Hominoid-specific enzyme GLUD2 promotes growth of IDH1R132H glioma
Hominoid-specific enzyme GLUD2 promotes growth of IDH1R132H glioma
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DOI：
10.1073/pnas.1409653111
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发表时间：
2014-09-30
影响因子：
11.1
通讯作者：
Phillips, Heidi S.
中科院分区：
文献类型：
--
作者：
Chen, Ruihuan;Nishimura, Merry C.;Phillips, Heidi S.
异柠檬酸脱氢酶1（IDH 1）的体细胞突变现在被认为是继发性胶质母细胞瘤最常见的起始事件，这是一种在额叶发生频率很高的脑肿瘤类型。IDH 1突变的一个令人困惑的特点是选择性表现为胶质瘤作为唯一的肿瘤经常与早期合子后发生这种基因组改变。我们在这里报告，IDH 1（R132 H）表现出生长抑制作用，在谷氨酸脱氢酶2（GLUD 2）的存在下被废除，这是一种古猿特异性酶，据称优化，以促进谷氨酸在人类前脑的营业额。使用小鼠神经胶质瘤祖细胞，我们证明IDH 1（R132 H）发挥生长抑制作用，这是由葡萄糖和谷氨酰胺的代谢通量不足脂质。检查人神经胶质瘤，我们发现谷氨酸脱氢酶1（GLUD 1）和GLUD 2在IDH 1突变型肿瘤中过表达，并且通过敲低GLUD 1/2抑制IDH 1突变型神经胶质瘤系的原位生长。引人注目的是，将GLUD 2引入鼠神经胶质瘤祖细胞逆转了IDH 1突变对代谢通量和肿瘤生长的有害影响。此外，我们报告说，谷氨酸，底物GLUD 2和丰富的哺乳动物新皮层的神经递质，可以支持神经胶质瘤祖细胞的生长，无论IDH 1突变状态。这些发现表明，人类新皮层对高谷氨酸神经递质通量的专门化创造了一个有利于IDH 1突变肿瘤生长的代谢生态位。
Somatic mutation of isocitrate dehydrogenase 1 (IDH1) is now recognized as the most common initiating event for secondary glioblastoma, a brain tumor type arising with high frequency in the frontal lobe. A puzzling feature of IDH1 mutation is the selective manifestation of glioma as the only neoplasm frequently associated with early postzygotic occurrence of this genomic alteration. We report here that IDH1(R132H) exhibits a growth-inhibitory effect that is abrogated in the presence of glutamate dehydrogenase 2 (GLUD2), a hominoid-specific enzyme purportedly optimized to facilitate glutamate turnover in human forebrain. Using murine glioma progenitor cells, we demonstrate that IDH1(R132H) exerts a growth-inhibitory effect that is paralleled by deficiency in metabolic flux from glucose and glutamine to lipids. Examining human gliomas, we find that glutamate dehydrogenase 1 (GLUD1) and GLUD2 are overexpressed in IDH1-mutant tumors and that orthotopic growth of an IDH1-mutant glioma line is inhibited by knock down of GLUD1/2. Strikingly, introduction of GLUD2 into murine glioma progenitor cells reverses deleterious effects of IDH1 mutation on metabolic flux and tumor growth. Further, we report that glutamate, a substrate of GLUD2 and a neurotransmitter abundant in mammalian neocortex, can support growth of glioma progenitor cells irrespective of IDH1 mutation status. These findings suggest that specialization of human neocortex for high glutamate neurotransmitter flux creates a metabolic niche conducive to growth of IDH1 mutant tumors.