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IDH1 Mutation Induces Reprogramming of Pyruvate Metabolism
Open accessPublished version of a preprint
Abstract
Mutant isocitrate dehydrogenase 1 (IDH1) catalyzes the production of 2-hydroxyglutarate but also elicits additional metabolic changes. Levels of both glutamate and pyruvate dehydrogenase (PDH) activity have been shown to be affected in U87 glioblastoma cells or normal human astrocyte (NHA) cells expressing mutant IDH1, as compared with cells expressing wild-type IDH1. In this study, we show how these phenomena are linked through the effects of IDH1 mutation, which also reprograms pyruvate metabolism. Reduced PDH activity in U87 glioblastoma and NHA IDH1 mutant cells was associated with relative increases in PDH inhibitory phosphorylation, expression of pyruvate dehydrogenase kinase-3, and levels of hypoxia inducible factor-1α. PDH activity was monitored in these cells by hyperpolarized 13C-magnetic resonance spectroscopy (13C-MRS), which revealed a reduction in metabolism of hyperpolarized 2-13C-pyruvate to 5-13C-glutamate, relative to cells expressing wild-type IDH1. 13C-MRS also revealed a reduction in glucose flux to glutamate in IDH1 mutant cells. Notably, pharmacological activation of PDH by cell exposure to dichloroacetate (DCA) increased production of hyperpolarized 5-13C-glutamate in IDH1 mutant cells. Furthermore, DCA treatment also abrogated the clonogenic advantage conferred by IDH1 mutation. Using patient-derived mutant IDH1 neurosphere models, we showed that PDH activity was essential for cell proliferation. Taken together, our results established that the IDH1 mutation induces an MRS-detectable reprogramming of pyruvate metabolism, which is essential for cell proliferation and clonogenicity, with immediate therapeutic implications. Cancer Res; 75(15); 2999–3009. ©2015 AACR.
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Metadata
- Authors
- Izquierdo-Garcia, J. L., Viswanath, P., Eriksson, P., Cai, L., Radoul, M., Chaumeil, M. M., Blough, M., Luchman, H. A., Weiss, S., Cairncross, J. G., Phillips, J. J., Pieper, R. O., & Ronen, S. M.
- Affiliations
- 1Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, California.
- University of California, San Francisco (US)
- University of Calgary (CA)
- Corresponding author
- Ronen, Sabrina M.
- ORCID
- Venue
- Cancer Research
- Published
- 2015-08-01
- Volume
- 75
- Issue
- 15
- Pages
- 2999-3009
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC4526330
- OpenAlex
- W2140821112
- Cited by
- 123
- References
- 53
- Citations by year
- 2026: 6 · 2025: 7 · 2024: 6 · 2023: 10 · 2022: 11 · 2021: 13 · 2020: 18 · 2019: 12 · 2018: 15 · 2017: 14 · 2016: 8 · 2015: 3
- FWCI
- 4.41
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Cancer Institute (R21CA161545, R01CA172845, R01CA154915)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Oncology › Glioma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Biochemical Acid Research Studies
- Keywords
- IDH1 mutation, pyruvate metabolism, pyruvate dehydrogenase, 2-hydroxyglutarate, hypoxia-inducible factor-1α, dichloroacetate, hyperpolarized [1-13C]pyruvate, glutamate synthesis, glioblastoma, astrocytes, cell proliferation, clonogenicity, metabolic reprogramming
- MeSH terms
- Astrocytes, Dichloroacetic Acid, Glioblastoma, Glutarates, Humans, Isocitrate Dehydrogenase, Mutation, Magnetic Resonance Spectroscopy, Pyruvate Dehydrogenase Complex, Pyruvates, Down-Regulation, Glutamic Acid, Cell Line, Tumor, Cell Proliferation
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