Department of Radiation Oncology.
Department of Obstetrics & Gynecology.
JCI Insight. 2018 Feb 8;3(3). doi: 10.1172/jci.insight.98096.
Cancer stem cells (CSCs) - known to be resistant to genotoxic radiation and chemotherapy - are fundamental to therapy failure and cancer relapse. Here, we reveal that glioma CSCs are hypersensitive to radiation, but a temporal DNA repair mechanism converts the intrinsic sensitivity to genomic instability and treatment resistance. Transcriptome analysis identifies DNA-dependent protein kinase (DNA-PK) as a predominant DNA repair enzyme in CSCs. Notably, DNA-PK activity is suppressed after irradiation when ROS induce the dissociation of DNA-PKcs with Ku70/80, resulting in delayed DNA repair and radiosensitivity; subsequently, after ROS clearance, the accumulated DNA damage and robust activation of DNA-PK induce genomic instability, facilitated by Rad50-mediated cell-cycle arrest, leading to enhanced malignancy, CSC overgrowth, and radioresistance. Finally, we show a requisite in vivo role for DNA-PK in CSC-mediated radioresistance and glioma progression. These findings identify a time-sensitive mechanism controlling CSC resistance to DNA-damaging treatments and suggest DNA-PK/Rad50 as promising targets for CSC eradication.
癌症干细胞（CSCs）——已知对遗传毒性辐射和化疗具有抗性——是治疗失败和癌症复发的基础。在这里，我们揭示了神经胶质瘤 CSCs 对辐射高度敏感，但一个暂时的 DNA 修复机制将内在的敏感性转化为基因组不稳定性和治疗抗性。转录组分析将 DNA 依赖性蛋白激酶 (DNA-PK) 鉴定为 CSCs 中的主要 DNA 修复酶。值得注意的是，当 ROS 诱导 DNA-PKcs 与 Ku70/80 解离时，DNA-PK 活性在照射后受到抑制，导致 DNA 修复和放射敏感性延迟；随后，ROS 清除后，积累的 DNA 损伤和 DNA-PK 的强烈激活通过 Rad50 介导的细胞周期阻滞诱导基因组不稳定性，从而增强恶性、CSC 过度生长和放射抗性。最后，我们证明了 DNA-PK 在 CSC 介导的放射抗性和神经胶质瘤进展中的体内必需性。这些发现确定了一种控制 CSC 对 DNA 损伤性治疗的抗性的时间敏感机制，并表明 DNA-PK/Rad50 是消除 CSC 的有前途的靶标。
