TTK inhibitor promotes radiosensitivity of liver cancer cells through p21
TTK inhibitor promotes radiosensitivity of liver cancer cells through p21
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DOI：
10.1016/j.bbrc.2021.01.089
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发表时间：
2021-03-06
影响因子：
3.1
通讯作者：
Liang，Xiaodong
中科院分区：
文献类型：
--
作者：
Zhang，Haibo;Yao，Weiping;Liang，Xiaodong
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传导中起重要作用。为了探讨TTK抑制与辐射敏感性之间的可能关系，我们检测了TTK抑制是否影响细胞的辐射敏感性。并进一步揭示了其作用机制。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分析显示，TTK表达水平低得患者得总生存期长于TTK表达水平高得患者. TTK抑制剂AZ3146可诱导肝癌细胞在G2/M期聚集，最终增强辐射诱导的DNA损伤，γ-H2AX灶增多，凋亡和坏死增多，提示TTK抑制对肝癌细胞辐射敏感。此外，TTK抑制改变细胞周期进程，并加剧中心体异常，导致增强有丝分裂灾难（MC）辐射诱导的p21介导的方式。本研究证明TTK抑制剂通过p21介导的细胞周期调控作用，在体外促进肝癌细胞的放射增敏，提示TTK抑制剂可能是一种有吸引力的肝癌放射增敏剂。
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.