The MTH1 inhibitor TH588 is a microtubule-modulating agent that eliminates cancer cells by activating the mitotic surveillance pathway
The MTH1 inhibitor TH588 is a microtubule-modulating agent that eliminates cancer cells by activating the mitotic surveillance pathway
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DOI：
10.1038/s41598-019-51205-w
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发表时间：
2019-10-11
影响因子：
4.6
通讯作者：
Lindahl, Per
中科院分区：
文献类型：
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作者：
Gul, Nadia;Karlsson, Joakim;Lindahl, Per
mutt同源物-1 （MTH1）抑制剂TH588在临床前癌症研究中显示出前景，但其靶向特异性受到质疑。已经提出了TH588抗癌作用的其他机制，但问题尚未解决。在这里，我们对人肺癌细胞进行了无偏倚的CRISPR筛选，以确定TH588细胞毒性作用背后的潜在机制。筛选确定了参与有丝分裂纺锤体调节的途径和复合物。通过免疫荧光和活细胞成像，我们发现TH588以浓度依赖但与mth1无关的方式迅速降低微管+端迁移率，破坏有丝分裂纺锤体，延长有丝分裂。这些效应激活了USP28-p53通路——有丝分裂监视通路——在有丝分裂延长后阻断细胞周期再进入；USP28作用于p53的上游，在细胞周期的g1期阻滞th588处理的细胞。我们得出结论，TH588是一种微管调节剂，可以激活有丝分裂监视途径，从而阻止癌细胞重新进入细胞周期。
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.