title: A novel mechanism for imatinib mesylate-induced cell death of BCR-ABL-positive human leukemic cells: caspase-independent, necrosis-like programmed cell death mediated by serine protease activity.
abstract: Caspase-independent programmed cell death can exhibit either an apoptosis-like or a necrosis-like morphology. The ABL kinase inhibitor, imatinib mesylate, has been reported to induce apoptosis of BCR-ABL-positive cells in a caspase-dependent fashion. We investigated whether caspases alone were the mediators of imatinib mesylate-induced cell death. In contrast to previous reports, we found that a broad caspase inhibitor, zVAD-fmk, failed to prevent the death of imatinib mesylate-treated BCR-ABL-positive human leukemic cells. Moreover, zVAD-fmk-preincubated, imatinib mesylate-treated cells exhibited a necrosis-like morphology characterized by cellular pyknosis, cytoplasmic vacuolization, and the absence of nuclear signs of apoptosis. These cells manifested a loss of the mitochondrial transmembrane potential, indicating the mitochondrial involvement in this caspase-independent necrosis. We excluded the participation of several mitochondrial factors possibly involved in caspase-independent cell death such as apoptosis-inducing factor, endonuclease G, and reactive oxygen species. However, we observed the mitochondrial release of the serine protease Omi/HtrA2 into the cytosol of the cells treated with imatinib mesylate or zVAD-fmk plus imatinib mesylate. Furthermore, serine protease inhibitors prevented the caspase-independent necrosis. Taken together, our results suggest that imatinib mesylate induces a caspase-independent, necrosis-like programmed cell death mediated by the serine protease activity of Omi/HtrA2.
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Okada
authors.forename: Souichi
authors.initials: S
authors.lastname: Adachi
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Imai
authors.forename: Ken-ichiro
authors.initials: K
authors.lastname: Watanabe
authors.forename: Shin-ya
authors.initials: SY
authors.lastname: Toyokuni
authors.forename: Masaki
authors.initials: M
authors.lastname: Ueno
authors.forename: Antonis S
authors.initials: AS
authors.lastname: Zervos
authors.forename: Guido
authors.initials: G
authors.lastname: Kroemer
authors.forename: Tatsutoshi
authors.initials: T
authors.lastname: Nakahata
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D051033:Apoptosis Inducing Factor; D001549:Benzamides; D053148:Caspase 3; D053453:Caspase 9; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D002467:Cell Nucleus / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D005420:Flavoproteins / Q000378:metabolism; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism; D000074923:High-Temperature Requirement A Serine Peptidase 2; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D008564:Membrane Potentials / Q000502:physiology; D008565:Membrane Proteins / Q000378:metabolism; D008928:Mitochondria / Q000502:physiology; D024101:Mitochondrial Proteins; D009336:Necrosis; D009707:Nucleosomes / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012697:Serine Endopeptidases / Q000378:metabolism*
chemical_list: C494829:AIFM1 protein, human; D000590:Amino Acid Chloromethyl Ketones; D000970:Antineoplastic Agents; D051033:Apoptosis Inducing Factor; D001549:Benzamides; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D005420:Flavoproteins; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D009707:Nucleosomes; D010879:Piperazines; D011743:Pyrimidines; D017382:Reactive Oxygen Species; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; C114880:trypsin-like serine protease; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; D012697:Serine Endopeptidases; C000615914:HTRA2 protein, human; D000074923:High-Temperature Requirement A Serine Peptidase 2; C505407:CASP3 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases