A vimentin binding small molecule leads to mitotic disruption in mesenchymal cancers

被引:58
作者
Bollong, Michael J. [1 ]
Pietila, Mika [2 ]
Pearson, Aaron D. [1 ]
Sarkar, Tapasree Roy [2 ]
Ahmad, Insha [1 ]
Soundararajan, Rama [2 ]
Lyssiotis, Costas A. [1 ,3 ]
Mani, Sendurai A. [2 ]
Schultz, Peter G. [1 ]
Lairson, Luke L. [1 ]
机构
[1] Scripps Res Inst, Dept Chem, La Jolla, CA 92037 USA
[2] Univ Texas MD Anderson Canc Ctr, Dept Translat Mol Pathol, Houston, TX 77030 USA
[3] Univ Michigan, Dept Mol & Integrat Physiol, Ann Arbor, MI 48109 USA
关键词
vimentin; epithelial-to-mesenchymal transition; cancer stem cell; mitosis; drug discovery; INTERMEDIATE-FILAMENT NETWORKS; BREAST-CANCER; PROTEIN-VIMENTIN; EPITHELIAL-CELLS; IN-VITRO; PHOSPHORYLATION; WITHAFERIN; TRANSITION; METASTASIS; INHIBITION;
D O I
10.1073/pnas.1716009114
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Expression of the transcription factor FOXC2 is induced and necessary for successful epithelial-mesenchymal transition, a developmental program that when activated in cancer endows cells with metastatic potential and the properties of stem cells. As such, identifying agents that inhibit the growth of FOXC2-transformed cells represents an attractive approach to inhibit chemotherapy resistance and metastatic dissemination. From a high throughput synthetic lethal screen, we identified a small molecule, FiVe1, which selectively and irreversibly inhibits the growth of mesenchymally transformed breast cancer cells and soft tissue sarcomas of diverse histological subtypes. FiVe1 targets the intermediate filament and mesenchymal marker vimentin (VIM) in a mode which promotes VIM disorganization and phosphorylation during metaphase, ultimately leading to mitotic catastrophe, multinucleation, and the loss of stemness. These findings illustrate a previously undescribed mechanism for interrupting faithful mitotic progression and may ultimately inform the design of therapies for a broad range of mesenchymal cancers.
引用
收藏
页码:E9903 / E9912
页数:10
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