title: MCL-1 degradation mediated by JNK activation via MEKK1/TAK1-MKK4 contributes to anticancer activity of new tubulin inhibitor MT189.
abstract: 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.
authors.affiliation: Authors' Affiliations: Division of Antitumor Pharmacology and Division of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, People's Republic of China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Authors' Affiliations: Division of Antitumor Pharmacology and Division of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, People's Republic of China.
authors.forename: Ying-Qing
authors.initials: YQ
authors.lastname: Wang
authors.affiliation: Authors' Affiliations: Division of Antitumor Pharmacology and Division of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, People's Republic of China.
authors.forename: Tao
authors.initials: T
authors.lastname: Meng
authors.affiliation: Authors' Affiliations: Division of Antitumor Pharmacology and Division of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, People's Republic of China.
authors.forename: Jun-Mei
authors.initials: JM
authors.lastname: Yi
authors.affiliation: Authors' Affiliations: Division of Antitumor Pharmacology and Division of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, People's Republic of China.
authors.forename: Xia-Juan
authors.initials: XJ
authors.lastname: Huan
authors.affiliation: Authors' Affiliations: Division of Antitumor Pharmacology and Division of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, People's Republic of China.
authors.forename: Lan-Ping
authors.initials: LP
authors.lastname: Ma
authors.affiliation: Authors' Affiliations: Division of Antitumor Pharmacology and Division of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, People's Republic of China.
authors.forename: Lin-Jiang
authors.initials: LJ
authors.lastname: Tong
authors.affiliation: Authors' Affiliations: Division of Antitumor Pharmacology and Division of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, People's Republic of China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Authors' Affiliations: Division of Antitumor Pharmacology and Division of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, People's Republic of China.
authors.forename: Jian
authors.initials: J
authors.lastname: Ding
authors.affiliation: Authors' Affiliations: Division of Antitumor Pharmacology and Division of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, People's Republic of China zhmiao@simm.ac.cn jkshen@simm.ac.cn.
authors.forename: Jing-Kang
authors.initials: JK
authors.lastname: Shen
authors.affiliation: Authors' Affiliations: Division of Antitumor Pharmacology and Division of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, People's Republic of China zhmiao@simm.ac.cn jkshen@simm.ac.cn.
authors.forename: Ze-Hong
authors.initials: ZH
authors.lastname: Miao
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D019073:HT29 Cells; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D048728:MAP Kinase Kinase Kinase 1 / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D051379:Mice; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D010766:Phosphorylation; D059748:Proteolysis / Q000187:drug effects; D011725:Pyridines / Q000008:administration & dosage*; D014404:Tubulin / Q000378:metabolism; D050257:Tubulin Modulators / Q000008:administration & dosage*; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D000970:Antineoplastic Agents; D007093:Imidazoles; D048670:MAP Kinase Kinase 4; D048728:MAP Kinase Kinase Kinase 1; D020930:MAP Kinase Kinase Kinases; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D011725:Pyridines; D014404:Tubulin; D050257:Tubulin Modulators; D000099151:MAP Kinase Kinase Kinase 7; C000595238:2-(6-fluoro-3-((4-methoxybenzyl)amino)imidazo(1,2-alpha)pyridin-2-yl)phenol; C579095:MCL1 protein, human; C482576:MAP3K1 protein, human; C482559:MAP2K4 protein, human