Cancer-associated IDH mutations induce Glut1 expression and glucose metabolic disorders through a PI3K/Akt/mTORC1-Hif1α axis.
Cancer-associated IDH mutations induce Glut1 expression and glucose metabolic disorders through a PI3K/Akt/mTORC1-Hif1α axis.
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与癌症相关的IDH突变通过PI3K/AKT/MTORC1-HIF1α轴诱导GLUT1表达和葡萄糖代谢性疾病。
DOI：
10.1371/journal.pone.0257090
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发表时间：
2021
期刊：
影响因子：
3.7
通讯作者：
Ikenoue T
中科院分区：
文献类型：
--
作者：
Liu X;Yamaguchi K;Takane K;Zhu C;Hirata M;Hikiba Y;Maeda S;Furukawa Y;Ikenoue T
异柠檬酸脱氢酶1和2（IDH 1/2）突变及其关键效应物2-羟基戊二酸（2-HG）已被报道促进各种人类癌症中的肿瘤发生。为了阐明与IDH 1/2突变相关的分子机制，我们建立了稳定表达癌症相关IDH 1 R132 C或IDH 2 R172 S的小鼠胚胎成纤维细胞（MEF）细胞和人结直肠癌细胞，并分析了这些细胞代谢特征的变化。我们发现IDH 1/2突变体诱导细胞内2-HG积累并抑制细胞增殖。通过RNA-seq分析葡萄糖转运蛋白1（Glut 1）在MEF细胞中的表达谱显示，葡萄糖转运蛋白1（Glut 1）在IDH 1/2突变体或2-HG处理中被诱导。同时，葡萄糖摄取和乳酸产生增加的突变体，表明糖代谢的失调。此外，PI 3 K/Akt/mTOR通路和HIF 1 α表达参与了Glut 1的上调。总之，这些结果表明，Glut 1是由癌症相关IDH 1/2突变调控的潜在靶点。
Isocitrate dehydrogenase 1 and 2 (IDH1/2) mutations and their key effector 2-hydroxyglutarate (2-HG) have been reported to promote oncogenesis in various human cancers. To elucidate molecular mechanism(s) associated with IDH1/2 mutations, we established mouse embryonic fibroblasts (MEF) cells and human colorectal cancer cells stably expressing cancer-associated IDH1R132C or IDH2R172S, and analyzed the change in metabolic characteristics of the these cells. We found that IDH1/2 mutants induced intracellular 2-HG accumulation and inhibited cell proliferation. Expression profile analysis by RNA-seq unveiled that glucose transporter 1 (Glut1) was induced by the IDH1/2 mutants or treatment with 2-HG in the MEF cells. Consistently, glucose uptake and lactate production were increased by the mutants, suggesting the deregulation of glucose metabolism. Furthermore, PI3K/Akt/mTOR pathway and Hif1α expression were involved in the up-regulation of Glut1. Together, these results suggest that Glut1 is a potential target regulated by cancer-associated IDH1/2 mutations.
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影响因子：
56.9
作者：
Jaakkola, P;Mole, DR;Ratcliffe, PJ
通讯作者：
Ratcliffe, PJ
影响因子：
8
作者：
通讯作者：
--
影响因子：
13.8
作者：
Liberti MV;Locasale JW
通讯作者：
Locasale JW
影响因子：
64.8
作者：
通讯作者：
--
Warburg效应决定了丁酸酯介导的组蛋白乙酰化和细胞增殖的机制。
影响因子：
16
作者：
Donohoe, Dallas R.;Collins, Leonard B.;Wali, Aminah;Bigler, Rebecca;Sun, Wei;Bultman, Scott J.
通讯作者：
Bultman, Scott J.