Oncogenic R132 IDH1 Mutations Limit NADPH for De Novo Lipogenesis through (D)2-Hydroxyglutarate Production in Fibrosarcoma Cells
| العنوان: | Oncogenic R132 IDH1 Mutations Limit NADPH for De Novo Lipogenesis through (D)2-Hydroxyglutarate Production in Fibrosarcoma Cells |
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| المؤلفون: | Kun-Liang Guan, Shenghong Ma, Thekla Cordes, Mehmet G. Badur, Seth J. Parker, Samuel K. McBrayer, Thangaselvam Muthusamy, Jose H. Magana, Christian M. Metallo |
| المصدر: | Cell reports, vol 25, iss 4 Cell reports Cell Reports, Vol 25, Iss 4, Pp 1018-1026.e4 (2018) |
| بيانات النشر: | Elsevier BV, 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | 0301 basic medicine, Fibrosarcoma, Cell, Medical Physiology, Endogeny, Regenerative Medicine, medicine.disease_cause, 0302 clinical medicine, Cytosol, metabolic flux analysis, 2.1 Biological and endogenous factors, Limit (mathematics), NADPH regeneration, Aetiology, lcsh:QH301-705.5, deuterium, Tumor, Chemistry, redox metabolism, Lipids, Isocitrate Dehydrogenase, 3. Good health, Cell biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Lipogenesis, IDH1, IDH2, 2-hydroxyglutrate, Article, General Biochemistry, Genetics and Molecular Biology, Cell Line, Glutarates, 03 medical and health sciences, Cell Line, Tumor, Genetics, NADPH, medicine, Humans, cancer, Oncogenes, medicine.disease, Molecular biology, Brain Disorders, 030104 developmental biology, lcsh:Biology (General), Cell culture, Mutation, Biochemistry and Cell Biology, D-2-hydroxyglutarate, Carcinogenesis, metabolism, Flux (metabolism), NADP |
| الوصف: | SUMMARY 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. In Brief Badur et al. apply metabolic flux analysis to understand how oncogenic mutations in IDH1 alter redox metabolism. Production of (D)2-hydroxyglutarate (D2HG) consumes NADPH at levels similar to de novo lipogenesis, and removal of lipids compromises in vitro growth of IDH1-mutant cells. Graphical Abstract |
| وصف الملف: | application/pdf |
| تدمد: | 2211-1247 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::2a732802778d456b030b95512d99a73a https://doi.org/10.1016/j.celrep.2018.09.074 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....2a732802778d456b030b95512d99a73a |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 22111247 |
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