The DOI matches its Crossref record; 52 of the 53 references it cites were found in a registry or an index.
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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“one likely role is as an inflammatory signal, acting via SUCNR14,5,161,162.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [162]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Hallmarks of Cancer: The Next Generation
Hanahan, D., & Weinberg, R. A. (2011) · Cell · doi:10.1016/j.cell.2011.02.013 · Cited by 66,590
Understanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation
Vander Heiden, M. G., Cantley, L. C., & Thompson, C. B. (2009) · Science · doi:10.1126/science.1160809 · Cited by 16,197
An Integrated Genomic Analysis of Human Glioblastoma Multiforme
Parsons, D. W., Jones, S., Zhang, X., Lin, J. C.-H., Leary, R. J., Angenendt, P., Mankoo, P., Carter, H., Siu, I.-M., Gallia, G. L., et al. (2008) · Science · doi:10.1126/science.1164382 · Cited by 5,857
Why Do Cancers Have High Aerobic Glycolysis?
Gatenby, R. A., & Gillies, R. J. (2004) · Nature reviews. Cancer · doi:10.1038/nrc1478 · Cited by 4,784
Cancer-associated IDH1 mutations produce 2-hydroxyglutarate
Dang, L., White, D. W., Gross, S., Bennett, B. D., Bittinger, M. A., Driggers, E. M., Fantin, V. R., Jang, H. G., Jin, S., Keenan, M. C., et al. (2009) · Nature · doi:10.1038/nature08617 · Cited by 4,154
Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate
Ward, P. S., & Thompson, C. B. (2012) · Cancer Cell · doi:10.1016/j.ccr.2012.02.014 · Cited by 3,233
Xu, W., Yang, H., Liu, Y., Yang, Y., Wang, P., Kim, S.-H., Ito, S., Yang, C., Wang, P., Xiao, M.-T., et al. (2011) · Cancer Cell · doi:10.1016/j.ccr.2010.12.014 · Cited by 2,875
Increase in signal-to-noise ratio of > 10,000 times in liquid-state NMR
Ardenkjær‐Larsen, J. H., Fridlund, B., Gram, A., Hansson, G., Hansson, L., Lerche, M. H., Servin, R., Thaning, M., & Golman, K. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1733835100 · Cited by 2,870
Tumor cell metabolism: cancer's Achilles' heel
Kroemer, G., & Pouyssegur, J. (2008) · Cancer Cell · doi:10.1016/j.ccr.2008.05.005 · Cited by 2,337
Ward, P. S., Patel, J., Wise, D. R., Abdel-Wahab, O., Bennett, B. D., Coller, H. A., Cross, J. R., Fantin, V. R., Hedvat, C. V., Perl, A. E., et al. (2010) · Cancer Cell · doi:10.1016/j.ccr.2010.01.020 · Cited by 2,020
Primary Bioassay of Human Tumor Stem Cells
Hamburger, A. W., & Salmon, S. E. (1977) · Science · doi:10.1126/science.560061 · Cited by 1,650
HIF-1 mediates metabolic responses to intratumoral hypoxia and oncogenic mutations
Semenza, G. L. (2013) · Journal of Clinical Investigation · doi:10.1172/jci67230 · Cited by 1,335
Metabolic Imaging of Patients with Prostate Cancer Using Hyperpolarized [1- 13 C]Pyruvate
Nelson, S. J., Kurhanewicz, J. V., Vigneron, D. B., Larson, P. E. Z., Harzstark, A. L., Ferrone, M., Criekinge, M. V., Chang, J. W., Bok, R., Park, I., et al. (2013) · Science Translational Medicine · doi:10.1126/scitranslmed.3006070 · Cited by 1,289
Glioma-Derived Mutations in IDH1 Dominantly Inhibit IDH1 Catalytic Activity and Induce HIF-1α
Zhao, S., Lin, Y., Xu, W., Jiang, W., Zha, Z., Wang, P., Yu, W., Li, Z., Gong, L., Peng, Y., et al. (2009) · Science · doi:10.1126/science.1170944 · Cited by 1,119
Targeting metabolic transformation for cancer therapy
Tennant, D. A., Durán, R. V., & Gottlieb, E. (2010) · Nature reviews. Cancer · doi:10.1038/nrc2817 · Cited by 1,073
2-hydroxyglutarate detection by magnetic resonance spectroscopy in IDH-mutated patients with gliomas
Choi, C., Ganji, S. K., DeBerardinis, R. J., Hatanpaa, K. J., Rakheja, D., Kovacs, Z., Yang, X.-L., Mashimo, T., Raisanen, J. M., Marin-Valencia, I., et al. (2012) · Nature Medicine · doi:10.1038/nm.2682 · Cited by 839
Choline metabolism in malignant transformation
Glunde, K., Bhujwalla, Z. M., & Ronen, S. M. (2011) · Nature reviews. Cancer · doi:10.1038/nrc3162 · Cited by 826
Self-citationMetabolic Modulation of Glioblastoma with Dichloroacetate
Michelakis, E. D., Sutendra, G., Dromparis, P., Webster, L., Haromy, A., Niven, E. B., Maguire, C., Gammer, T.-L., Mackey, J. R., Fulton, D. S., et al. (2010) · Science Translational Medicine · doi:10.1126/scitranslmed.3000677 · Cited by 744
Transformation by the (R)-enantiomer of 2-hydroxyglutarate linked to EGLN activation
Koivunen, P., Lee, S., Duncan, C. G., Lopez, G., Lu, G., Ramkissoon, S., Losman, J. A., Joensuu, P., Bergmann, U., Gross, S., et al. (2012) · Nature · doi:10.1038/nature10898 · Cited by 727
Self-citationKurhanewicz, J., Vigneron, D. B., Brindle, K., Chekmenev, E. Y., Comment, A., Cunningham, C. H., DeBerardinis, R. J., Green, G. G., Leach, M. O., Rajan, S. S., et al. (2011) · Neoplasia · doi:10.1593/neo.101102 · Cited by 681
Golman, K., Zandt, R. I. ‘., & Thaning, M. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0601319103 · Cited by 661
Inhibition of Glutaminase Preferentially Slows Growth of Glioma Cells with Mutant IDH1
Seltzer, M. J., Bennett, B. D., Joshi, A. D., Gao, P., Thomas, A. G., Ferraris, D. V., Tsukamoto, T., Rojas, C. J., Slusher, B. S., Rabinowitz, J. D., et al. (2010) · Cancer Research · doi:10.1158/0008-5472.can-10-1666 · Cited by 528
IDH1andIDH2Mutations in Tumorigenesis: Mechanistic Insights and Clinical Perspectives
Yang, H., Ye, D., Guan, K., & Xiong, Y. (2012) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-12-1773 · Cited by 477
Profiling the effects of isocitrate dehydrogenase 1 and 2 mutations on the cellular metabolome
Reitman, Z. J., Jin, G., Karoly, E. D., Spasojevic, I., Yang, J., Kinzler, K. W., He, Y., Bigner, D. D., Vogelstein, B., & Yan, H. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1019393108 · Cited by 449 · cited 2×
“To confirm that increased HIF1a and PDK3 levels and reduced PDH activity were associated with mutant IDH1-induced 2-HG production, we measured PDH activity in NHAIDHwt and U87IDHwt cells treated with exogenous 2-HG, previously shown to model the effect of the IDH1 mutation (10, 34, 35).”
BackgroundMethodAndronesi, O. C., Kim, G. S., Gerstner, E., Batchelor, T., Tzika, A. A., Fantin, V. R., Vander Heiden, M. G., & Sorensen, A. G. (2012) · Science Translational Medicine · doi:10.1126/scitranslmed.3002693 · Cited by 438
Pope, W. B., Prins, R. M., Albert Thomas, M., Nagarajan, R., Yen, K. E., Bittinger, M. A., Salamon, N., Chou, A. P., Yong, W. H., Soto, H., et al. (2012) · Journal of Neuro-Oncology · doi:10.1007/s11060-011-0737-8 · Cited by 318
Sasaki, M., Knobbe, C. B., Itsumi, M., Elia, A. J., Harris, I. S., Chio, I. I. C., Cairns, R. A., McCracken, S., Wakeham, A., Haight, J., et al. (2012) · Genes & Development · doi:10.1101/gad.198200.112 · Cited by 296
Grassian, A. R., Parker, S. J., Davidson, S. M., Divakaruni, A. S., Green, C. R., Zhang, X., Slocum, K. L., Pu, M., Lin, F., Vickers, C., et al. (2014) · Cancer Research · doi:10.1158/0008-5472.can-14-0772-t · Cited by 280
Pyruvate dehydrogenase kinase as a novel therapeutic target in oncology
Sutendra, G., & Michelakis, E. D. (2013) · Frontiers in Oncology · doi:10.3389/fonc.2013.00038 · Cited by 275
Roche, T. E., & Hiromasa, Y. (2007) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-007-6380-z · Cited by 265
Schroeder, M., Atherton, H. J., Ball, D. R., Cole, M. A., Heather, L. C., Griffin, J. L., Clarke, K., Radda, G. K., & Tyler, D. J. (2009) · The FASEB Journal · doi:10.1096/fj.09-129171 · Cited by 221
Lactate dehydrogenase A silencing in IDH mutant gliomas
Chesnelong, C., Chaumeil, M. M., Blough, M. D., Al-Najjar, M., Stechishin, O. D., Chan, J. A., Pieper, R. O., Ronen, S. M., Weiss, S., Luchman, H. A., et al. (2014) · Neuro-Oncology · doi:10.1093/neuonc/not243 · Cited by 210
Self-citationAn in vivo patient-derived model of endogenous IDH1-mutant glioma
Luchman, H. A., Stechishin, O. D. M., Dang, N. H., Blough, M. D., Chesnelong, C., Kelly, J. J., Nguyen, S. A., Chan, J. A.-W., Weljie, A. M., Cairncross, J. G., et al. (2011) · Neuro-Oncology · doi:10.1093/neuonc/nor207 · Cited by 194
Self-citationMagnetic Resonance of 2-Hydroxyglutarate in IDH1 -Mutated Low-Grade Gliomas
Elkhaled, A., Jalbert, L. E., Phillips, J. J., Yoshihara, H. A. I., Parvataneni, R., Srinivasan, R., Bourne, G., Berger, M. S., Chang, S. M., Cha, S., et al. (2012) · Science Translational Medicine · doi:10.1126/scitranslmed.3002796 · Cited by 180
Self-citationWard, C. S., Venkatesh, H. S., Chaumeil, M. M., Brandes, A., Criekinge, M. V., Dafni, H., Sukumar, S., Nelson, S. J., Vigneron, D. B., Kurhanewicz, J. V., et al. (2010) · Cancer Research · doi:10.1158/0008-5472.can-09-2251 · Cited by 153
Self-citationIDH1 R132H decreases proliferation of glioma cell lines in vitro and in vivo
Bralten, L. B. C., Kloosterhof, N. K., Balvers, R. K., Sacchetti, A., Lapre, L., Lamfers, M. L. M., Leenstra, S., de Jonge, H. R., Kros, J. M., Jansen, E. E. W., et al. (2011) · Annals of Neurology · doi:10.1002/ana.22390 · Cited by 148
Sanchez, W. Y., McGee, S. L., Connor, T., Mottram, B. M., Wilkinson, A., Whitehead, J. P., Vučković, S., & Catley, L. P. (2013) · British Journal of Cancer · doi:10.1038/bjc.2013.120 · Cited by 144
Non-invasive in vivo assessment of IDH1 mutational status in glioma
Chaumeil, M. M., Larson, P. E. Z., Yoshihara, H. A. I., Danforth, O. M., Vigneron, D. B., Nelson, S. J., Pieper, R. O., Phillips, J. J., & Ronen, S. M. (2013) · Nature Communications · doi:10.1038/ncomms3429 · Cited by 142
Self-citationQuantitative metabolome analysis profiles activation of glutaminolysis in glioma with IDH1 mutation
Ohka, F., Ito, M., Ranjit, M., Senga, T., Motomura, A., Motomura, K., Saito, K., Kato, K., Kato, Y., Wakabayashi, T., et al. (2014) · Tumor Biology · doi:10.1007/s13277-014-1784-5 · Cited by 124
Hominoid-specific enzyme GLUD2 promotes growth of IDH1 R132H glioma
Chen, R., Nishimura, M. C., Kharbanda, S., Peale, F., Deng, Y., Daemen, A., Forrest, W. F., Kwong, M., Hedehus, M., Hatzivassiliou, G., et al. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1409653111 · Cited by 112
Oligodendroglioma cell lines containing t(1;19)(q10;p10)
Kelly, J. J., Blough, M. D., Stechishin, O. D. M., Chan, J. A.-W., Beauchamp, D. R., Perizzolo, M., Demetrick, D. J., Steele, L., Auer, R. N., Hader, W. J., et al. (2010) · Neuro-Oncology · doi:10.1093/neuonc/noq031 · Cited by 94
Self-citationReitman, Z. J., Duncan, C. G., Poteet, E. C., Winters, A., Yan, L., Gooden, D. M., Spasojević, I., Boros, L. G., Yang, S.-H., & Yan, H. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.575183 · Cited by 93
Metabolic Reprogramming in Mutant IDH1 Glioma Cells
Izquierdo-García, J. L., Viswanath, P., Eriksson, P., Chaumeil, M. M., Pieper, R. O., Phillips, J. J., & Ronen, S. M. (2015) · PLoS ONE · doi:10.1371/journal.pone.0118781 · Cited by 90
Self-citationNelson, S. J. (2011) · NMR in Biomedicine · doi:10.1002/nbm.1669 · Cited by 87
Hyperpolarized [1-13C] Glutamate: A Metabolic Imaging Biomarker of IDH1 Mutational Status in Glioma
Chaumeil, M. M., Larson, P. E. Z., Woods, S. M., Cai, L., Eriksson, P., Robinson, A. E., Lupo, J., Vigneron, D. B., Nelson, S. J., Pieper, R. O., et al. (2014) · Cancer Research · doi:10.1158/0008-5472.can-14-0680 · Cited by 87
Self-citationIDH1 R132H Mutation Generates a Distinct Phospholipid Metabolite Profile in Glioma
Esmaeili, M., Hamans, B. C., Navis, A. C., van Horssen, R., Bathen, T. F., Gribbestad, I. S., Leenders, W. P. J., & Heerschap, A. (2014) · Cancer Research · doi:10.1158/0008-5472.can-14-0008 · Cited by 86
Choi, C., Ganji, S., Hulsey, K., Madan, A., Kovács, Z. Z., Dimitrov, I. E., Zhang, S., Pichumani, K., Mendelsohn, D. B., Mickey, B., et al. (2013) · NMR in Biomedicine · doi:10.1002/nbm.2943 · Cited by 83
Glioma Cells with the IDH1 Mutation Modulate Metabolic Fractional Flux through Pyruvate Carboxylase
Izquierdo-García, J. L., Cai, L. M., Chaumeil, M. M., Eriksson, P., Robinson, A. E., Pieper, R. O., Phillips, J. J., & Ronen, S. M. (2014) · PLoS ONE · doi:10.1371/journal.pone.0108289 · Cited by 73
Self-citationPark, J. M., Josan, S., Grafendorfer, T., Yen, Y., Hurd, R. E., Spielman, D. M., & Mayer, D. (2013) · NMR in Biomedicine · doi:10.1002/nbm.2935 · Cited by 70
Lodi, A., Woods, S. M., & Ronen, S. M. (2012) · NMR in Biomedicine · doi:10.1002/nbm.2848 · Cited by 64
Self-citationPrabhu, A. H., Sarcar, B., Miller, C. R., Kim, S.-H., Nakano, I., Forsyth, P. A., & Chinnaiyan, P. (2015) · Neuro-Oncology · doi:10.1093/neuonc/nou369 · Cited by 41
Studies of the metabolism of human breast cancer spheroids by NMR
Ronen, S. M., & Degani, H. (1989) · Magnetic Resonance in Medicine · doi:10.1002/mrm.1910120217 · Cited by 38
Self-citation
Research works printed but not linked: 1
- Warburg, 1924, Ueber den Stoffwechsel der Tumoren, Biochemische Zeitschrift, 152, 319
Cited by
Sorted by citations
Hyperpolarized 13C MRI: Path to Clinical Translation in Oncology
Kurhanewicz, J. V., Vigneron, D. B., Ardenkjær‐Larsen, J. H., Bankson, J. A., Brindle, K. M., Cunningham, C. H., Gallagher, F. A., Keshari, K. R., Kjær, A., Laustsen, C., et al. (2018) · Neoplasia · doi:10.1016/j.neo.2018.09.006 · Cited by 441
Self-citationStacpoole, P. W. (2017) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djx071 · Cited by 418
Coupling Krebs cycle metabolites to signalling in immunity and cancer
Ryan, D. G., Murphy, M. P., Frezza, C., Prag, H. A., Chouchani, E. T., O’Neill, L. A., & Mills, E. L. (2018) · Nature Metabolism · doi:10.1038/s42255-018-0014-7 · Cited by 398
Metabolic Reprogramming in Glioma
Strickland, M., & Stoll, E. A. (2017) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2017.00043 · Cited by 357
Metabolism, Activity, and Targeting of D- and L-2-Hydroxyglutarates
Ye, D., Guan, K.-L., & Xiong, Y. (2018) · Trends in Cancer · doi:10.1016/j.trecan.2017.12.005 · Cited by 242
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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
