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

Badur, Mehmet G.; Muthusamy, Thangaselvam; Parker, Seth J.; Ma, Shenghong; McBrayer, Samuel K.; Cordes, Thekla; Magaña, Jose H.; Guan, Kun Liang; Metallo, Christian M.

doi:10.1016/j.celrep.2018.09.074

Cited by 65 publications

(48 citation statements)

References 65 publications

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“…Earlier investigations have exhaustively explored ways to target central carbon metabolism [ 7 ]. However, few studies have explored alteration in the lipidome that are relevant for IDH1 mut gliomas [ 22 , 27 ]. Our laboratory has begun to unravel unique perturbations along lipid pathways that are associated with IDH1 mutations and offer potential avenues for translation to therapeutic targets [ 22 ].…”

Section: Discussionmentioning

confidence: 99%

Sphingolipid Pathway as a Source of Vulnerability in IDH1mut Glioma

Dowdy

Zhang

Celiku

et al. 2020

Cancers

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In addition to providing integrity to cellular structure, the various classes of lipids participate in a multitude of functions including secondary messengers, receptor stimulation, lymphocyte trafficking, inflammation, angiogenesis, cell migration, proliferation, necrosis and apoptosis, thus highlighting the importance of understanding their role in the tumor phenotype. In the context of IDH1mut glioma, investigations focused on metabolic alterations involving lipidomics’ present potential to uncover novel vulnerabilities. Herein, a detailed lipidomic analysis of the sphingolipid metabolism was conducted in patient-derived IDH1mut glioma cell lines, as well as model systems, with the of identifying points of metabolic vulnerability. We probed the effect of decreasing D-2HG levels on the sphingolipid pathway, by treating these cell lines with an IDH1mut inhibitor, AGI5198. The results revealed that N,N-dimethylsphingosine (NDMS), sphingosine C17 and sphinganine C18 were significantly downregulated, while sphingosine-1-phosphate (S1P) was significantly upregulated in glioma cultures following suppression of IDH1mut activity. We exploited the pathway using a small-scale, rational drug screen and identified a combination that was lethal to IDHmut cells. Our work revealed that further addition of N,N-dimethylsphingosine in combination with sphingosine C17 triggered a dose-dependent biostatic and apoptotic response in a panel of IDH1mut glioma cell lines specifically, while it had little effect on the IDHWT cells probed here. To our knowledge, this is the first study that shows how altering the sphingolipid pathway in IDH1mut gliomas elucidates susceptibility that can arrest proliferation and initiate subsequent cellular death.

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Section: Discussionmentioning

confidence: 99%

Sphingolipid Pathway as a Source of Vulnerability in IDH1mut Glioma

Dowdy

Zhang

Celiku

et al. 2020

Cancers

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“…For lactate isotopomer analysis the samples were analyzed directly. The relative quantities of M0, M1, M2 and M3 lactate were corrected for natural carbon-13 abundance using the IsoCorrectoR software package 58 and the oxidative PPP shunting ratio was calculated by taking the ratio M1/(M1+M2) 59 ; since there is no difference in growth rates between the 786-O-EV and 786-O-SLC7A11 cell lines we assume that the biosynthetic demand for ribose-5-phosphate or any other PPP intermediate is the same in each case, so any increase in this ratio should only reflect an increase in NADPH production by the oxidative PPP.…”

Section: Methodsmentioning

confidence: 99%

Cystine transporter regulation of pentose phosphate pathway dependency and disulfide stress exposes a targetable metabolic vulnerability in cancer

et al. 2020

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SLC7A11-mediated cystine uptake is critical for maintaining redox balance and cell survival. Here, we show that this comes at a significant cost for cancer cells with high SLC7A11 expression. Actively importing cystine is potentially toxic due to its low solubility, forcing SLC7A11-high cancer cells to constitutively reduce cystine to the more soluble cysteine. This presents a substantial drain on the cellular NADPH pool and renders such cells dependent on the pentose phosphate pathway (PPP). Limiting glucose supply to SLC7A11-high cancer cells results in marked accumulation of intracellular cystine, redox system collapse, and rapid cell death, which can be rescued by treatments that prevent disulfide accumulation. We further show that glucose transporter (GLUT) inhibitors selectively kill SLC7A11-high cancer cells and suppress SLC7A11-high tumor growth. Our results identify a coupling between SLC7A11-associated cystine metabolism and the PPP, and uncover an accompanying metabolic vulnerability for therapeutic targeting in SLC7A11-high cancers.

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“…This reaction produces a 50- to 100-fold increase in 2HG levels in cells harboring the mutation [ 6 , 7 ]. This mutation is considered to be a major feature in reshaping the metabolic landscape of tumors such as gliomas [ 8 , 9 ] or fibrosacromas [ 10 ], along with a defective activity of the WT reaction, which reversibly interconverts isocitrate and αKG [ 11 ]. However, it is not clear whether the IDH1 mutation by itself is sufficient to describe the metabolic complexity and heterogeneity of these tumors in time and space.…”

Section: Introductionmentioning

confidence: 99%

Metabolic Landscape of a Genetically Engineered Mouse Model of IDH1 Mutant Glioma

Ruiz‐Rodado

Seki

Dowdy

et al. 2020

Cancers

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Understanding the metabolic reprogramming of aggressive brain tumors has potential applications for therapeutics as well as imaging biomarkers. However, little is known about the nutrient requirements of isocitrate dehydrogenase 1 (IDH1) mutant gliomas. The IDH1 mutation involves the acquisition of a neomorphic enzymatic activity which generates D-2-hydroxyglutarate from α-ketoglutarate. In order to gain insight into the metabolism of these malignant brain tumors, we conducted metabolic profiling of the orthotopic tumor and the contralateral regions for the mouse model of IDH1 mutant glioma; as well as to examine the utilization of glucose and glutamine in supplying major metabolic pathways such as glycolysis and tricarboxylic acid (TCA). We also revealed that the main substrate of 2-hydroxyglutarate is glutamine in this model, and how this re-routing impairs its utilization in the TCA. Our 13C tracing analysis, along with hyperpolarized magnetic resonance experiments, revealed an active glycolytic pathway similar in both regions (tumor and contralateral) of the brain. Therefore, we describe the reprogramming of the central carbon metabolism associated with the IDH1 mutation in a genetically engineered mouse model which reflects the tumor biology encountered in glioma patients.

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

Cited by 65 publications

References 65 publications

Sphingolipid Pathway as a Source of Vulnerability in IDH1mut Glioma

Sphingolipid Pathway as a Source of Vulnerability in IDH1mut Glioma

Cystine transporter regulation of pentose phosphate pathway dependency and disulfide stress exposes a targetable metabolic vulnerability in cancer

Metabolic Landscape of a Genetically Engineered Mouse Model of IDH1 Mutant Glioma

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