Cancer-Associated isocitrate dehydrogenase 1 (IDH1) R132H mutation and D-2-hydroxyglutarate stimulate glutamine metabolism under hypoxia

Zachary J. Reitman, Christopher G. Duncan, Ethan Poteet, Ali Winters, Liang-Jun Yan, David M. Gooden, Ivan Spasojevic, Laszlo G. Boros, Shaohua Yang, Hai Yan

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Abstract

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 R132Hisobolome by using targeted 13C 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.

Original languageEnglish
Pages (from-to)23318-23328
Number of pages11
JournalJournal of Biological Chemistry
Volume289
Issue number34
DOIs
StatePublished - 1 Jan 2014

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Isocitrate Dehydrogenase
Glutamine
Metabolism
Mutation
Neoplasms
alpha-hydroxyglutarate
Hypoxia
Cells
Lipogenesis
Acetyl Coenzyme A
Metabolic Networks and Pathways
Codon
NADP
Esters
Adenocarcinoma
Up-Regulation
Therapeutics
Tumors

Cite this

Reitman, Zachary J. ; Duncan, Christopher G. ; Poteet, Ethan ; Winters, Ali ; Yan, Liang-Jun ; Gooden, David M. ; Spasojevic, Ivan ; Boros, Laszlo G. ; Yang, Shaohua ; Yan, Hai. / Cancer-Associated isocitrate dehydrogenase 1 (IDH1) R132H mutation and D-2-hydroxyglutarate stimulate glutamine metabolism under hypoxia. In: Journal of Biological Chemistry. 2014 ; Vol. 289, No. 34. pp. 23318-23328.
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Cancer-Associated isocitrate dehydrogenase 1 (IDH1) R132H mutation and D-2-hydroxyglutarate stimulate glutamine metabolism under hypoxia. / Reitman, Zachary J.; Duncan, Christopher G.; Poteet, Ethan; Winters, Ali; Yan, Liang-Jun; Gooden, David M.; Spasojevic, Ivan; Boros, Laszlo G.; Yang, Shaohua; Yan, Hai.

In: Journal of Biological Chemistry, Vol. 289, No. 34, 01.01.2014, p. 23318-23328.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Reitman, Zachary J.

AU - Duncan, Christopher G.

AU - Poteet, Ethan

AU - Winters, Ali

AU - Yan, Liang-Jun

AU - Gooden, David M.

AU - Spasojevic, Ivan

AU - Boros, Laszlo G.

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AU - Yan, Hai

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