Palbociclib enhances radiosensitivity of hepatocellular carcinoma and cholangiocarcinoma via inhibiting ataxia telangiectasia-mutated kinase-mediated DNA damage response
Palbociclib enhances radiosensitivity of hepatocellular carcinoma and cholangiocarcinoma via inhibiting ataxia telangiectasia-mutated kinase-mediated DNA damage response
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DOI：
10.1016/j.ejca.2018.07.010
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发表时间：
2018-10-01
影响因子：
8.4
通讯作者：
Chen, Kuen-Feng
中科院分区：
文献类型：
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作者：
Huang, Chao-Yuan;Hsieh, Feng-Shu;Chen, Kuen-Feng
目的：Palbociclib是一种口服细胞周期蛋白依赖性激酶4/6抑制剂，对乳腺癌有较好的疗效。目前，有许多活跃的临床试验测试帕波西利单独或与其他药物联合治疗各种类型的恶性肿瘤。在这里，我们评价了帕波西利联合放射治疗(RT)治疗人肝细胞癌(HCC)和胆管癌细胞(CCA)的抗癌作用，并探讨了联合治疗背后的分子机制。方法：采用免疫荧光染色方法检测帕波西利对双链断裂(DSB)修复的影响。通过克隆形成实验、球体形成实验和细胞死亡实验，研究了帕波西利对辐射诱导的细胞毒性的增敏作用。用Western印迹分析检测DSB修复通路中信号的变化。最后，我们在临床前肝癌移植瘤模型中评价了联合治疗的体内抗癌活性和相关的分子事件。结果：Palbociclib影响了DNA修复的动力学，并增加了肝癌细胞和CCA细胞的辐射敏感性。重要的是，我们发现，Palbociclib抑制共济失调毛细血管扩张突变(ATM)激酶，这是响应RT诱导的DSB的关键上游激酶。此外，我们还发现，Palbociclib对RT诱导的ATM激酶激活的抑制作用是通过蛋白磷酸酶5(PP5)介导的。体外和体内研究均表明，在DNA损伤后，Palbociclib对PP5-ATM轴的抑制是Palbociclib与RT协同作用的原因。结论：我们的研究结果为抗肝癌细胞提供了一种新的联合策略。在RT中使用Palbociclib作为佐剂的临床试验是有根据的。(C)2018爱思唯尔有限公司。保留所有权利。
Aim: Palbociclib is an oral cyclin-dependent kinase 4/6 inhibitor, which is efficacious in treating breast cancer. Currently, there are numerous active clinical trials testing palbociclib alone or in combination with other medications for treating various types of malignancies. Here, we evaluated the anti-cancer effect of palbociclib in combination with radiation therapy (RT) for treating human hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) and addressed the molecular mechanism behind the combination therapy.Methods: Immunofluorescence staining of gH2AX or 53BP1 was used to determine the effect of palbociclib on double-strand break (DSB) repair. Clonogenic assays, sphere formation and cell death ELISA were performed to study the sensitising effect of palbociclib on radiation-induced cytotoxicity. Signal alteration in DSB repair pathways was examined by Western blot analysis. Finally, we evaluated the in vivo anti-cancer activity and the associated molecular events of the combination therapy in a preclinical HCC xenograft model.Results: Palbociclib affected the kinetics of DNA repair and enhanced the radiation sensitivity of HCC and CCA cells. Importantly, we found that palbociclib inhibits ataxia telangiectasiae mutated (ATM) kinase, the key upstream kinase responding to RT-induced DSBs. Furthermore, we showed that the inhibitory effect of palbociclib on RT-induced ATM kinase activation is mediated by protein phosphatase 5 (PP5). Both in vitro and in vivo investigations revealed that the inhibition of the PP5-ATM axis by palbociclib after DNA damage is responsible for the synergism between palbociclib and RT.Conclusion: Our findings provide a novel combination strategy against liver cancer cells. Clinical trials using palbociclib as an adjuvant in RT are warranted. (C) 2018 Elsevier Ltd. All rights reserved.