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PMID: 23793099 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

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

Nature medicine ·Vol. 19 ·No. 7 ·2013-07-00 ·Pages 901-908

Tönjes M, Barbus S, Park YJ, Wang W, Schlotter M, Lindroth AM, Pleier SV, Bai AHC, Karra D, Piro RM, Felsberg J, Addington A, Lemke D, Weibrecht I, Hovestadt V, Rolli CG, Campos B, Turcan S, Sturm D, Witt H, Chan TA, Herold-Mende C, Kemkemer R, König R, Schmidt K, Hull WE, Pfister SM, Jugold M, Hutson SM, Plass C, Okun JG, Reifenberger G, Lichter P, Radlwimmer B

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.

MeSH Terms
Amino Acids, Branched-Chain/metabolism Animals Brain Neoplasms/genetics,metabolism,pathology Cell Line, Tumor Cell Proliferation Female Glioma/genetics,metabolism,pathology HEK293 Cells Humans Isocitrate Dehydrogenase/genetics,physiology Metabolism/genetics Mice Mice, Nude Models, Biological Transaminases/genetics,metabolism,physiology
Chemicals
Amino Acids, Branched-Chain Isocitrate Dehydrogenase IDH1 protein, human BCAT1 protein, human Transaminases
Authors & Affiliations
34 authors, click to expand affiliations / ORCID
Tönjes Martje
Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Barbus Sebastian
Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Park Yoon Jung
Division of Epigenomics and Cancer Risk Factors, DKFZ, Heidelberg, Germany. | Department of Nutritional Science and Food Management, College of Health Science, Ewha Womans University, Seoul, South Korea.
Wang Wei
Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Schlotter Magdalena
Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Lindroth Anders M
Division of Epigenomics and Cancer Risk Factors, DKFZ, Heidelberg, Germany.
Pleier Sabrina V
Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany. | Division of Pediatric Neurooncology, DKFZ, Heidelberg, Germany.
Bai Alfa H C
Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Karra Daniela
Department of Neuropathology, Heinrich Heine University, Düsseldorf, Germany.
Piro Rosario M
Department of Bioinformatics and Functional Genomics, Institute of Pharmacy and Molecular Biotechnology and Bioquant, University of Heidelberg, Heidelberg, Germany. | Division of Theoretical Bioinformatics, DKFZ, Heidelberg, Germany.
Felsberg Jörg
Department of Neuropathology, Heinrich Heine University, Düsseldorf, Germany.
Addington Adele
Department of Human Nutrition, Foods and Exercise, Virginia Polytechnic Institute, Blacksburg, Virginia, USA.
Lemke Dieter
Clinical Cooperation Unit Neurooncology, DKFZ, Heidelberg, Germany.
Weibrecht Irene
Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Hovestadt Volker
Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Rolli Claudio G
Department of New Materials and Biosystems, Max Planck Institute for Intelligent Systems, Stuttgart, Germany.
Campos Benito
Division of Experimental Neurosurgery, University of Heidelberg, Heidelberg, Germany. | Department of Neurosurgery, University of Heidelberg, Heidelberg, Germany.
Turcan Sevin
Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
Sturm Dominik
Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany. | Division of Pediatric Neurooncology, DKFZ, Heidelberg, Germany. | Department of Pediatric Oncology, Hematology and Immunology, Heidelberg University Hospital, Heidelberg, Germany.
Witt Hendrik
Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany. | Division of Pediatric Neurooncology, DKFZ, Heidelberg, Germany. | Department of Pediatric Oncology, Hematology and Immunology, Heidelberg University Hospital, Heidelberg, Germany.
Chan Timothy A
Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
Herold-Mende Christel
Division of Experimental Neurosurgery, University of Heidelberg, Heidelberg, Germany. | Department of Neurosurgery, University of Heidelberg, Heidelberg, Germany.
Kemkemer Ralf
Department of New Materials and Biosystems, Max Planck Institute for Intelligent Systems, Stuttgart, Germany. | Reutlingen University of Applied Science, Reutlingen, Germany.
König Rainer
Department of Bioinformatics and Functional Genomics, Institute of Pharmacy and Molecular Biotechnology and Bioquant, University of Heidelberg, Heidelberg, Germany. | Division of Theoretical Bioinformatics, DKFZ, Heidelberg, Germany.
Schmidt Kathrin
Department of General Pediatrics, Division of Inborn Metabolic Diseases, University Children's Hospital, Heidelberg, Germany.
Hull William-Edmund
Core Facility, Molecular Structural Analysis, DKFZ, Heidelberg, Germany.
Pfister Stefan M
Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany. | Division of Pediatric Neurooncology, DKFZ, Heidelberg, Germany. | Department of Pediatric Oncology, Hematology and Immunology, Heidelberg University Hospital, Heidelberg, Germany.
Jugold Manfred
Core Facility, Small Animal Imaging Center, DKFZ, Heidelberg, Germany.
Hutson Susan M
Department of Human Nutrition, Foods and Exercise, Virginia Polytechnic Institute, Blacksburg, Virginia, USA.
Plass Christoph
Division of Epigenomics and Cancer Risk Factors, DKFZ, Heidelberg, Germany.
Okun Jürgen G
Department of General Pediatrics, Division of Inborn Metabolic Diseases, University Children's Hospital, Heidelberg, Germany.
Reifenberger Guido
Department of Neuropathology, Heinrich Heine University, Düsseldorf, Germany. | German Cancer Consortium (DKTK), DKFZ, Heidelberg, Germany.
Lichter Peter
Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Radlwimmer Bernhard
Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
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Article Info
Journal
Nature medicine
Abbr.
Nat Med
ISSN
1546-170X
DOI
10.1038/nm.3217
Published
2013-07-00
Epub
2013-00-23
Pages
901-908
Language
English
Region
United States
NLM ID
9502015
PMCID
PMC4916649
Subset
IM
Grants
NCI NIH HHS · T32 CA160001 · United States
Corrections
CommentIn
PMID: 23835536
CommentIn
PMID: 23836221
External Links
PubMed source DOI: 10.1038/nm.3217 PMC Full Text View journal details
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