The MTH1 inhibitor TH588 is a microtubule-modulating agent that eliminates cancer cells by activating the mitotic surveillance pathway
| Autor: | Nadia Gul, Carolina Tängemo, Chandu Ala, Martin O. Bergo, Rosie Perkins, Sanna Linsefors, Per Lindahl, Samuel Tuyizere, Erik Larsson, Joakim Karlsson, Zhiyuan Zou |
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| Rok vydání: | 2019 |
| Předmět: |
lcsh:Medicine
Mitosis Antineoplastic Agents Spindle Apparatus Biology Microtubules Article Target validation 03 medical and health sciences Targeted therapies 0302 clinical medicine Live cell imaging Microtubule Cell Line Tumor medicine Humans Cytotoxic T cell lcsh:Science 030304 developmental biology 0303 health sciences Multidisciplinary lcsh:R Cell Cycle G1 Phase Cancer Cell cycle medicine.disease Phosphoric Monoester Hydrolases Tubulin Modulators 3. Good health Cell biology Spindle apparatus Gene Expression Regulation Neoplastic DNA Repair Enzymes Pyrimidines 030220 oncology & carcinogenesis Cancer cell Carcinoma Large Cell lcsh:Q CRISPR-Cas Systems Tumor Suppressor Protein p53 Ubiquitin Thiolesterase |
| Zdroj: | Scientific Reports Scientific Reports, Vol 9, Iss 1, Pp 1-12 (2019) |
| ISSN: | 2045-2322 |
| DOI: | 10.1038/s41598-019-51205-w |
| Popis: | The mut-T homolog-1 (MTH1) inhibitor TH588 has shown promise in preclinical cancer studies but its targeting specificity has been questioned. Alternative mechanisms for the anti-cancer effects of TH588 have been suggested but the question remains unresolved. Here, we performed an unbiased CRISPR screen on human lung cancer cells to identify potential mechanisms behind the cytotoxic effect of TH588. The screen identified pathways and complexes involved in mitotic spindle regulation. Using immunofluorescence and live cell imaging, we showed that TH588 rapidly reduced microtubule plus-end mobility, disrupted mitotic spindles, and prolonged mitosis in a concentration-dependent but MTH1-independent manner. These effects activated a USP28-p53 pathway – the mitotic surveillance pathway – that blocked cell cycle reentry after prolonged mitosis; USP28 acted upstream of p53 to arrest TH588-treated cells in the G1-phase of the cell cycle. We conclude that TH588 is a microtubule-modulating agent that activates the mitotic surveillance pathway and thus prevents cancer cells from re-entering the cell cycle. |
| Databáze: | OpenAIRE |
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