title: Imatinib inhibits inactivation of the ATM/ATR signaling pathway and recovery from adriamycin/doxorubicin-induced DNA damage checkpoint arrest.
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.
authors: Department of Molecular Cell Biology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, 260-8675, Japan.
authors: Mariko
authors: M
authors: Morii
authors: Department of Molecular Cell Biology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, 260-8675, Japan.
authors: Yasunori
authors: Y
authors: Fukumoto
authors: Department of Molecular Cell Biology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, 260-8675, Japan.
authors: Sho
authors: S
authors: Kubota
authors: Department of Molecular Cell Biology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, 260-8675, Japan.
authors: Noritaka
authors: N
authors: Yamaguchi
authors: Department of Molecular Cell Biology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, 260-8675, Japan.|Present address: Department of Biochemistry & Molecular Biology, Kyoto Pharmaceutical University, Kyoto, 607-8414, Japan.
authors: Yuji
authors: Y
authors: Nakayama
authors: Department of Molecular Cell Biology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, 260-8675, Japan.
authors: Naoto
authors: N
authors: Yamaguchi
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D000071877:Checkpoint Kinase 1; D004249:DNA Damage; D004260:DNA Repair; D004317:Doxorubicin / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D000068877:Imatinib Mesylate / Q000494:pharmacology*; D007191:Indazoles; D011494:Protein Kinases / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology; D000076183:Tripartite Motif-Containing Protein 28
chemical_list: D007191:Indazoles; D011743:Pyrimidines; D012097:Repressor Proteins; D013449:Sulfonamides; C516667:pazopanib; D004317:Doxorubicin; D000068877:Imatinib Mesylate; C101116:TRIM28 protein, human; D000076183:Tripartite Motif-Containing Protein 28; D011494:Protein Kinases; C576324:ATM protein, human; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1
keywords: DNA damage; PDGFR/c-Kit; cell cycle; checkpoint recovery; imatinib