In silico gene expression analysis reveals glycolysis and acetate anaplerosis in IDH1 wild-type glioma and lactate and glutamate anaplerosis in IDH1-mutated glioma.
In silico gene expression analysis reveals glycolysis and acetate anaplerosis in IDH1 wild-type glioma and lactate and glutamate anaplerosis in IDH1-mutated glioma.
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在硅基因表达分析中，揭示了IDH1野生型神经胶质瘤，乳酸和乳酸和谷氨酸胶质酸胶质瘤的糖酵解和乙酸酯的溶无体病。
DOI：
10.18632/oncotarget.17106
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发表时间：
2017-07-25
期刊：
影响因子：
--
通讯作者：
van Noorden CJF
中科院分区：
文献类型：
--
作者：
Khurshed M;Molenaar RJ;Lenting K;Leenders WP;van Noorden CJF
异柠檬酸脱氢酶1(Idh1)的热点突变启动低级别胶质瘤和继发性胶质母细胞瘤，并诱导新的活性，将α-酮戊二酸(α-KG)转化为肿瘤代谢物D-2-羟基戊二酸(D-2-HG)。它会导致新陈代谢重新布线，这一点还没有完全被理解。我们通过对癌症基因组图谱的数据挖掘，研究了IDH1突变(IDH1MUT)对代谢酶编码基因表达的影响。我们分析了112例IDH1野生型(IDH1WT)和399例IDH1MUT低级别胶质瘤，以及157例IDH1WT和9例IDH1MUT胶质母细胞瘤样本。在这两种类型的胶质瘤中，IDH1WT与参与糖酵解和醋酸盐分解的酶的编码基因的高表达有关，而IDH1MUT胶质瘤过表达参与氧化三羧酸(TCA)循环的酶的基因。在体外，我们观察到IDH1MUT癌细胞比IDH1WT癌细胞有更高的基础呼吸，抑制IDH1MUT通过减少氧气消耗和增加糖酵解来改变代谢。我们的发现表明，IDH1WT胶质瘤具有典型的Warburg表型，而在IDH1MUT胶质瘤中，主要的代谢途径是TCA循环，而不是糖酵解乳酸的产生。我们的数据进一步表明，IDH1MUT胶质瘤的TCA是由乳酸和谷氨酸失活驱动的，以促进α-KG的产生，并最终产生D-2-HG。这种代谢重组可能是IDH1MUT和IDH1WT胶质瘤新疗法的基础。
Hotspot mutations in isocitrate dehydrogenase 1 (IDH1) initiate low-grade glioma and secondary glioblastoma and induce a neomorphic activity that converts α-ketoglutarate (α-KG) to the oncometabolite D-2-hydroxyglutarate (D-2-HG). It causes metabolic rewiring that is not fully understood. We investigated the effects of IDH1 mutations (IDH1MUT) on expression of genes that encode for metabolic enzymes by data mining The Cancer Genome Atlas. We analyzed 112 IDH1 wild-type (IDH1WT) versus 399 IDH1MUT low-grade glioma and 157 IDH1WT versus 9 IDH1MUT glioblastoma samples. In both glioma types, IDH1WT was associated with high expression levels of genes encoding enzymes that are involved in glycolysis and acetate anaplerosis, whereas IDH1MUT glioma overexpress genes encoding enzymes that are involved in the oxidative tricarboxylic acid (TCA) cycle. In vitro, we observed that IDH1MUT cancer cells have a higher basal respiration compared to IDH1WT cancer cells and inhibition of the IDH1MUT shifts the metabolism by decreasing oxygen consumption and increasing glycolysis. Our findings indicate that IDH1WT glioma have a typical Warburg phenotype whereas in IDH1MUT glioma the TCA cycle, rather than glycolytic lactate production, is the predominant metabolic pathway. Our data further suggest that the TCA in IDH1MUT glioma is driven by lactate and glutamate anaplerosis to facilitate production of α-KG, and ultimately D-2-HG. This metabolic rewiring may be a basis for novel therapies for IDH1MUT and IDH1WT glioma.
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具有IDH1突变的胶质瘤细胞通过丙酮酸羧化酶调节代谢分数通量。
影响因子：
3.7
作者：
Izquierdo-Garcia JL;Cai LM;Chaumeil MM;Eriksson P;Robinson AE;Pieper RO;Phillips JJ;Ronen SM
通讯作者：
Ronen SM
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
DOI：
10.1126/science.1211485
发表时间：
2011-12-02
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Anastasiou D;Poulogiannis G;Asara JM;Boxer MB;Jiang JK;Shen M;Bellinger G;Sasaki AT;Locasale JW;Auld DS;Thomas CJ;Vander Heiden MG;Cantley LC
通讯作者：
Cantley LC
影响因子：
50.3
作者：
Figueroa ME;Abdel-Wahab O;Lu C;Ward PS;Patel J;Shih A;Li Y;Bhagwat N;Vasanthakumar A;Fernandez HF;Tallman MS;Sun Z;Wolniak K;Peeters JK;Liu W;Choe SE;Fantin VR;Paietta E;Löwenberg B;Licht JD;Godley LA;Delwel R;Valk PJ;Thompson CB;Levine RL;Melnick A
通讯作者：
Melnick A