Cancer-associated isocitrate dehydrogenase 1 (IDH1) R132H mutation and d-2-hydroxyglutarate stimulate glutamine metabolism under hypoxia.
Cancer-associated isocitrate dehydrogenase 1 (IDH1) R132H mutation and d-2-hydroxyglutarate stimulate glutamine metabolism under hypoxia.
- 2014
Available online through MWHC library: 1905 - 2006
Mutations in the cytosolic NADP(+)-dependent isocitrate dehydrogenase (IDH1) occur in several types of cancer, and altered cellular metabolism associated with IDH1 mutations presents unique therapeutic opportunities. By altering IDH1, these mutations target a critical step in reductive glutamine metabolism, the metabolic pathway that converts glutamine ultimately to acetyl-CoA for biosynthetic processes. While IDH1-mutated cells are sensitive to therapies that target glutamine metabolism, the effect of IDH1 mutations on reductive glutamine metabolism remains poorly understood. To explore this issue, we investigated the effect of a knock-in, single-codon IDH1-R132H mutation on the metabolism of the HCT116 colorectal adenocarcinoma cell line. Here we report the R132H-isobolome by using targeted (13)C isotopomer tracer fate analysis to trace the metabolic fate of glucose and glutamine in this system. We show that introduction of the R132H mutation into IDH1 up-regulates the contribution of glutamine to lipogenesis in hypoxia, but not in normoxia. Treatment of cells with a d-2-hydroxyglutarate (d-2HG) ester recapitulated these changes, indicating that the alterations observed in the knocked-in cells were mediated by d-2HG produced by the IDH1 mutant. These studies provide a dynamic mechanistic basis for metabolic alterations observed in IDH1-mutated tumors and uncover potential therapeutic targets in IDH1-mutated cancers. Copyright © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.
English
0021-9258
*Cell Hypoxia
*Glutarates/me [Metabolism]
*Isocitrate Dehydrogenase/ge [Genetics]
*Neoplasms/en [Enzymology]
Cell Line, Tumor
Glycolysis
HCT116 Cells
Humans
Isocitrate Dehydrogenase/me [Metabolism]
Mitochondria/ph [Physiology]
Neoplasms/pa [Pathology]
MedStar Union Memorial Hospital
Medicine/Pathology
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Available online through MWHC library: 1905 - 2006
Mutations in the cytosolic NADP(+)-dependent isocitrate dehydrogenase (IDH1) occur in several types of cancer, and altered cellular metabolism associated with IDH1 mutations presents unique therapeutic opportunities. By altering IDH1, these mutations target a critical step in reductive glutamine metabolism, the metabolic pathway that converts glutamine ultimately to acetyl-CoA for biosynthetic processes. While IDH1-mutated cells are sensitive to therapies that target glutamine metabolism, the effect of IDH1 mutations on reductive glutamine metabolism remains poorly understood. To explore this issue, we investigated the effect of a knock-in, single-codon IDH1-R132H mutation on the metabolism of the HCT116 colorectal adenocarcinoma cell line. Here we report the R132H-isobolome by using targeted (13)C isotopomer tracer fate analysis to trace the metabolic fate of glucose and glutamine in this system. We show that introduction of the R132H mutation into IDH1 up-regulates the contribution of glutamine to lipogenesis in hypoxia, but not in normoxia. Treatment of cells with a d-2-hydroxyglutarate (d-2HG) ester recapitulated these changes, indicating that the alterations observed in the knocked-in cells were mediated by d-2HG produced by the IDH1 mutant. These studies provide a dynamic mechanistic basis for metabolic alterations observed in IDH1-mutated tumors and uncover potential therapeutic targets in IDH1-mutated cancers. Copyright © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.
English
0021-9258
*Cell Hypoxia
*Glutarates/me [Metabolism]
*Isocitrate Dehydrogenase/ge [Genetics]
*Neoplasms/en [Enzymology]
Cell Line, Tumor
Glycolysis
HCT116 Cells
Humans
Isocitrate Dehydrogenase/me [Metabolism]
Mitochondria/ph [Physiology]
Neoplasms/pa [Pathology]
MedStar Union Memorial Hospital
Medicine/Pathology
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't