Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, China.
Hunan Key Laboratory of Molecular Radiation Oncology, Xiangya Hospital, Central South University, Changsha, China.
Oncogene. 2019 Jan;38(4):549-563. doi: 10.1038/s41388-018-0460-4. Epub 2018 Aug 29.
Ionizing radiation (IR) is a conventional cancer therapeutic, to which cancer cells develop radioresistance with exposure. The residual cancer cells after radiation treatment also have increased metastatic potential. The mechanisms by which cancer cells develop radioresistance and gain metastatic potential are still unknown. In this study acute IR exposure induced cancer cell senescence and apoptosis, but after long-term IR exposure, cancer cells exhibited radioresistance. The proliferation of radioresistant cells was retarded, and most cells were arrested in G0/G1 phase. The radioresistant cells simultaneously showed resistance to further IR-induced apoptosis, premature senescence, and epithelial to mesenchymal transformation (EMT). Acute IR exposure steadily elevated CDC6 protein levels due to the attenuation of ubiquitination, while CDC6 overexpression was observed in the radioresistant cells because the insufficiency of CDC6 phosphorylation blocked protein translocation from nucleus to cytoplasm, resulting in subcellular protein accumulation when the cells were arrested in G0/G1 phase. CDC6 ectopic overexpression in CNE2 cells resulted in apoptosis resistance, G0/G1 cell cycle arrest, premature senescence, and EMT, similar to the characteristics of radioresistant CNE2-R cells. Targeting CDC6 with siRNA promoted IR-induced senescence, sensitized cancer cells to IR-induced apoptosis, and reversed EMT. Furthermore, CDC6 depletion synergistically repressed the growth of CNE2-R xenografts when combined with IR. The study describes for the first time cell models for IR-induced senescence, apoptosis resistance, and EMT, three major mechanisms by which radioresistance develops. CDC6 is a novel radioresistance switch regulating senescence, apoptosis, and EMT. These studies suggest that CDC6KI67 represents a new diagnostic marker of radiosensitivity, and CDC6 represents a new therapeutic target for cancer radiosensitization.
电离辐射 (IR) 是一种常规的癌症治疗方法，癌细胞在暴露于辐射后会产生放射抗性。放射治疗后残留的癌细胞也具有增加的转移潜力。癌细胞产生放射抗性和获得转移潜力的机制尚不清楚。在这项研究中，急性 IR 暴露诱导癌细胞衰老和凋亡，但长期 IR 暴露后，癌细胞表现出放射抗性。耐辐射细胞的增殖受到抑制，大多数细胞停滞在 G0/G1 期。耐辐射细胞同时表现出对进一步的 IR 诱导凋亡、过早衰老和上皮到间充质转化 (EMT) 的抗性。急性 IR 暴露由于泛素化的减弱而稳定地升高 CDC6 蛋白水平，而耐辐射细胞中观察到 CDC6 过表达，因为 CDC6 磷酸化的不足阻止了蛋白质从核到细胞质的易位，从而导致细胞停滞在 G0/G1 期时细胞内蛋白质积累。CDC6 在 CNE2 细胞中的异位过表达导致凋亡抵抗、G0/G1 细胞周期停滞、过早衰老和 EMT，与耐辐射的 CNE2-R 细胞的特征相似。用 siRNA 靶向 CDC6 可促进 IR 诱导的衰老，使癌细胞对 IR 诱导的凋亡敏感，并逆转 EMT。此外，CDC6 耗竭与 IR 联合使用时协同抑制 CNE2-R 异种移植物的生长。该研究首次描述了 IR 诱导的衰老、凋亡抵抗和 EMT 的细胞模型，这是放射抗性发展的三个主要机制。CDC6 是调节衰老、凋亡和 EMT 的新型放射抗性开关。这些研究表明，CDC6KI67 代表了放射敏感性的新诊断标志物，CDC6 代表了癌症放射增敏的新治疗靶点。
