Inhibition of glutaminase preferentially slows growth of glioma cells with mutant IDH1.
Inhibition of glutaminase preferentially slows growth of glioma cells with mutant IDH1.
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DOI：
10.1158/0008-5472.can-10-1666
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发表时间：
2010-11-15
期刊：
影响因子：
11.2
通讯作者：
Riggins GJ
中科院分区：
文献类型：
--
作者：
Seltzer MJ;Bennett BD;Joshi AD;Gao P;Thomas AG;Ferraris DV;Tsukamoto T;Rojas CJ;Slusher BS;Rabinowitz JD;Dang CV;Riggins GJ
IDH 1的R132残基突变，经常在神经胶质瘤和急性髓性白血病中发现，产生一种新酶，从α-酮戊二酸（α-KG）产生2-羟基戊二酸（2-HG）。我们试图在需要来自谷氨酰胺的α-KG的突变IDH 1细胞中治疗性地利用这种新反应。谷氨酰胺通过谷氨酰胺酶（GLS）转化为谷氨酸，并进一步代谢为α-KG。因此，我们用siRNA或小分子抑制剂BPTES（双-2-（5-苯基乙酰氨基-1，2，4-噻二唑-2-基）乙基硫醚）抑制GLS，并发现与表达野生型IDH 1的胶质母细胞瘤细胞相比，表达突变体IDH 1的胶质母细胞瘤细胞生长减慢。BPTES对突变IDH 1细胞的生长抑制作用可通过加入外源性α-KG来解除。BPTES抑制GLS活性，降低谷氨酸和α-KG水平，增加糖酵解中间产物，而总2-HG水平不受影响。通过抑制脱氢酶选择性地减缓IDH 1突变细胞生长的能力表明了中间代谢的独特重编程和潜在的治疗策略。
Mutation at the R132 residue of IDH1, frequently found in gliomas and acute myelogenous leukemia, creates a neo-enzyme that produces 2-hydroxyglutarate (2-HG) from α-ketoglutarate (α-KG). We sought to therapeutically exploit this neo-reaction in mutant IDH1 cells which requires α-KG derived from glutamine. Glutamine is converted to glutamate by glutaminase (GLS) and further metabolized to α-KG. Therefore, we inhibited GLS with siRNA or the small molecule inhibitor BPTES (bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide) and found slowed growth of glioblastoma cells expressing mutant IDH1 compared to those expressing wild-type IDH1. Growth suppression of mutant IDH1 cells by BPTES was rescued by adding exogenous α-KG. BPTES inhibited GLS activity, lowered glutamate and α-KG levels, and increased glycolytic intermediates while leaving total 2-HG levels unaffected. The ability to selectively slow growth in cells with IDH1 mutations by inhibiting glutaminase suggests a unique re-programming of intermediary metabolism and a potential therapeutic strategy.