Open AccessCancer-associated IDH mutations induce Glut1 expression and glucose metabolic disorders through a PI3K/Akt/mTORC1-Hif1α axis
Author(s) -
Xun Liu,
Kiyoshi Yamaguchi,
Kiyoko Takane,
Ce Zhu,
Makoto Hirata,
Yohko Hikiba,
Shin Maeda,
Yoichi Furukawa,
Tsuneo Ikenoue
Publication year - 2021
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0257090
Subject(s) - glut1 , isocitrate dehydrogenase , pi3k/akt/mtor pathway , biology , carcinogenesis , glucose transporter , protein kinase b , cancer cell , idh1 , mtorc1 , glucose transporter type 1 , microbiology and biotechnology , cancer research , cancer , mutant , biochemistry , signal transduction , genetics , gene , enzyme , endocrinology , insulin
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 IDH1 R132C or IDH2 R172S , 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.