1. ¹Inserm U 517, Ecole Pratique des Hautes Etudes, IFR100, Faculty of Medicine, Dijon cedex, France
2. ²Clinical Hematology Unit, CHU Le Bocage, BP1542, Dijon, France

Correspondence: Dr A Bettaieb, Inserm U517, Ecole Pratique des Hautes Etudes, IFR100, Faculty of Medicine, 7 boulevard Jeanne d'Arc, 21079 Dijon cedex, France. E-mail: ali.bettaieb@u-bourgogne.fr

³These authors contributed equally to this work.

Received 17 January 2006; Revised 26 April 2006; Accepted 5 May 2006; Published online 12 June 2006.

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.