE functions as an executioner caspase in anticancer drug-induced apoptosis

Oncogene volume 19, pages 4563–4573 (2000)Cite this article

Abstract

Caspase-8 plays an essential role in apoptosis triggered by death receptors. Through the cleavage of Bid, a proapoptotic Bcl-2 member, it further activates the mitochondrial cytochrome c/Apaf-1 pathway. Because caspase-8 can be processed also by anticancer drugs independently of death receptors, we investigated its exact role and order in the caspase cascade. We show that in Jurkat cells either deficient for caspase-8 or overexpressing its inhibitor c-FLIP apoptosis mediated by CD95, but not by anticancer drugs was inhibited. In the absence of active caspase-8, anticancer drugs still induced the processing of caspase-9, -3 and Bid, indicating that Bid cleavage does not require caspase-8. Overexpression of Bcl-xL prevented the processing of caspase-8 as well as caspase-9, -6 and Bid in response to drugs, but was less effective in CD95-induced apoptosis. Similar responses were observed by overexpression of a dominant-negative caspase-9 mutant. To further determine the order of caspase-8 activation, we employed MCF7 cells lacking caspase-3. In contrast to caspase-9 that was cleaved in these cells, anticancer drugs induced caspase-8 activation only in caspase-3 transfected MCF7 cells. Thus, our data indicate that, unlike its proximal role in receptor signaling, in the mitochondrial pathway caspase-8 rather functions as an amplifying executioner caspase.

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Acknowledgements

The authors wish to thank Drs ES Alnemri, J Blenis, Y Lazebnik, CB Thompson, J Tschopp, J Yuan, P Vandenabeele and H Walczak for providing many valuable cell lines and reagents. This work was supported in part by grants from the Federal Ministry of Education, Science, Research and Technology (Fö. 01KS9602) and the Interdisciplinary Center of Clinical Research Center (IZKF) Tübingen. S Wesselborg acknowledges a fellowship from the Federal Ministry of Education, Science, Research and Technology, and C Berg from the Fortune Program of the University of Tübingen.

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Author notes

  1. Ingo H Engels and Ania Stepczynska: IH Engels and A Stepczynska share equal first authorship

  2. Klaus Schulze-Osthoff and Sebastian Wesselborg: K Schulze-Osthoff and S Wesselborg share equal senior authorship

Authors and Affiliations

  1. Department of Immunology and Cell Biology, University of Münster, Germany

    Ingo H Engels, Ania Stepczynska, Christopher Stroh, Reiner U Jänicke & Klaus Schulze-Osthoff

  2. Department of Internal Medicine I, University of Tübingen, Germany

    Kirsten Lauber, Christoph Berg, Michael Gregor & Sebastian Wesselborg

  3. Institute of Cell Biology and Immunology, University of Stuttgart, Germany

    Ralf Schwenzer & Harald Wajant

  4. Institute of Molecular and Cell Biology, Republic of Singapore

    Alan G Porter

  5. Department of Radiation and Oncology, University of Tübingen, Germany

    Claus Belka

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  1. Ingo H Engels
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Engels, I., Stepczynska, A., Stroh, C. et al. Caspase-8/FLICE functions as an executioner caspase in anticancer drug-induced apoptosis. Oncogene 19, 4563–4573 (2000). https://doi.org/10.1038/sj.onc.1203824

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