A vimentin binding small molecule leads to mitotic disruption in mesenchymal cancers
| Autor: | Insha Ahmad, Rama Soundararajan, Mika Pietilä, Costas A. Lyssiotis, Aaron D. Pearson, Sendurai A. Mani, Tapasree Roy Sarkar, Peter G. Schultz, Michael J. Bollong, Luke L. Lairson |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Epithelial-Mesenchymal Transition Intermediate Filaments Mitosis Breast Neoplasms Vimentin 03 medical and health sciences 0302 clinical medicine Cancer stem cell Cell Line Tumor Drug Discovery Humans Epithelial–mesenchymal transition Phosphorylation Mitotic catastrophe Multidisciplinary biology Mesenchymal stem cell Forkhead Transcription Factors Sarcoma Cell biology Gene Expression Regulation Neoplastic 030104 developmental biology PNAS Plus 030220 oncology & carcinogenesis Neoplastic Stem Cells biology.protein Female Stem cell FOXC2 Transcription Factors |
| Zdroj: | Proceedings of the National Academy of Sciences. 114 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.1716009114 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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