摘要

Oncogenic mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) occur in several types of cancer, but the metabolic consequences of these genetic changes are not fully understood. In this study, we performed (13)C metabolic flux analysis on a panel of isogenic cell lines containing heterozygous IDH1/2 mutations. We observed that under hypoxic conditions, IDH1-mutant cells exhibited increased oxidative tricarboxylic acid metabolism along with decreased reductive glutamine metabolism, but not IDH2-mutant cells. However, selective inhibition of mutant IDH1 enzyme function could not reverse the defect in reductive carboxylation activity. Furthermore, this metabolic reprogramming increased the sensitivity of IDH1-mutant cells to hypoxia or electron transport chain inhibition in vitro. Lastly, IDH1-mutant cells also grew poorly as subcutaneous xenografts within a hypoxic in vivo microenvironment. Together, our results suggest therapeutic opportunities to exploit the metabolic vulnerabilities specific to IDH1 mutation.

译文

异柠檬酸脱氢酶 1 和 2 (IDH1/2) 的致癌突变发生在几种类型的癌症中,但是这些基因变化的代谢后果还不完全清楚。在这项研究中,我们对一组含有杂合子 IDH1/2 突变的等基因细胞系进行了 (13) C 代谢通量分析。我们观察到,在缺氧条件下,IDH1-mutant 细胞表现出氧化三羧酸代谢增加以及还原型谷氨酰胺代谢减少,但不 IDH2-mutant 细胞。然而,对突变 IDH1 酶功能的选择性抑制不能逆转还原羧化活性的缺陷。此外,这种代谢重编程增加了体外 IDH1-mutant 细胞对缺氧或电子传递链抑制的敏感性。最后,IDH1-mutant 细胞在体内缺氧微环境中作为皮下异种移植细胞生长不良。总之,我们的结果表明了利用 IDH1 突变特有的代谢漏洞的治疗机会。

Citric acid cycle

内分泌 生化反应 临床研究术语
概述  :  

柠檬酸循环(CAC)也称为TCA循环(三羧酸循环)或Krebs循环,是所有有氧生物利用的一系列化学反应,通过乙酰基的氧化释放来源于碳水化合物,脂肪和蛋白质储存的能量-CoA,转变为三磷酸腺苷(ATP)和二氧化碳。另外,该循环提供了某些氨基酸的前体以及还原剂NADH,其可用于许多其他反应中。它对许多生化途径的重要意义表明,它是细胞代谢最早建立的成分之一,可能起源于生物。 循环结果 循环的第一轮产物是一个GTP(或ATP),三个N

citric   英 /ˈsɪtrɪk/   美 /ˈsɪtrɪk/

释    义   adj. 柠檬的;采自柠檬的

例    句   The clock derives its energy from electrolysis of the citric acid and this helps you leave those toxic batteries away.这种时钟可以从柠檬酸的电解过程中获取能量,这样你就不需要用那些有害的电池了。

 

acid    英 /ˈæsɪd/   美 /ˈæsɪd/

释    义   n. 酸;迷幻药

               adj. 酸的;讽刺的;刻薄的

例    句   A lemon is an acid fruit.柠檬是一种酸味水果。

 

cycle   英 /ˈsaɪkl/   美 /ˈsaɪkl/

释    义   n. 循环;周期;自行车;整套;一段时间

               vt. 使循环;使轮转

               vi. 循环;骑自行车;轮转

例    句   Adopt modern tools for every stage of the development life cycle from requirements to design to development and testing. 对于从需求到设计以至开发和测试的每个开发生命周期阶段采用最新的工具。

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