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

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...

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Hauptverfasser: Tönjes, Martje (VerfasserIn) , Bărbuş, Sebastian Liviu (VerfasserIn) , Park, Yoon Jung (VerfasserIn) , Wei, Wang (VerfasserIn) , Schlotter, Magdalena (VerfasserIn) , Lindroth, Anders M. (VerfasserIn) , Pleier, Sabrina Valesca (VerfasserIn) , Bai, Alfa H. C. (VerfasserIn) , Karra, Daniela (VerfasserIn) , Piro, Rosario M. (VerfasserIn) , Felsberg, Jörg (VerfasserIn) , Addington, Adele (VerfasserIn) , Lemke, Dieter (VerfasserIn) , Weibrecht, Irene (VerfasserIn) , Hovestadt, Volker (VerfasserIn) , Rolli, Claudio G. (VerfasserIn) , Campos, Benito (VerfasserIn) , Turcan, Sevin (VerfasserIn) , Sturm, Dominik (VerfasserIn) , Witt, Hendrik (VerfasserIn) , Chan, Timothy A. (VerfasserIn) , Herold-Mende, Christel (VerfasserIn) , Kemkemer, Ralf (VerfasserIn) , König, Rainer (VerfasserIn) , Schmidt, Kathrin V. (VerfasserIn) , Hull, William Edmund (VerfasserIn) , Pfister, Stefan (VerfasserIn) , Jugold, Manfred (VerfasserIn) , Hutson, Susan M. (VerfasserIn) , Plass, Christoph (VerfasserIn) , Okun, Jürgen G. (VerfasserIn) , Reifenberger, Guido (VerfasserIn) , Lichter, Peter (VerfasserIn) , Radlwimmer, Bernhard (VerfasserIn)
Dokumenttyp: Article (Journal)
Sprache:Englisch
Veröffentlicht: 23 June 2013
In: Nature medicine
Year: 2013, Jahrgang: 19, Heft: 7, Pages: 901-908
ISSN:1546-170X
DOI:10.1038/nm.3217
Online-Zugang:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1038/nm.3217
Verlag, lizenzpflichtig, Volltext: https://www.nature.com/articles/nm.3217
Volltext
Verfasserangaben:Martje Tönjes, Sebastian Barbus, Yoon Jung Park, Wei Wang, Magdalena Schlotter, Anders M. Lindroth, Sabrina V. Pleier, Alfa H. C. Bai, Daniela Karra, Rosario M. Piro, Jörg Felsberg, Adele Addington, Dieter Lemke, Irene Weibrecht, Volker Hovestadt, Claudio G. Rolli, Benito Campos, Sevin Turcan, Dominik Sturm, Hendrik Witt, Timothy A. Chan, Christel Herold-Mende, Ralf Kemkemer, Rainer König, Kathrin Schmidt, William-Edmund Hull, Stefan M. Pfister, Manfred Jugold, Susan M. Hutson, Christoph Plass, Jürgen G. Okun, Guido Reifenberger, Peter Lichter & Bernhard Radlwimmer

MARC

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520 |a 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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