Cited by 487Glioma Diagnosis and TreatmentAmino Acid Enzymes and MetabolismCancer, Hypoxia, and Metabolism

BCAT1 promotes cell proliferation through amino acid catabolism in gliomas carrying wild-type IDH1

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Tönjes, Martje, Barbus, Sebastian, Park, Yoon Jung, Wang, Wei, Schlotter, Magdalena, Lindroth, Anders M, Pleier, Sabrina V, Bai, Alfa H C +26 more·2013·Nature Medicine

Abstract

Here we show that glioblastoma express high levels of branched-chain amino acid transaminase 1 (BCAT1), the enzyme that initiates the catabolism of branched-chain amino acids (BCAAs). Expression of BCAT1 was exclusive to tumors carrying wild-type isocitrate dehydrogenase 1 (IDH1) and IDH2 genes and was highly correlated with methylation patterns in the BCAT1 promoter region. BCAT1 expression was dependent on the concentration of α-ketoglutarate substrate in glioma cell lines and could be suppressed by ectopic overexpression of mutant IDH1 in immortalized human astrocytes, providing a link between IDH1 function and BCAT1 expression. Suppression of BCAT1 in glioma cell lines blocked the excretion of glutamate and led to reduced proliferation and invasiveness in vitro, as well as significant decreases in tumor growth in a glioblastoma xenograft model. These findings suggest a central role for BCAT1 in glioma pathogenesis, making BCAT1 and BCAA metabolism attractive targets for the development of targeted therapeutic approaches to treat patients with glioblastoma.

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  • Tumors of other lineages, including some glioblastomas and blast crisis chronic myeloid leukemia, are also dependent on BCAA transaminases.

    “Tumors of other lineages are also dependent on BCAA transaminases, including some glioblastomas and blast crisis chronic myeloid leukemia (Hattori et al., 2017; Tonjes et al., 2013).”

    From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Tonjes et al., 2013

  • Late-passage IDH1 mutant NHA cells had low BCAT1 protein levels.

    “our late-passage IDH1 mutant NHA cells also had low BCAT1 protein levels.”

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Research works printed but not linked: 2

  1. [62]Turcan S IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype Nature 2012 483 479 483 22343889 PMC3351699
  2. [70]She P Disruption of BCATm in mice leads to increased energy expenditure associated with the activation of a futile protein turnover cycle Cell Metab 2007 6 181 194 17767905 PMC2693888

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Authors
Tönjes, M., Barbus, S., Park, Y. J., Wang, W., Schlotter, M., Lindroth, A. M., Pleier, S. V., Bai, A. H. C., Karra, D., Piro, R. M., Felsberg, J., Addington, A., Lemke, D., Weibrecht, I., Hovestadt, V., Rolli, C. G., Campos, B., Turcan, S., Sturm, D., Witt, H., Chan, T. A., Herold-Mende, C., Kemkemer, R., König, R., Schmidt, K., Hull, W.-E., Pfister, S. M., Jugold, M., Hutson, S. M., Plass, C., Okun, J. G., Reifenberger, G., Lichter, P., & Radlwimmer, B.
Affiliations
  • German Cancer Research Center (DE)
  • Ewha Womans University (KR)
  • Heinrich Heine University Düsseldorf (DE)
  • Virginia Tech (US)
  • Max Planck Institute for Intelligent Systems (DE)
  • Heidelberg University (DE)
  • Memorial Sloan Kettering Cancer Center (US)
Corresponding author
Radlwimmer, Bernhard
Venue
Nature Medicine
Published
2013-06-23
Volume
19
Issue
7
Pages
901-908
ISSN
  • 1078-8956 (ISSN-L)
  • 1546-170X
OpenAlex
W2074983857
Cited by
486
References
71
Citations by year
2026: 28 · 2025: 35 · 2024: 39 · 2023: 40 · 2022: 49 · 2021: 58 · 2020: 52 · 2019: 31 · 2018: 38 · 2017: 38 · 2016: 29 · 2015: 24 · 2014: 19 · 2013: 5
FWCI
12.63
Type
journal article
Language
en
Open access
Locations
  • Nature Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • MPG.PuRe (Max Planck Society) (submittedVersion)
Funders
National Cancer Institute (T32CA160001)
Topics
  • Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
Keywords
BCAT1, branched-chain amino acid catabolism, glioblastoma, IDH2, promoter methylation, alpha-ketoglutarate, tumor cell proliferation, tumor invasion, targeted therapy
MeSH terms
Amino Acids, Branched-Chain, Transaminases, Animals, Brain Neoplasms, Female, Glioma, Humans, Isocitrate Dehydrogenase, Metabolism, Mice, Nude, Models, Biological, Cell Line, Tumor, Cell Proliferation, Mice, HEK293 Cells

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