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Cell type specific involvement of death receptor and mitochondrial pathways in drug-induced apoptosis

Oncogene volume 20, pages 1063–1075 (2001)Cite this article

Abstract

Apoptosis in response to cellular stress such as treatment with cytotoxic drugs is mediated by effector caspases (caspase-3) which can be activated by different initiator pathways. Here, we report on a cell type specific triggering of death receptor and/or mitochondrial pathways upon drug treatment. In type I cells (BJAB), both the receptor and the mitochondrial pathway were activated upon drug treatment, since blockade of either the receptor pathway by overexpression of dominant negative FADD (FADD-DN) or of the mitochondrial pathway by overexpression of Bcl-XL only partially inhibited apoptosis. Drug treatment induced formation of a FADD- and caspase-8-containing CD95 death-inducing signaling complex (DISC) in type I cells resulting in activation of caspase-8 as the most apical caspase. In contrast, in type II cells (Jurkat), apoptosis was predominantly controlled by mitochondria, since overexpression of Bcl-2 completely blocked drug-induced apoptosis, while overexpression of FADD-DN had no protective effect. In these cells, caspases including caspase-8 were activated by mitochondria-driven signaling events and no DISC was detected despite expression levels of CD95, FADD and caspase-8 proteins comparable to type I cells. Likewise, drug-induced CD95 aggregation was predominantly found in type I cells. Bid was cleaved prior to mitochondrial alterations in type I cells providing a molecular link between caspase-8 activation and mitochondrial perturbations, whereas in type II cells, Bid was cleaved downstream of mitochondria. Our findings of a cell type specific response to cytotoxic drugs have implications for the identification of molecular parameters for chemosensitivity or resistance in different tumor cells.

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Acknowledgements

We thank PH Krammer (DKFZ, Heidelberg, Germany) for anti-FLICE and anti-FADD antibody, VM Dixit (Genentech, South San Francisco, CA, USA) for the FADD clone NFD4, B Antonsson (Serono, Geneva, Switzerland) for anti-Bid antibody and BB Wolf (La Jolla Institute for Allergy and Immunology, San Diego, CA, USA) for anti-caspase-9 antibody. This work has been partially supported by grants from the Deutsche Forschungsgemeinschaft, the Bundesministerium für Forschung and Technologie, Bonn, the Tumor Center Heidelberg/Mannheim and the Deutsche Leukämieforschungshilfe (to K-M Debatin), European Commission (to K-M Debatin and G Kroemer) and Ligue Nationale contre le Cancer (to G Kroemer). SA Susin receives a European Community Marie Curie fellowship.

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Authors and Affiliations

  1. University Children's Hospital, Prittwitzstr. 43, Ulm, D-89075, Germany

    Simone Fulda, Eric Meyer, Claudia Friesen & Klaus-Michael Debatin

  2. Centre Nationale de la Recherche Scientifique, Unité Mixte de Recherche 1599, Institut Gustave Roussy, 39 rue Camille Desmoulins, Villejuif, F-94805, France

    Santos A Susin & Guido Kroemer

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Fulda, S., Meyer, E., Friesen, C. et al. Cell type specific involvement of death receptor and mitochondrial pathways in drug-induced apoptosis. Oncogene 20, 1063–1075 (2001). https://doi.org/10.1038/sj.onc.1204141

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