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Caspase-10 involvement in cytotoxic drug-induced apoptosis of tumor cells

Oncogene volume 25, pages 7635–7645 (2006)Cite this article

Abstract

Anticancer drugs can induce tumor cell death by caspase-dependent apoptosis. The observation that procaspase-10 expression decreased in leukemic cells from acute myeloblastic leukemia patients at first relapse led us to explore the role of caspase-10 in cytotoxic drug-induced apoptosis. We show that caspase-10 is activated in etoposide-treated cells in a dose- and time-dependent manner. A caspase-10 peptide inhibitor, a caspase-10 dominant-negative mutant or a small interfering RNA (siRNA)-mediated downregulation of the enzyme negatively interfere with drug-induced cell death and caspase-2, -3, -8 and -9 activation. The extrinsic pathway to apoptosis is not involved in drug-induced caspase-10 activation that occurs downstream of Bax redistribution to mitochondria and cytochrome c release from this organelle. siRNA-mediated downregulation of Apaf-1 prevents etoposide-mediated activation of caspase-10. In a cell-free assay, cytochrome c and dATP treatment of cell extracts after immunodepletion of either caspase-3 or caspase-9 indicates that caspase-10 is activated downstream of caspase-9. Then, caspase-10 is involved in a feedback amplification loop that amplifies caspase-9 and -3 activities. Altogether, these data indicate an active role for caspase-10 in cytotoxic drug-induced tumor cell death, downstream of the mitochondria.

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Acknowledgements

Our group is supported by grants from the Ligue Nationale Contre le Cancer to AB (Saône et Loire and Nièvre committees), to ES and CR (‘équipe labellisée’) and to RF (Haute Marne and Allier committees): LP is the recipient of INSERM and région de Bourgogne fellowship. We thank Dr Lenardo (Laboratory of immunology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, USA) for kindly providing plasmids encoding caspase-10 mutants. We thank Drs L Corcos (Inserm U 517, Dijon, France) and Marc Maynadié (Hematology Laboratory, CHU Bocage, Dijon) for help in designing siRNA sequences and obtaining AML samples, respectively.

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  1. R Filomenko and L Prévotat: These authors contributed equally to this work.

Authors and Affiliations

  1. Inserm U 517, Ecole Pratique des Hautes Etudes, IFR100, Faculty of Medicine, Dijon cedex, France

    R Filomenko, L Prévotat, C Rébé, M Cortier, J-F Jeannin, E Solary & A Bettaieb

  2. Clinical Hematology Unit, CHU Le Bocage, Dijon, BP1542, France

    E Solary

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  1. R Filomenko
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Correspondence to A Bettaieb.

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Filomenko, R., Prévotat, L., Rébé, C. et al. Caspase-10 involvement in cytotoxic drug-induced apoptosis of tumor cells. Oncogene 25, 7635–7645 (2006). https://doi.org/10.1038/sj.onc.1209733

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