Department of Radiation Oncology, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang, 310014, PR China.
Graduate Department, Bengbu Medical College, Bengbu, Anhui, 233000, PR China; Department of Radiation Oncology, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang, 310014, PR China.
Biochem Biophys Res Commun. 2021 Apr 23;550:84-91. doi: 10.1016/j.bbrc.2021.01.089. Epub 2021 Mar 6.
The monopolar spindle 1 ((hMps1/TTK) is a serine/threonine kinase that plays an important role in spindle assembly checkpoint signaling. To explore the possible relationship between TTK inhibition and radiosensitivity, we examined whether TTK inhibition influences cellular susceptibility of radiation. And we further revealed its mechanisms. We found that the expression of TTK was obviously higher in liver cancer tissues compared to the normal liver tissues. Kaplan-Meier Plotter demonstrated that patients with low TTK expression levels had a longer overall survival than patients with high TTK expression levels. TTK inhibitor AZ3146 could simulated liver cancer cells to accumulate in the G2/M phase, which ultimately enhances DNA damage with more γ-H2AX foci and more apoptosis and necrosis induced by radiation, which prompted that TTK inhibition sensitized liver cancer cells to radiation. In addition, TTK inhibition altered cell-cycle progression and exacerbated centrosome abnormalities, resulting in enhanced mitotic catastrophe (MC) induced by radiation in a p21-mediated manner. In this study, we present evidences that the TTK inhibitor promotes the radiosensitivity of liver cancer cells through regulating cell cycle in p21-mediated manner in vitro, indicating that TTK inhibitor may be an attractive radiosensitizer for the patients with liver cancer.
单极纺锤体 1((hMps1/TTK) 是一种丝氨酸/苏氨酸激酶，在纺锤体组装检查点信号转导中发挥重要作用。为了探讨 TTK 抑制与放射敏感性之间的可能关系，我们研究了 TTK 抑制是否影响细胞对辐射的敏感性。我们进一步揭示了其机制。我们发现 TTK 在肝癌组织中的表达明显高于正常肝组织。Kaplan-Meier Plotter 表明，TTK 低表达水平的患者总生存期长于 TTK 高表达水平的患者。TTK 抑制剂 AZ3146 可模拟肝癌细胞在 G2/M 期积累，最终通过更多 γ-H2AX 焦点和更多由辐射诱导的细胞凋亡和坏死来增强 DNA 损伤，提示 TTK 抑制可使肝癌细胞对辐射敏感。此外，TTK 抑制改变细胞周期进程并加剧中心体异常，导致辐射诱导的有丝分裂灾难 (MC) 增强，这是通过 p21 介导的方式。在这项研究中，我们提供的证据表明，TTK 抑制剂通过 p21 介导的方式调节细胞周期，在体外促进肝癌细胞的放射敏感性，表明 TTK 抑制剂可能是肝癌患者有吸引力的放射增敏剂。
