Oncogenic R132 IDH1 Mutations Limit NADPH for De Novo Lipogenesis Through (D)2-Hydroxyglutarate Production in Fibrosarcoma Sells

Overview

Journal Cell Rep

Publisher Cell Press

Specialties Biology
Cell Biology
Molecular Biology

Date 2018 Oct 26

PMID 30355481

Citations 34

Authors

Mehmet G Badur

Thangaselvam Muthusamy

Seth J Parker

Shenghong Ma

Samuel K McBrayer

Thekla Cordes

Jose H Magana

Kun-Liang Guan

Christian M Metallo

Affiliations

Soon will be listed here.

Abstract

Neomorphic mutations in NADP-dependent isocitrate dehydrogenases (IDH1 and IDH2) contribute to tumorigenesis in several cancers. Although significant research has focused on the hypermethylation phenotypes associated with (D)2-hydroxyglutarate (D2HG) accumulation, the metabolic consequences of these mutations may also provide therapeutic opportunities. Here we apply flux-based approaches to genetically engineered cell lines with an endogenous IDH1 mutation to examine the metabolic impacts of increased D2HG production and altered IDH flux as a function of IDH1 mutation or expression. D2HG synthesis in IDH1-mutant cells consumes NADPH at rates similar to de novo lipogenesis. IDH1-mutant cells exhibit increased dependence on exogenous lipid sources for in vitro growth, as removal of medium lipids slows growth more dramatically in IDH1-mutant cells compared with those expressing wild-type or enzymatically inactive alleles. NADPH regeneration may be limiting for lipogenesis and potentially redox homeostasis in IDH1-mutant cells, highlighting critical links between cellular biosynthesis and redox metabolism.

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