Naphthalimides Induce G(2) Arrest Through the ATM-Activated Chk2-Executed Pathway in HCT116 Cells

doi:10.1593/neo.09986

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	Naphthalimides Induce G(2) Arrest Through the ATM-Activated Chk2-Executed Pathway in HCT116 Cells
	Zhu, Hong 1; Miao, Ze-Hong 1; Huang, Min1 ; Feng, Jian-Ming 1; Zhang, Zhi-Xiang 1; Lu, Jin-Jian 1; Cai, Yu-Jun 1; Tong, Lin-Jiang 1; Xu, Yu-Fang 2; Qian, Xu-Hong 2
刊名	NEOPLASIA
	2009-11
卷号	11 期号:11 页码:1226-1234
ISSN号	1522-8002
DOI	10.1593/neo.09986
文献子类	Article
英文摘要	Naphthalimides, particularly amonafide and 2-(2-dimethylamino)-6-thia-2-aza-benzo[def]chrysene-1,3-diones (R16), have been identified to possess anticancer activities and to induce G(2)-M arrest through inhibiting topoisomerase II accompanied by Chk1 degradation. The current study was designed to precisely dissect the signaling pathway(s) responsible for the naphthalimide-induced cell cycle arrest in human colon carcinoma HCT116 cells. Using phosphorylated histone H3 and mitotic protein monoclonal 2 as mitosis markers, we first specified the G(2) arrest elicited by the R16 and amonafide. Then, R16 and amonafide were revealed to induce phosphorylation of the DNA damage sensor ataxia telangiectasia-mutated (ATM) responding to DNA double-strand breaks (DSBs). Inhibition of ATM by both the pharmacological inhibitor caffeine and the specific small interference RNA (siRNA) rescued the G(2) arrest elicited by R16, indicating its ATM-dependent characteristic. Furthermore, depletion of Chk2, but not Chk1 with their corresponding siRNA, statistically significantly reversed the R16- and amonafide-triggered G(2) arrest. Moreover, the naphthalimides phosphorylated Chk2 in an ATM-dependent manner but induced Chk1 degradation. These data indicate that R16 and amonafide preferentially used Chk2 as evidenced by the differential ATM-executed phosphorylation of Chk1 and Chk2. Thus, a clear signaling pathway can be established, in which ATM relays the DNA DSBs signaling triggered by the naphthalimides to the checkpoint kinases, predominantly to Chk2, which finally elicits G(2) arrest. The mechanistic elucidation not only favors the development of the naphthalimides as anticancer agents but also provides an alternative strategy of Chk2 inhibition to potentiate the anticancer activities of these agents.
资助项目	National Natural Science Foundation of China[30772588] ; National Natural Science Foundation of China[30721005] ; Science and Technology Commission of Shanghai Municipality[08DZ1980200]
WOS关键词	TOPOISOMERASE-II ; IONIZING-RADIATION ; HUMAN CHK1 ; DNA ; CHECKPOINT ; KINASE ; PHOSPHORYLATION ; APOPTOSIS ; CANCER ; DEGRADATION
WOS研究方向	Oncology
语种	英语
出版者	NEOPLASIA PRESS
WOS记录号	WOS:000272473900011
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/279095]
专题	药理学第一研究室中科院受体结构与功能重点实验室新药研究国家重点实验室
通讯作者	Miao, Ze-Hong
作者单位	1.Chinese Acad Sci, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China; 2.E China Univ Sci & Technol, Shanghai Key Lab Chem Biol, Shanghai 200237, Peoples R China
推荐引用方式 GB/T 7714	Zhu, Hong,Miao, Ze-Hong,Huang, Min,et al. Naphthalimides Induce G(2) Arrest Through the ATM-Activated Chk2-Executed Pathway in HCT116 Cells[J]. NEOPLASIA,2009,11(11):1226-1234.
APA	Zhu, Hong.,Miao, Ze-Hong.,Huang, Min.,Feng, Jian-Ming.,Zhang, Zhi-Xiang.,...&Ding, Jian.(2009).Naphthalimides Induce G(2) Arrest Through the ATM-Activated Chk2-Executed Pathway in HCT116 Cells.NEOPLASIA,11(11),1226-1234.
MLA	Zhu, Hong,et al."Naphthalimides Induce G(2) Arrest Through the ATM-Activated Chk2-Executed Pathway in HCT116 Cells".NEOPLASIA 11.11(2009):1226-1234.