Imatinib induces H2AX phosphorylation and apoptosis in chronic myelogenous leukemia cells in vitro via caspase-3/Mst1 pathway.
Acta Pharmacol Sin
; 33(4): 551-7, 2012 Apr.
Article
en En
| MEDLINE
| ID: mdl-22388075
ABSTRACT
AIM:
Histone H2AX is a novel tumor suppressor and its phosphorylation at the C terminus (Ser139 and Tyr142) is required for tumor cell apoptosis. The aim of the present study was to elucidate the mechanisms underlying imatinib-induced C-terminal phosphorylation of H2AX in chronic myelogenous leukemia cells in vitro.METHODS:
BCR-ABL-positive K562 cells were used. Microscopy, Western blotting and flow cytometry were used to study the signaling pathways that regulate imatinib-induced H2AX phosphorylation and the apoptotic mechanisms.RESULTS:
Treatment of K562 cells with imatinib (1-8 µmol/L) induced phosphorylation of H2AX at Ser139 and Tyr142 in time- and dose-dependent manners. In contrast, imatinib at the same concentrations did not affect H2AX acetylation at Lys 5, and the acetylated H2AX maintained a higher level in the cells. Meanwhile, imatinib (1-8 µmol/L) activated caspase-3 and its downstream mammalian STE20-like kinase 1 (Mst1), and induced apoptosis of K562 cells. The caspase-3 inhibitor Z-VAD (40 µmol/L) reduced imatinib-induced H2AX phosphorylation at Ser139 and Tyr142 and blocked imatinib-induced apoptosis of K562 cells. Imatinib (4 µmol/L) induced expression of Williams-Beuren syndrome transcription factor (WSTF), but not wild-type p53-induced phosphatase 1 (Wip1) in K562 cells.CONCLUSION:
The caspase-3/Mst1 pathway is required for H2AX C-terminal phosphorylation at Ser139 and Tyr142 and subsequent apoptosis in Bcr-Abl-positive K562 cells induced by imatinib.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Piperazinas
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Pirimidinas
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Histonas
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Leucemia Mielógena Crónica BCR-ABL Positiva
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Proteínas Proto-Oncogénicas
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Factor de Crecimiento de Hepatocito
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Caspasa 3
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Antineoplásicos
Límite:
Humans
Idioma:
En
Revista:
Acta Pharmacol Sin
Asunto de la revista:
FARMACOLOGIA
Año:
2012
Tipo del documento:
Article
País de afiliación:
China