| Literature DB >> 23793099 |
Martje Tönjes1, Sebastian Barbus1, Yoon Jung Park2,3, Wei Wang1, Magdalena Schlotter1, Anders M Lindroth2, Sabrina V Pleier1,4, Alfa H C Bai1, Daniela Karra5, Rosario M Piro6,7, Jörg Felsberg5, Adele Addington8, Dieter Lemke9, Irene Weibrecht1, Volker Hovestadt1, Claudio G Rolli10, Benito Campos11,12, Sevin Turcan13, Dominik Sturm1,4,14, Hendrik Witt1,4,14, Timothy A Chan13, Christel Herold-Mende11,12, Ralf Kemkemer10,15, Rainer König6,7, Kathrin Schmidt16, William-Edmund Hull17, Stefan M Pfister1,4,14, Manfred Jugold18, Susan M Hutson8, Christoph Plass2, Jürgen G Okun16, Guido Reifenberger5,19, Peter Lichter1, Bernhard Radlwimmer1.
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.Entities:
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Year: 2013 PMID： 23793099 PMCID： PMC4916649 DOI： 10.1038/nm.3217
Source DB: PubMed Journal: Nat Med ISSN： 1078-8956 Impact factor: 53.440