Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Institute of Biotechnology, Shanxi University, Taiyuan 030006, PR China.
Biochem Biophys Res Commun. 2011 Jul 1;410(2):218-23. doi: 10.1016/j.bbrc.2011.05.108. Epub 2011 May 27.
Heterozygous mutations in either the R132 residue of isocitrate dehydrogenase I (IDH1) or the R172 residue of IDH2 in human gliomas were recently highlighted. In the present study, we report that mutations of IDH1 and IDH2 are not detected in the rat C6 glioma cell line model, which suggests that these mutations are not required for the development of glioblastoma induced by N,N'-nitroso-methylurea. The effects of IDH2 and IDH2(R172G) on C6 cells proliferation and sensitivity to chemotherapy and the possible mechanism are analyzed at the cellular level. IDH1 and IDH2 mutations lead to simultaneous loss and gain of activities in the production of α-ketoglutarate (α-KG) and 2-hydroxyglutarate (2HG), respectively, and result in lowering NADPH levels even further. The low NADPH levels can sensitize tumors to chemotherapy, and account for the prolonged survival of patients harboring the mutations. Our data extrapolate potential importance of the in vitro rat C6 glioma cell model, show that the IDH2(R172G) mutation in gliomas may give a benefit to traditional chemotherapy of this cancer and serve as an important complement to existing research on this topic.
最近在人类胶质瘤中发现异柠檬酸脱氢酶 I（IDH1）的 R132 残基或 IDH2 的 R172 残基的杂合突变。在本研究中，我们报告 IDH1 和 IDH2 的突变在大鼠 C6 神经胶质瘤细胞系模型中未检测到，这表明这些突变不是 N,N'-亚硝基甲脲诱导的神经胶质瘤发生所必需的。在细胞水平上分析 IDH2 和 IDH2（R172G）对 C6 细胞增殖和化疗敏感性的影响及其可能的机制。IDH1 和 IDH2 突变分别导致 α-酮戊二酸（α-KG）和 2-羟基戊二酸（2HG）产生的活性同时丧失和获得，从而导致 NADPH 水平进一步降低。低 NADPH 水平可使肿瘤对化疗敏感，并解释了携带突变的患者生存期延长的原因。我们的数据推断出体外大鼠 C6 神经胶质瘤细胞模型的潜在重要性，表明胶质瘤中的 IDH2（R172G）突变可能使这种癌症的传统化疗受益，并为该主题的现有研究提供重要补充。
