Department of Radiation Oncology, Qilu Hospital of Shandong University, 250012, Jinan, Shandong, China.
Department of Pathology, Xuzhou Central Hospital, 221009, Xuzhou, Jiangsu, China.
Br J Cancer. 2020 Jul;123(1):126-136. doi: 10.1038/s41416-020-0852-4. Epub 2020 May 5.
Antioxidase alleviates the accumulation of radiation-induced reactive oxygen species (ROS) and therefore has strong connections with radioresistance. Isocitrate dehydrogenase 2 (IDH2) facilitates the turnover of antioxidase, but its role in radiotherapeutic efficiency in oesophageal squamous cell carcinoma (ESCC) still remains elusive.
The involvement of IDH2 in radiotherapeutic efficacy in ESCC was investigated in vitro and vivo by IDH2 knockdown. IDH2 expression in biopsy specimens of 141 patients was identified to evaluate its clinical significance.
We found that Kyse510 and Kyse140 cells were more radioresistant and had higher IDH2 expression. In these two cell lines, IDH2 knockdown intensified the radiation-induced ROS overload and oxidative damage on lipid, protein, and nucleic acids. In addition, IDH2 silencing aggravated the radiation-induced mitochondrial dysfunction and cell apoptosis and ultimately promoted radiosensitisation via inhibiting AKT phosphorylation in a ROS-dependent manner. Furthermore, IDH2 depletion facilitated the radiation-induced growth inhibition and cell apoptosis in murine xenografts. Finally, IDH2 expression was correlated with definite chemoradiotherapy (dCRT) efficacy and served as an independent prognostic factor for survival of ESCC patients.
IDH2 plays a key role in the radioresistance of ESCC. Targeting IDH2 could be a promising regimen to improve radiotherapeutic efficiency in ESCC patients.
抗氧化酶可减轻辐射诱导的活性氧（ROS）的积累，因此与放射抵抗性有很强的关联。异柠檬酸脱氢酶 2（IDH2）促进抗氧化酶的转化，但它在食管鳞状细胞癌（ESCC）放射治疗中的作用仍不清楚。
通过 IDH2 敲低，在体外和体内研究 IDH2 对 ESCC 放射治疗效果的影响。评估了 141 例患者活检标本中 IDH2 的表达，以评估其临床意义。
我们发现 Kyse510 和 Kyse140 细胞具有更强的放射抗性和更高的 IDH2 表达。在这两种细胞系中，IDH2 敲低加剧了辐射引起的 ROS 过载和对脂质、蛋白质和核酸的氧化损伤。此外，IDH2 沉默加剧了辐射引起的线粒体功能障碍和细胞凋亡，并最终通过 ROS 依赖性抑制 AKT 磷酸化促进放射增敏。此外，IDH2 耗竭促进了小鼠异种移植中辐射引起的生长抑制和细胞凋亡。最后，IDH2 的表达与明确的放化疗（dCRT）疗效相关，并作为 ESCC 患者生存的独立预后因素。
IDH2 在 ESCC 的放射抵抗中起关键作用。靶向 IDH2 可能是提高 ESCC 患者放射治疗效果的有前途的方案。
