論文 - 詳細
| RRC ID | 1383 |
|---|---|
| 著者 | Okada M, Adachi S, Imai T, Watanabe K, Toyokuni SY, Ueno M, Zervos AS, Kroemer G, Nakahata T. |
| タイトル | 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. |
| ジャーナル | Blood |
| 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. |
| 巻・号 | 103(6) |
| ページ | 2299-307 |
| 公開日 | 2004-3-15 |
| DOI | 10.1182/blood-2003-05-1605 |
| PII | S0006-4971(20)50026-8 |
| PMID | 14645012 |
| MeSH | Amino Acid Chloromethyl Ketones / pharmacology Antineoplastic Agents / pharmacology* Apoptosis / drug effects* Apoptosis / physiology Apoptosis Inducing Factor Benzamides Caspase 3 Caspase 9 Caspase Inhibitors Caspases / metabolism Cell Line, Tumor / cytology Cell Line, Tumor / drug effects Cell Line, Tumor / enzymology Cell Nucleus / metabolism Cysteine Proteinase Inhibitors / pharmacology Flavoproteins / metabolism Fusion Proteins, bcr-abl / metabolism High-Temperature Requirement A Serine Peptidase 2 Humans Imatinib Mesylate Leukemia, Myelogenous, Chronic, BCR-ABL Positive* Membrane Potentials / physiology Membrane Proteins / metabolism Mitochondria / physiology Mitochondrial Proteins Necrosis Nucleosomes / metabolism Piperazines / pharmacology* Pyrimidines / pharmacology* Reactive Oxygen Species / metabolism Serine Endopeptidases / metabolism* |
| IF | 17.794 |
| 引用数 | 80 |
| WOS 分野 | HEMATOLOGY |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 各媒体での言及数の合計 | 0 |
| リソース情報 | |
| ヒト・動物細胞 | K562(RCB0027) |