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Inhibition of TRAIL-induced apoptosis by Bcl-2 overexpression

Oncogene volume 21, pages 2283–2294 (2002)Cite this article

Abstract

Primary or acquired resistance to current treatment protocols remains a major concern in clinical oncology and may be caused by defects in apoptosis programs. Since recent data suggest that TRAIL can bypass apoptosis resistance caused by Bcl-2, we further investigated the role of Bcl-2 in TRAIL-induced apoptosis. Here we report that overexpression of Bcl-2 conferred protection against TRAIL in neuroblastoma, glioblastoma or breast carcinoma cell lines. Bcl-2 overexpression reduced TRAIL-induced cleavage of caspase-8 and Bid indicating that caspase-8 was activated upstream and also downstream of mitochondria in a feedback amplification loop. Importantly, Bcl-2 blocked cleavage of caspases-9, -7 and -3 into active subunits and cleavage of the caspase substrates DFF45 or PARP. Also, Bcl-2 blocked cleavage of XIAP and overexpression of XIAP conferred resistance against TRAIL indicating that apoptosis was also amplified through a feedforward loop between caspases and XIAP. In contrast, in SKW lymphoblastoid cells, TRAIL-induced activation of caspase-8 directly translated into full activation of caspases, cleavage of XIAP, DFF45 or PARP and apoptosis independent of Bcl-2 overexpression, although Bcl-2 similarly inhibited loss of mitochondrial membrane potential and the release of cytochrome c, AIF and Smac from mitochondria in all cell types. By demonstrating a cell type dependent regulation of the TRAIL signaling pathway at different level, e.g. by Bcl-2 and by XIAP, these findings may have important clinical implication. Thus, strategies targeting the molecular basis of resistance towards TRAIL may be necessary in some tumors for cancer therapy with TRAIL.

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Acknowledgements

We thank Petra Miller-Rostek for expert technical assistance, PH Krammer (DKFZ, Heidelberg, Germany) for anti-FLICE antibody, X Wang for anti-Smac antibody (University of Texas, Dallas, TX, USA), G Kroemer (CNRS, Villejuif, France) for anti-AIF antibody, JC Reed (Burnham Institute, San Diego, CA, USA) for XIAP cDNA plasmid, A Lopez-Rivas (University of Granada, Spain) for MCF-7 breast carcinoma and M Weller (University of Tuebingen, Germany) for LN-229 glioblastoma cells. This work has been partially supported by grants from the Deutsche Forschungsgemeinschaft, the Bundesministerium für Forschung and Technologie, Bonn, the Deutsche Leukämieforschungshilfe, the Wilhelm Sander-Stiftung and the European community.

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

    Simone Fulda, Eric Meyer & Klaus-Michael Debatin

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  1. Simone Fulda
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Correspondence to Klaus-Michael Debatin.

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Fulda, S., Meyer, E. & Debatin, KM. Inhibition of TRAIL-induced apoptosis by Bcl-2 overexpression. Oncogene 21, 2283–2294 (2002). https://doi.org/10.1038/sj.onc.1205258

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