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PLoS One. 2015 Feb 23;10(2):e0118781. doi: 10.1371/journal.pone.0118781. eCollection 2015.

Metabolic reprogramming in mutant IDH1 glioma cells.

Author information

1
Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, California, United States of America.
2
Department of Neurological Surgery, Helen Diller Research Center, University of California San Francisco, San Francisco, California, United States of America; Brain Tumor Research Center, University of California San Francisco, San Francisco, California, United States of America.
3
Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, California, United States of America; Brain Tumor Research Center, University of California San Francisco, San Francisco, California, United States of America.

Abstract

BACKGROUND:

Mutations in isocitrate dehydrogenase (IDH) 1 have been reported in over 70% of low-grade gliomas and secondary glioblastomas. IDH1 is the enzyme that catalyzes the oxidative decarboxylation of isocitrate to α-ketoglutarate while mutant IDH1 catalyzes the conversion of α-ketoglutarate into 2-hydroxyglutarate. These mutations are associated with the accumulation of 2-hydroxyglutarate within the tumor and are believed to be one of the earliest events in the development of low-grade gliomas. The goal of this work was to determine whether the IDH1 mutation leads to additional magnetic resonance spectroscopy (MRS)-detectable changes in the cellular metabolome.

METHODS:

Two genetically engineered cell models were investigated, a U87-based model and an E6/E7/hTERT immortalized normal human astrocyte (NHA)-based model. For both models, wild-type IDH1 cells were generated by transduction with a lentiviral vector coding for the wild-type IDH1 gene while mutant IDH1 cells were generated by transduction with a lentiviral vector coding for the R132H IDH1 mutant gene. Metabolites were extracted from the cells using the dual-phase extraction method and analyzed by 1H-MRS. Principal Component Analysis was used to analyze the MRS data.

RESULTS:

Principal Component Analysis clearly discriminated between wild-type and mutant IDH1 cells. Analysis of the loading plots revealed significant metabolic changes associated with the IDH1 mutation. Specifically, a significant drop in the concentration of glutamate, lactate and phosphocholine as well as the expected elevation in 2-hydroxyglutarate were observed in mutant IDH1 cells when compared to their wild-type counterparts.

CONCLUSION:

The IDH1 mutation leads to several, potentially translatable MRS-detectable metabolic changes beyond the production of 2-hydroxyglutarate.

PMID:
25706986
PMCID:
PMC4338038
DOI:
10.1371/journal.pone.0118781
[Indexed for MEDLINE]
Free PMC Article

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