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Arsenic trioxide induces regulated, death receptor-independent cell death through a Bcl-2-controlled pathway

Oncogene volume 24, pages 7031–7042 (2005)Cite this article

Abstract

Arsenic trioxide (As2O3, arsenite) efficiently kills cells from various hematologic malignancies and has successfully been employed especially for the treatment of acute promyelocytic leukemia. There and in lymphoid cells, we demonstrated that As2O3 induces cell death in a caspase-2- and -9-independent fashion. Here, we address a potential role of death receptor signaling through the FADD/caspase-8 death-inducing signaling complex in As2O3-induced cell death. In detail, we demonstrate that As2O3 induces cell death independently of caspase-8 or FADD and cannot be blocked by disruption of CD95/Fas receptor ligand interaction. Unlike in death receptor ligation-induced apoptosis, As2O3-induced cell death was not blocked by the broad-spectrum caspase inhibitor z-VAD-fmk or the caspase-8-specific inhibitor z-IETD-fmk. Nevertheless, As2O3-induced cell death occurred in a regulated manner and was abrogated upon Bcl-2 overexpression. In contrast, As2O3-induced cell demise was neither blocked by the caspase-9 inhibitor z-LEHD-fmk nor substantially inhibited through the expression of a dominant negative caspase-9 mutant. Altogether our data demonstrate that As2O3-induced cell death occurs independently of the extrinsic death receptor pathway of apoptosis. Cell death proceeds entirely via an intrinsic, Bcl-2-controlled mitochondrial pathway that does, however, not rely on caspase-9.

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Acknowledgements

This work was supported by a grant SCHO 534/2-1 from the Deutsche Forschungsgemeinschaft and a grant DJCLS-R01/02 from the Deutsche José Carreras Stiftung.

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Authors and Affiliations

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

    Christian Scholz, Antje Richter, Mario Lehmann, Bernd Dörken & Peter T Daniel

  2. Institute of Molecular Medicine, Heinrich Heine University, Düsseldorf, Germany

    Klaus Schulze-Osthoff

  3. Clinical and Molecular Oncology, Max Delbrück Center for Molecular Medicine, Berlin, 13125, Germany

    Peter T Daniel

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  1. Christian Scholz
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Correspondence to Peter T Daniel.

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Scholz, C., Richter, A., Lehmann, M. et al. Arsenic trioxide induces regulated, death receptor-independent cell death through a Bcl-2-controlled pathway. Oncogene 24, 7031–7042 (2005). https://doi.org/10.1038/sj.onc.1208868

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