American Association for Cancer Research
15357163mct130629-sup-fig_3.pdf (194.71 kB)

Supplementary Figure 3 from MCL-1 Degradation Mediated by JNK Activation via MEKK1/TAK1-MKK4 Contributes to Anticancer Activity of New Tubulin Inhibitor MT189

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journal contribution
posted on 2023-04-03, 14:08 authored by Wei Wang, Ying-Qing Wang, Tao Meng, Jun-Mei Yi, Xia-Juan Huan, Lan-Ping Ma, Lin-Jiang Tong, Yi Chen, Jian Ding, Jing-Kang Shen, Ze-Hong Miao

PDF - 194K, MT189 causes cellular microtubulin depolymerization in a time-dependent manner and induces reversible M arrest.



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. Mol Cancer Ther; 13(6); 1480–91. ©2014 AACR.