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

Abstract:

: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.

authors

Bollong MJ,Pietilä M,Pearson AD,Sarkar TR,Ahmad I,Soundararajan R,Lyssiotis CA,Mani SA,Schultz PG,Lairson LL

doi

10.1073/pnas.1716009114

subject

Has Abstract

pub_date

2017-11-14 00:00:00

pages

E9903-E9912

issue

46

eissn

0027-8424

issn

1091-6490

pii

1716009114

journal_volume

114

pub_type

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