Cancer-associated IDH mutations induce Glut1 expression and glucose metabolic disorders through a PI3K/Akt/mTORC1-Hif1α axis.

Xun Liu,Tsuneo Ikenoue,Chi Zhu,Shin Maeda,Yoichi Furukawa,Yoko Hikiba,Makoto Hirata,Kiyoshi Yamaguchi,Kiyoko Takane,Irina U Agoulnik

doi:10.1371/journal.pone.0257090

Abstract

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.

Highlights

IDH1 and IDH2 are metabolic enzymes that catalyze oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG) [1,2,3]
These results indicate that the phosphatidylinositol 3-kinase (PI3K)/Akt/mTORC1-Hif1α axis is involved in the induction of glucose transporter 1 (Glut1) by the Isocitrate dehydrogenase 1 and 2 (IDH1/2) mutants
We have shown that oncogenic IDH1/2 mutations induce the expression of Glut1 in mouse embryonic fibroblasts (MEF) cells and HCT116 cells, and that activation of PI3K/Akt/mTOR pathway and up-regulation of Hif1α are involved in the induction of Glut1 (S3 Fig)

Summary

Introduction

IDH1 and IDH2 are metabolic enzymes that catalyze oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG) [1,2,3]. Both IDH1 and IDH2 have hydrogenase activities, and generate NADPH using nicotinamide adenine dinucleotide phosphate (NADP+) as electron acceptors [2,3,4,5]. Recurrent mutations of IDH were initially identified in gliomas by a cancer genome sequencing project [6].

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