by Izquierdo-García, José L, Viswanath, Pavithra, Eriksson, Pia, Chaumeil, Myriam M, Pieper, Russell O, Phillips, Joanna J and Ronen, Sabrina M
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 $alpha$-ketoglutarate while mutant IDH1 catalyzes the conversion of $alpha$-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.
Reference:
Metabolic reprogramming in mutant IDH1 glioma cells. (Izquierdo-García, José L, Viswanath, Pavithra, Eriksson, Pia, Chaumeil, Myriam M, Pieper, Russell O, Phillips, Joanna J and Ronen, Sabrina M), In PLoS ONE, volume 10, 2015.
Bibtex Entry:
@article{IzquierdoGarcia:2015ds,
author = {Izquierdo-Garc{'i}a, Jos{'e} L and Viswanath, Pavithra and Eriksson, Pia and Chaumeil, Myriam M and Pieper, Russell O and Phillips, Joanna J and Ronen, Sabrina M},
title = {{Metabolic reprogramming in mutant IDH1 glioma cells.}},
journal = {PLoS ONE},
year = {2015},
volume = {10},
number = {2},
pages = {e0118781},
affiliation = {Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, California, United States of America.},
doi = {10.1371/journal.pone.0118781},
pmid = {25706986},
pmcid = {PMC4338038},
language = {English},
rating = {0},
date-added = {2018-03-16T12:39:55GMT},
date-modified = {2018-11-22T21:14:03GMT},
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 $alpha$-ketoglutarate while mutant IDH1 catalyzes the conversion of $alpha$-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.},
url = {http://dx.plos.org/10.1371/journal.pone.0118781},
uri = {url{papers3://publication/doi/10.1371/journal.pone.0118781}}
}