Caspase-10 involvement in cytotoxic drug-induced apoptosis of tumor cells.
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.
Filomenko
R
R
Inserm U 517, Ecole Pratique des Hautes Etudes, IFR100, Faculty of Medicine, Dijon cedex, France.
Prévotat
L
L
Rébé
C
C
Cortier
M
M
Jeannin
J-F
JF
Solary
E
E
Bettaieb
A
A
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis; D053478:Apoptosomes / Q000187:drug effects / Q000378:metabolism; D053477:Apoptotic Protease-Activating Factor 1 / Q000378:metabolism; D053455:Caspase 10 / Q000502:physiology*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D005047:Etoposide / Q000494:pharmacology*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis; D008928:Mitochondria / Q000378:metabolism; D012008:Recurrence; D015398:Signal Transduction
D000972:Antineoplastic Agents, Phytogenic; D053478:Apoptosomes; D053477:Apoptotic Protease-Activating Factor 1; D005047:Etoposide; D053455:Caspase 10; D020169:Caspases