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Type I and type II reactions in TRAIL-induced apoptosis – results from dose–response studies

Oncogene volume 24, pages 130–140 (2005)Cite this article

Abstract

Death receptor-induced apoptosis is paradigmatically mediated via the recruitment of FADD adapter molecule to the ligand/receptor complex and subsequent activation of caspase-8. However, several observations provided evidence that components of the mitochondrial apoptosis pathway are involved in death receptor-mediated apoptosis. In this regard, caspase-8-mediated activation of Bid induces the release of cytochrome c from the mitochondria, which, in turn, triggers the formation of the apoptosome protein complex, resulting in the activation of caspase-9. Whereas Bax or Bak were shown to be required for the proapoptotic effect of Bid, Bcl-2 was described to interfere with its action. Up to now, contradictory results regarding the role of Bcl-2 in TRAIL-induced apoptosis have been published. In order to study the influence of Bcl-2 on TRAIL-induced cell death more detailed, we utilized a tetracycline-regulated Bcl-2 expression system in Jurkat T cells. After having analysed the dose response for TRAIL-induced activation of caspase-8, -9, -3, breakdown of the mitochondrial membrane potential, and changes in the apoptotic morphology in cells expressing different Bcl-2 levels, we conclude that overexpression of Bcl-2 mediates a partial resistance towards lower doses of TRAIL that can be overcome when higher doses of TRAIL are applied. Thus, the requirement of the mitochondrial pathway for death receptor-induced apoptosis in type II cells should be reconsidered, since the protective effect of Bcl-2 is limited to lower TRAIL doses or early observation time points.

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Acknowledgements

This study was supported by grants from the Interdisciplinary Centre for Clinical Research (IZKF IIIB3) to CB and from Deutsche Krebshilfe to CB and VJ 10-1764Be1, CB 10-1825Be2, and CB10-1970Be3.

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  1. Justine Rudner

    Present address: Mount Sinai School of Medicine, Derald H. Ruttenberg Cancer Center, One Gustave L. Levy Place, Box 1178, New York, NY, 10029, USA

Authors and Affiliations

  1. Department of Radiation Oncology, University of Tuebingen, Hoppe-Seyler-Str. 3, Tuebingen, D-72076, Germany

    Justine Rudner, Verena Jendrossek & Claus Belka

  2. Molecular Gastroenterology, University of Tuebingen, Otfried Müller Str. 10, Tuebingen, D-72076, Germany

    Kirsten Lauber & Sebastian Wesselborg

  3. Department of Molecular Hematology and Oncology, Humboldt University Berlin, Charité, Lindenberger Weg 80, D-13125, Berlin, Germany

    Peter T Daniel

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Rudner, J., Jendrossek, V., Lauber, K. et al. Type I and type II reactions in TRAIL-induced apoptosis – results from dose–response studies. Oncogene 24, 130–140 (2005). https://doi.org/10.1038/sj.onc.1208191

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