Thousand-and-one amino acid kinases (TAOK) 1 and 2 are activated catalytically during mitosis and can contribute to mitotic cell rounding and spindle positioning. Here, we characterize a compound that inhibits TAOK1 and TAOK2 activity with IC50 values of 11 to 15 nmol/L, is ATP-competitive, and targets these kinases selectively. TAOK inhibition or depletion in centrosome-amplified SKBR3 or BT549 breast cancer cell models increases the mitotic population, the percentages of mitotic cells displaying amplified centrosomes and multipolar spindles, induces cell death, and inhibits cell growth. In contrast, nontumorigenic and dividing bipolar MCF-10A breast cells appear less dependent on TAOK activity and can complete mitosis and proliferate in the presence of the TAOK inhibitor. We demonstrate that TAOK1 and TAOK2 localize to the cytoplasm and centrosomes respectively during mitosis. Live cell imaging shows that the TAOK inhibitor prolongs the duration of mitosis in SKBR3 cells, increases mitotic cell death, and reduces the percentages of cells exiting mitosis, whereas MCF-10A cells continue to divide and proliferate. Over 80% of breast cancer tissues display supernumerary centrosomes, and tumor cells frequently cluster extra centrosomes to avoid multipolar mitoses and associated cell death. Consequently, drugs that stimulate centrosome declustering and induce multipolarity are likely to target dividing centrosome-amplified cancer cells preferentially, while sparing normal bipolar cells. Our results demonstrate that TAOK inhibition can enhance centrosome declustering and mitotic catastrophe in cancer cells, and these proteins may therefore offer novel therapeutic targets suitable for drug inhibition and the potential treatment of breast cancers, where supernumerary centrosomes occur. Mol Cancer Ther; 16(11); 2410–21. ©2017 AACR.

中文翻译：

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使用新型抑制剂化合物靶向 TAO 激酶可延迟中心体扩增乳腺癌细胞的有丝分裂并诱导有丝分裂细胞死亡。


千零一氨基酸激酶 (TAOK) 1 和 2 在有丝分裂过程中被催化激活，有助于有丝分裂细胞变圆和纺锤体定位。在这里，我们表征了一种抑制 TAOK1 和 TAOK2 活性的化合物，其 IC50 值为 11 至 15 nmol/L，具有 ATP 竞争性，并选择性地靶向这些激酶。在中心体扩增的 SKBR3 或 BT549 乳腺癌细胞模型中，TAOK 抑制或缺失会增加有丝分裂群体、显示扩增中心体和多极纺锤体的有丝分裂细胞的百分比，诱导细胞死亡并抑制细胞生长。相比之下，非致瘤性和分裂性双极 MCF-10A 乳腺细胞似乎对 TAOK 活性的依赖程度较低，并且可以在 TAOK 抑制剂存在的情况下完成有丝分裂和增殖。我们证明 TAOK1 和 TAOK2 在有丝分裂过程中分别定位于细胞质和中心体。活细胞成像显示，TAOK 抑制剂延长了 SKBR3 细胞的有丝分裂持续时间，增加了有丝分裂细胞死亡，并降低了退出有丝分裂的细胞百分比，而 MCF-10A 细胞继续分裂和增殖。超过 80% 的乳腺癌组织表现出多余的中心体，肿瘤细胞经常聚集多余的中心体以避免多极有丝分裂和相关的细胞死亡。因此，刺激中心体去簇并诱导多极性的药物可能会优先靶向分裂中心体扩增的癌细胞，同时不伤害正常的双极细胞。 我们的结果表明，TAOK 抑制可以增强癌细胞中的中心体去簇和有丝分裂灾难，因此这些蛋白质可能提供适合药物抑制的新治疗靶点，并可能治疗出现多余中心体的乳腺癌。摩尔癌症治疗； 16（11）； 2410–21。 ©2017 AACR。