Institute of Metabolism and Systems Research, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
Institute of Cancer and Genomic Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK; Molecular & Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
Cell Rep. 2018 Mar 20;22(12):3107-3114. doi: 10.1016/j.celrep.2018.02.084.
Since the discovery of mutations in isocitrate dehydrogenase 1 (IDH1) in gliomas and other tumors, significant efforts have been made to gain a deeper understanding of the consequences of this oncogenic mutation. One aspect of the neomorphic function of the IDH1 R132H enzyme that has received less attention is the perturbation of cellular redox homeostasis. Here, we describe a biosynthetic pathway exhibited by cells expressing mutant IDH1. By virtue of a change in cellular redox homeostasis, IDH1-mutated cells synthesize excess glutamine-derived proline through enhanced activity of pyrroline 5-carboxylate reductase 1 (PYCR1), coupled to NADH oxidation. Enhanced proline biosynthesis partially uncouples the electron transport chain from tricarboxylic acid (TCA) cycle activity through the maintenance of a lower NADH/NAD ratio and subsequent reduction in oxygen consumption. Thus, we have uncovered a mechanism by which tumor cell survival may be promoted in conditions associated with perturbed redox homeostasis, as occurs in IDH1-mutated glioma.
自从在胶质瘤和其他肿瘤中发现异柠檬酸脱氢酶 1（IDH1）突变以来，人们已经做出了巨大的努力来深入了解这种致癌突变的后果。IDH1 R132H 酶的新功能的一个方面，即细胞氧化还原稳态的扰乱，受到的关注较少。在这里，我们描述了表达突变型 IDH1 的细胞表现出的生物合成途径。由于细胞氧化还原稳态的改变，突变型 IDH1 细胞通过增强吡咯啉 5-羧酸盐还原酶 1（PYCR1）的活性，与 NADH 氧化偶联，合成过量的谷氨酰胺衍生脯氨酸。增强的脯氨酸生物合成部分通过维持较低的 NADH/NAD 比和随后减少耗氧量，使电子传递链与三羧酸（TCA）循环活性解偶联。因此，我们已经发现了一种机制，即在与氧化还原稳态紊乱相关的条件下，肿瘤细胞的生存可能会得到促进，就像在 IDH1 突变的胶质瘤中一样。
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