Isocitrate dehydrogenase 2 contributes to radiation resistance of oesophageal squamous cell carcinoma via regulating mitochondrial function and ROS/pAKT signalling
Open Access
- 5 May 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in British Journal of Cancer
- Vol. 123 (1), 126-136
- https://doi.org/10.1038/s41416-020-0852-4
Abstract
Background 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. Methods 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. Results 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. Conclusions IDH2 plays a key role in the radioresistance of ESCC. Targeting IDH2 could be a promising regimen to improve radiotherapeutic efficiency in ESCC patients.Keywords
Funding Information
- National Natural Science Foundation of China (81773228)
This publication has 38 references indexed in Scilit:
- Cancer-associated Isocitrate Dehydrogenase Mutations Inactivate NADPH-dependent Reductive CarboxylationJournal of Biological Chemistry, 2012
- The Common Feature of Leukemia-Associated IDH1 and IDH2 Mutations Is a Neomorphic Enzyme Activity Converting α-Ketoglutarate to 2-HydroxyglutarateCancer Cell, 2010
- Regulation of ethanol-induced toxicity by mitochondrial NADP+-dependent isocitrate dehydrogenaseBiochimie, 2009
- IDH1andIDH2Mutations in GliomasThe New England Journal of Medicine, 2009
- Biomarkers of Response to Preoperative Chemoradiation in Esophageal CancersSeminars in Oncology, 2006
- Mitochondrial NADP+-Dependent Isocitrate Dehydrogenase Protects Cadmium-Induced ApoptosisMolecular Pharmacology, 2006
- Gene Expression Profiling of Localized Esophageal Carcinomas: Association With Pathologic Response to Preoperative ChemoradiationJournal of Clinical Oncology, 2006
- Role of NADP+‐dependent isocitrate dehydrogenase (NADP+‐ICDH) on cellular defence against oxidative injury byγ‐raysInternational Journal of Radiation Biology, 2004
- Molecular Biology of Esophageal CancerOncology Research and Treatment, 2004
- Control of Mitochondrial Redox Balance and Cellular Defense against Oxidative Damage by Mitochondrial NADP+-dependent Isocitrate DehydrogenaseJournal of Biological Chemistry, 2001