Inhibition of CHK1 kinase by Gö6976 converts 8-chloro-adenosine-induced G2/M arrest into S arrest in human myelocytic leukemia K562 cells |
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Authors: | Xiu-Zhen Jia Sheng-Yong Yang Jing Zhou Ju-Hua Ni Hong-Ti Jia |
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Affiliation: | a Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Xue Yuan Road 38, Beijing 100191, PR China b Molecular Medicine and Cancer Research Center,Chongqing Medical University, Yi Xue Yuan Road 1, Chongqing 400016, PR China c Department of Biochemistry and Molecular Biology, Capital Medical University, You An Men 8, Beijing 100054, PR China |
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Abstract: | 8-Chloro-cAMP (8-Cl-cAMP) and its metabolite 8-chloro-adenosine (8-Cl-Ado) inhibit cell growth by 8-Cl-Ado-converted 8-Cl-ATP that targets cell-cycle control and RNA metabolism. However, the cell-cycle checkpoint pathways remain to be identified. Recent studies have shown that 8-Cl-cAMP administration and 8-Cl-Ado exposure may damage chromosomal DNA in vivo and in vitro. In this study, we demonstrate that 8-Cl-Ado-induced DNA damage activates G2/M phase checkpoint, which is associated with ATM-activated CHK1-CDC25C-CDC2 pathway joined by BRCA1-CHK1 branch in apoptosis-resistant human myelocytic leukemia K562 (p53-null) cells. Inhibition of CHK1 kinase by Gö6976, an inhibitor of CHK1 activity, can promote DNA damage and lead to the activation of CHK2, converting G2/M checkpoint into intra-S-phase checkpoint in which two parallel branches, the ATM-CHK2-CDC25A-CDK2 and the ATM-NBS1/SMC1 cascades, are involved. These observations may provide aid in better understanding of the mechanisms of 8-Cl-cAMP and 8-Cl-Ado actions and in potential design of the combined therapy. |
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Keywords: | 8-Chloro-adenosine DNA damage G2/M checkpoint Intra-S-phase checkpoint CHK1 inhibitor/Gö 6976 Human myelocytic leukemia K562 cell |
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