Proteasome-dependent degradation of Chk1 kinase induced by the topoisomerase II inhibitor R16 contributes to its anticancer activity

doi:10.4161/cbt.7.11.6728

CORC > 上海药物研究所 > 中国科学院上海药物研究所 > 药理学第一研究室

	Proteasome-dependent degradation of Chk1 kinase induced by the topoisomerase II inhibitor R16 contributes to its anticancer activity
	Feng, Jian-Ming; Zhu, Hong; Zhang, Xiao-Wei; Ding, Jian; Miao, Ze-Hong
刊名	CANCER BIOLOGY & THERAPY
	2008-11
卷号	7 期号:11 页码:1726-1731
关键词	topoisomerase II inhibitor naphthalimide R16 colon carcinoma Chk1 proteasome anticancer activity
ISSN号	1538-4047
DOI	10.4161/cbt.7.11.6728
文献子类	Article
英文摘要	The novel naphthalimide derivative R16 has been demonstrated to exhibit potent in vitro and in vivo anticancer activity by inhibiting topoisomerase II (Top2). R16 induces G(2) arrest via an ATM-activated Chk2-executed pathway, accompanied by reducing Chk1. In this study, R16 was demonstrated to trigger time and concentration-dependent Chk1 reduction which was unrelated to the mRNA level and HSP90-involved degradation. Pretreatment of HCT116 cells with the proteasome inhibitors MG132 or lactacystin prevented Chk1 decline induced by R16, accompanied by significant accumulation of ubiquitinated Chk1 protein, indicating the involvement of ubiquitin-proteasome pathway. Meanwhile, R16 also resulted in loss of Chk1 function. By site-specifically mutating the phosphorylation sites of Chk1 protein at Ser317 or at Ser345, we further demonstrated that R16-triggered Chk1 reduction was associated with its apoptotic induction and cell killing. In conclusion, the data reveal that the novel Top2 inhibitor R16 induces degradation of Chk1 via the ubiquitin-proteasome pathway, impairing the function of Chk1 and thus contributing to the anticancer activity of R16.
资助项目	National Natural Sciences Foundation of China[30772588] ; National Natural Sciences Foundation of China[30721005]
WOS关键词	ADVANCED BREAST-CANCER ; ACETYLATOR PHENOTYPE ; CHECKPOINT KINASE-1 ; AMONAFIDE ; EXPRESSION ; PATHWAY ; PROTEIN ; STRESS
WOS研究方向	Oncology
语种	英语
出版者	TAYLOR & FRANCIS INC
WOS记录号	WOS:000261841700006
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/279445]
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	Chinese Acad Sci, Shanghai Inst Biol Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Feng, Jian-Ming,Zhu, Hong,Zhang, Xiao-Wei,et al. Proteasome-dependent degradation of Chk1 kinase induced by the topoisomerase II inhibitor R16 contributes to its anticancer activity[J]. CANCER BIOLOGY & THERAPY,2008,7(11):1726-1731.
APA	Feng, Jian-Ming,Zhu, Hong,Zhang, Xiao-Wei,Ding, Jian,&Miao, Ze-Hong.(2008).Proteasome-dependent degradation of Chk1 kinase induced by the topoisomerase II inhibitor R16 contributes to its anticancer activity.CANCER BIOLOGY & THERAPY,7(11),1726-1731.
MLA	Feng, Jian-Ming,et al."Proteasome-dependent degradation of Chk1 kinase induced by the topoisomerase II inhibitor R16 contributes to its anticancer activity".CANCER BIOLOGY & THERAPY 7.11(2008):1726-1731.