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The MTH1 inhibitor TH588 is a microtubule-modulating agent that eliminates cancer cells by activating the mitotic surveillance pathway

Journal article
Authors Nadia Gul
Joakim Karlsson
Carolina Tängemo
Sanna Linsefors
Samuel Tuyizere
Rosie Perkins
Chandu Ala
Zhiyuan V. Zou
Erik Larsson
M. O. Bergo
Per Lindahl
Published in Scientific Reports
Volume 9
ISSN 2045-2322
Publication year 2019
Published at Wallenberg Laboratory
Institute of Biomedicine, Department of Medical Biochemistry and Cell Biology
Core Facilities, Centre for Cellular Imaging
Institute of Clinical Sciences
Language en
Links dx.doi.org/10.1038/s41598-019-51205...
Keywords centrosome loss, growth, potent, Science & Technology
Subject categories Clinical Medicine

Abstract

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.

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