Department of Radiation Oncology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Department of Clinical Laboratory, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Int J Biol Sci. 2020 Feb 4;16(7):1096-1106. doi: 10.7150/ijbs.41246. eCollection 2020.
Repair of damaged DNA induced by radiation plays an important role in the development of radioresistance, which greatly restricts patients' benefit from radiotherapy. However, the relation between radioresistance development and DNA double-strand break repair pathways (mainly non-homologous end joining and homologous recombination) and how these pathways contribute to radioresistance are unclear. Here, we established a radioresistant breast cancer cell line by repeated ionizing radiation and studied the alteration in DNA repair capacity. Compared with parental sham-treated cells, radioresistant breast cancer cells present elevated radioresistance, enhanced malignancy, increased expression of Ataxia-telangiectasia mutated (ATM), and increased DNA damage repair efficiency, as reflected by accelerated γ-H2AX kinetic. These defects can be reversed by ATM inhibition or ATM knockdown, indicating a potential link between ATM, DNA repair pathway and radiosensitivity. We propose that cancer cells develop elevated radioresistance through enhanced DNA damage repair efficiency mediated by increased ATM expression. Our work might provide a new evidence supporting the potential of ATM as a potential target of cancer therapy.
辐射诱导的 DNA 损伤修复在耐药性的发展中起着重要作用，这极大地限制了患者从放疗中获益。然而，耐药性的发展与 DNA 双链断裂修复途径（主要是非同源末端连接和同源重组）之间的关系以及这些途径如何导致耐药性尚不清楚。在这里，我们通过反复电离辐射建立了一个耐辐射的乳腺癌细胞系，并研究了 DNA 修复能力的变化。与亲本假处理细胞相比，耐辐射乳腺癌细胞表现出更高的耐药性、增强的恶性程度、共济失调毛细血管扩张突变（ATM）的表达增加以及 DNA 损伤修复效率的提高，这反映在更快的 γ-H2AX 动力学上。这些缺陷可以通过 ATM 抑制或 ATM 敲低来逆转，表明 ATM、DNA 修复途径和放射敏感性之间存在潜在联系。我们提出，癌细胞通过增加 ATM 表达介导的增强的 DNA 损伤修复效率来发展出更高的耐药性。我们的工作可能为 ATM 作为癌症治疗的潜在靶点提供了新的证据支持。
