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MCL-1 Degradation Mediated by JNK Activation via MEKK1/TAK1-MKK4 Contributes to Anticancer Activity of New Tubulin Inhibitor MT189

文献类型：期刊论文

作者Wang, Wei1; Wang, Ying-Qing1; Meng, Tao2; Yi, Jun-Mei1; Huan, Xia-Juan1; Ma, Lan-Ping2; Tong, Lin-Jiang1; Chen, Yi1; Ding, Jian1; Shen, Jing-Kang2
刊名MOLECULAR CANCER THERAPEUTICS
出版日期2014-06
卷号13期号:6页码:1480-1491
ISSN号1535-7163
DOI10.1158/1535-7163.MCT-13-0629
文献子类Article
英文摘要Colchicine site-targeted tubulin inhibitors are a promising type of anticancer drugs. MT189 is a new derivative of MT119, a previously reported colchicine site-binding antitubulin agent. In this study, MT189 was demonstrated to retain the property of MT119 in disrupting microtubulin via binding to the colchicine site, causing mitotic arrest and inducing apoptosis, and to display 8.7-fold enhanced proliferative inhibition in a panel of cancer cells. MT189 was shown to elicit in vivo anticancer effects on MDA-MB-231 xenografts in nude mice, and the tumor growth was suppressed by 35.9% over 14 days. MT189 led to degradation of MCL-1, a member of the antiapoptotic BCL-2 protein family. Its overexpression reduced but its silenced expression increased the apoptotic induction followed by the treatment with MT189. Moreover, the treatment with MT189 caused activation of the MEKK1/TAK1-MKK4-JNK signaling pathway. The activated JNK resulted in phosphorylation of MCL-1, which facilitated its ubiquitination-mediated degradation. Our results show that MT189 inhibits microtubulin polymerization by binding to the colchicine site. Relief of apoptotic suppression by MCL-1 degradation together with mitotic arrest contributes to the anticancer activity of MT189. (C) 2014 AACR.
WOS关键词SPINDLE ASSEMBLY CHECKPOINT ; PSEUDOLARIC-ACID-B ; BCL-X-L ; MITOTIC ARREST ; GENE-EXPRESSION ; CELL-PROLIFERATION ; INDUCED APOPTOSIS ; BINDING AGENT ; CANCER-CELLS ; TUMOR-GROWTH
资助项目National Natural Science Foundation of China (NSFC)[81025020] ; National Natural Science Foundation of China (NSFC)[81202548] ; National Natural Science Foundation of China (NSFC)[81321092] ; National Basic Research Program of China[2012CB932502] ; National Science and Technology Major Project of China[2012ZX09301-001-002] ; "Interdisciplinary Cooperation Team" Program for Science and Technology Innovation of the Chinese Academy of Sciences[00000000]
WOS研究方向Oncology
语种英语
WOS记录号WOS:000337168600009
出版者AMER ASSOC CANCER RESEARCH
源URL[http://119.78.100.183/handle/2S10ELR8/277052]  
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
药理学第二研究室
通讯作者Miao, Ze-Hong
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, Shanghai 201203, Peoples R China;
2.Chinese Acad Sci, Shanghai Inst Mat Med, Div Med Chem, State Key Lab Drug Res, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Wang, Wei,Wang, Ying-Qing,Meng, Tao,et al. MCL-1 Degradation Mediated by JNK Activation via MEKK1/TAK1-MKK4 Contributes to Anticancer Activity of New Tubulin Inhibitor MT189[J]. MOLECULAR CANCER THERAPEUTICS,2014,13(6):1480-1491.
APA Wang, Wei.,Wang, Ying-Qing.,Meng, Tao.,Yi, Jun-Mei.,Huan, Xia-Juan.,...&Miao, Ze-Hong.(2014).MCL-1 Degradation Mediated by JNK Activation via MEKK1/TAK1-MKK4 Contributes to Anticancer Activity of New Tubulin Inhibitor MT189.MOLECULAR CANCER THERAPEUTICS,13(6),1480-1491.
MLA Wang, Wei,et al."MCL-1 Degradation Mediated by JNK Activation via MEKK1/TAK1-MKK4 Contributes to Anticancer Activity of New Tubulin Inhibitor MT189".MOLECULAR CANCER THERAPEUTICS 13.6(2014):1480-1491.

入库方式： OAI收割

来源：上海药物研究所

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