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

Gul, Nadia, 1980 (author): Gothenburg University,Göteborgs universitet,Wallenberglaboratoriet,Wallenberg Laboratory

Karlsson, Joakim (author): Gothenburg University,Göteborgs universitet,Institutionen för kliniska vetenskaper,Institute of Clinical Sciences

Tängemo, Carolina (author): Gothenburg University,Göteborgs universitet,Core Facilities, Centre for Cellular Imaging,Core Facilities, Centre for Cellular Imaging

Linsefors, Sanna (author): Gothenburg University,Göteborgs universitet,Wallenberglaboratoriet,Wallenberg Laboratory

Tuyizere, Samuel (author): Gothenburg University,Göteborgs universitet,Wallenberglaboratoriet,Wallenberg Laboratory

Perkins, Rosie, 1965 (author): Gothenburg University,Göteborgs universitet,Wallenberglaboratoriet,Wallenberg Laboratory

Ala, Chandu (author): Gothenburg University,Göteborgs universitet,Wallenberglaboratoriet,Wallenberg Laboratory

Zou, Zhiyuan V. (author): Gothenburg University,Göteborgs universitet,Wallenberglaboratoriet,Wallenberg Laboratory

Larsson, Erik, 1975 (author): Gothenburg University,Göteborgs universitet,Institutionen för biomedicin, avdelningen för medicinsk kemi och cellbiologi,Institute of Biomedicine, Department of Medical Biochemistry and Cell Biology

Lindahl, Per, 1967 (author): Gothenburg University,Göteborgs universitet,Wallenberglaboratoriet,Wallenberg Laboratory

Zou, ZY (author)

(creator_code:org_t)

2019-10-11
2019
English.
In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9

Related links:: https://www.nature.c...; show more...; https://gup.ub.gu.se...; https://doi.org/10.1...; http://kipublication...; show less...

Abstract Subject headings

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.

By the author/editor: Gul, Nadia, 1980; Karlsson, Joakim; Tängemo, Carolin ...; Linsefors, Sanna; Tuyizere, Samuel; Perkins, Rosie, ...; show more...; Ala, Chandu; Zou, Zhiyuan V.; Larsson, Erik, 1 ...; Bergo, M. O.; Lindahl, Per, 19 ...; Zou, ZY; show less...

About the subject

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