CDK5 Activates Hippo Signaling to Confer Resistance to Radiation Therapy Via Upregulating TAZ in Lung Cancer
CDK5 Activates Hippo Signaling to Confer Resistance to Radiation Therapy Via Upregulating TAZ in Lung Cancer
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CDK5 激活 Hippo 信号传导，通过上调肺癌中的 TAZ 赋予放射治疗耐药性
DOI：
10.1016/j.ijrobp.2020.05.005
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发表时间：
2020
影响因子：
7
通讯作者：
Shuangbing Xu
中科院分区：
文献类型：
--
作者：
Yulan Zeng;Quan Liu;Ye Wang;Chen Tian;Qifan Yang;Ye Zhao;Li Liu;Gang Wu;Shuangbing Xu
。目的：肿瘤对放射治疗的耐药是治疗非小细胞肺癌患者的一个挑战。细胞周期蛋白依赖性激酶5 （Cyclin-dependent kinase 5, CDK5）被认为参与细胞增殖、迁移和侵袭、耐药和免疫逃避。然而，CDK5在肺癌放射耐药中的功能和调控机制尚未得到研究。方法和材料：采用中性彗星法、γ-H2AX和Rad51聚焦染色法检测DNA损伤反应和修复。通过克隆生存试验和异种移植肿瘤模型研究CDK5在肺癌放射耐药中的生物学功能。小干扰rna和短发夹rna被用来敲低A549和H1299细胞中的CDK5。体外和体内研究了CDK5缺失对肺癌细胞致瘤行为的影响。采用RNA-seq和实时定量聚合酶链反应检测基因表达。结果：我们报告了CDK5缺失在体外和体内损害肺癌进展和放射耐药。在机制上，我们发现TAZ是Hippo通路的一个组成部分，是CDK5的一个关键下游效应物。CDK5缺失可下调TAZ表达并减弱Hippo信号激活。重要的是，我们提供的证据表明，TAZ是介导CDK5在肺癌中的生物学功能的主要效应物。结论：这些结果表明CDK5通过TAZ激活Hippo信号参与肿瘤发生和放射耐药，提示CDK5可能是治疗肺癌的一个有希望的放射增敏靶点。
.Purpose: Tumor resistance to radiation therapy is a therapeutic challenge in the treatment of patients with non-small cell lung cancer. Cyclin-dependent kinase 5 (CDK5) has been proposed to participate in cell proliferation, migration and invasion, drug resistance, and immune evasion. However, the functions and regulatory mechanisms of CDK5 in lung cancer radioresistance have not been investigated...Methods and materials: DNA damage response and repair were measured by neutral comet assay and γ-H2AX and Rad51 foci staining. The biological functions of CDK5 in lung cancer radioresistance were investigated with clonogenic survival assays and xenograft tumor models. Small interfering RNAs and short hairpin RNAs were used to knock down CDK5 in A549 and H1299 cells. The effects of CDK5 depletion on the tumorigenic behaviors of lung cancer cells were evaluated in vitro and in vivo. Gene expression was examined by RNA-seq and quantitative real-time polymerase chain reaction...Results: We report that CDK5 depletion impairs lung cancer progression and radioresistance in vitro and in vivo. Mechanistically, we identify TAZ, a component of the Hippo pathway, as a critical downstream effector of CDK5. Loss of CDK5 downregulates TAZ expression and attenuates Hippo signaling activation. Importantly, we provide evidence that TAZ is the major effector mediating the biological functions of CDK5 in lung cancer...Conclusions: These results illustrate that CDK5 activates Hippo signaling via TAZ to participate in tumorigenesis and radioresistance, suggesting that CDK5 may be a promising radiosensitization target for the treatment of lung cancer..