Imatinib inhibits inactivation of the ATM/ATR signaling pathway and recovery from adriamycin/doxorubicin-induced DNA damage checkpoint arrest.
Cell Biol Int
; 39(8): 923-32, 2015 Aug.
Article
em En
| MEDLINE
| ID: mdl-25790472
ABSTRACT
The DNA damage checkpoint arrests cell cycle progression to allow time for DNA repair. After completion of DNA repair, checkpoint activation is terminated, and cell cycle progression is resumed in a process called checkpoint recovery. The activation of the checkpoint has been studied in depth, but little is known about recovery from the DNA damage checkpoint. Recently we showed that Src family kinases promote recovery from the G2 DNA damage checkpoint. Here we show that imatinib inhibits inactivation of ATM/ATR signaling pathway to suppress recovery from Adriamycin/doxorubicin-induced DNA damage checkpoint arrest. Imatinib and pazopanib, two distinct inhibitors of PDGFR/c-Kit family kinases, delayed recovery from checkpoint arrest and inhibited the subsequent S-G2-M transition after Adriamycin exposure. By contrast, imatinib and pazopanib did not delay the recovery from checkpoint arrest in the presence of an ATM/ATR inhibitor caffeine. Consistently, imatinib induced a persistent activation of ATR-Chk1 signaling. By the way, the maintenance of G2 checkpoint arrest is largely dependent on ATR-Chk1 signaling. However, unlike Src inhibition, imatinib did not delay the recovery from checkpoint arrest in the presence of an ATM inhibitor KU-55933. Furthermore, imatinib induced a persistent activation of ATM-KAP1 signaling, and a possible involvement of imatinib in an ATM-dependent DNA damage response is suggested. These results reveal that imatinib inhibits recovery from Adriamycin-induced DNA damage checkpoint arrest in an ATM/ATR-dependent manner and raise the possibility that imatinib may inhibit resumption of tumor proliferation after chemo- and radiotherapy.
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Base de dados:
MEDLINE
Assunto principal:
Dano ao DNA
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Doxorrubicina
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Proteínas Mutadas de Ataxia Telangiectasia
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Mesilato de Imatinib
Limite:
Humans
Idioma:
En
Ano de publicação:
2015
Tipo de documento:
Article