Cancer-associated IDH mutations induce Glut1 expression and glucose metabolic disorders through a PI3K/Akt/mTORC1-Hif1α axis.
Animals
Cell Proliferation
Fibroblasts
/ metabolism
Gene Expression Regulation, Neoplastic
Glucose
/ metabolism
Glucose Metabolism Disorders
/ genetics
Glucose Transporter Type 1
/ metabolism
Glutarates
/ metabolism
Glycolysis
HCT116 Cells
Humans
Hypoxia-Inducible Factor 1, alpha Subunit
Intracellular Space
/ metabolism
Isocitrate Dehydrogenase
/ genetics
Lactic Acid
/ metabolism
Mechanistic Target of Rapamycin Complex 1
/ metabolism
Mice, Inbred C57BL
Mutant Proteins
/ metabolism
Mutation
/ genetics
Neoplasms
/ genetics
Phosphatidylinositol 3-Kinases
/ metabolism
Proto-Oncogene Proteins c-akt
/ metabolism
Signal Transduction
Journal
PloS one
ISSN: 1932-6203
Titre abrégé: PLoS One
Pays: United States
ID NLM: 101285081
Informations de publication
Date de publication:
2021
2021
Historique:
received:
25
02
2021
accepted:
23
08
2021
entrez:
13
9
2021
pubmed:
14
9
2021
medline:
17
11
2021
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 34516556
doi: 10.1371/journal.pone.0257090
pii: PONE-D-21-06211
pmc: PMC8437293
doi:
Substances chimiques
Glucose Transporter Type 1
0
Glutarates
0
Hif1a protein, mouse
0
Hypoxia-Inducible Factor 1, alpha Subunit
0
Mutant Proteins
0
alpha-hydroxyglutarate
2889-31-8
Lactic Acid
33X04XA5AT
Isocitrate Dehydrogenase
EC 1.1.1.41
Mechanistic Target of Rapamycin Complex 1
EC 2.7.11.1
Proto-Oncogene Proteins c-akt
EC 2.7.11.1
Glucose
IY9XDZ35W2
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e0257090Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
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