Abstract
BackgroundThe mitochondrial branched-chain aminotransferase (BCATm) is a recently discovered cancer marker with a poorly defined role in tumour progression.MethodsTo understand how a loss of function of BCATm affects cancer, the global knockout mouse BCATmKO was challenged with EL-4 lymphoma under different diet compositions with varying amounts of branched-chain amino acids (BCAAs). Next, the growth and metabolism of EL-4 cells were studied in the presence of different leucine concentrations in the growth medium.ResultsBCATmKO mice experienced delayed tumour growth when fed standard rodent chow or a normal BCAA diet. Tumour suppression correlated with 37.6- and 18.9-fold increases in plasma and tumour BCAAs, 37.5% and 30.4% decreases in tumour glutamine and alanine, and a 3.5-fold increase in the phosphorylation of tumour AMPK in BCATmKO mice on standard rodent chow. Similar results were obtained with a normal but not with a choice BCAA diet.ConclusionsGlobal deletion of BCATm caused a dramatic build-up of BCAAs, which could not be utilised for energy or amino acid synthesis, ultimately delaying the growth of lymphoma tumours. Furthermore, physiological, but not high, leucine concentrations promoted the growth of EL-4 cells. BCATm and BCAA metabolism were identified as attractive targets for anti-lymphoma therapy.
Highlights
The mitochondrial branched-chain aminotransferase (BCATm) is a recently discovered cancer marker with a poorly defined role in tumour progression
BCATmKO mice display delayed tumour growth and smaller tumour sizes when challenged with EL-4 lymphoma To determine whether global deletion of BCATm impacts the growth of lymphoma in mice, we subcutaneously injected EL-4 cells in the upper back of BCATmKO and Wild type (WT) mice
High leucine concentrations are not beneficial for the growth or the glycolytic metabolism of EL-4 cells To understand why a build-up of branched-chain amino acids (BCAAs) correlated with reduced tumour growth in BCATmKO mice, we studied the impact of one of the BCAAs on the growth of EL-4 cells in vitro
Summary
The mitochondrial branched-chain aminotransferase (BCATm) is a recently discovered cancer marker with a poorly defined role in tumour progression. METHODS: To understand how a loss of function of BCATm affects cancer, the global knockout mouse BCATmKO was challenged with EL-4 lymphoma under different diet compositions with varying amounts of branched-chain amino acids (BCAAs). RESULTS: BCATmKO mice experienced delayed tumour growth when fed standard rodent chow or a normal BCAA diet. Known to influence muscle protein synthesis, insulin resistance, and brain amino acid uptake, BCAAs are considered important sources of carbon metabolites, nitrogen, and energy for cancer growth.[1,2,3,4,5] The enzymes catalysing the first step in BCAA degradation (cytosolic and mitochondrial branched-chain aminotransferases, BCATc and BCATm, respectively) are recognised as prognostic tumour markers in several cancer types.[6,7,8,9,10,11] These enzymes catalyse the reversible transamination of BCAAs, which comprises a transfer of the α-amino group of a BCAA to α-ketoglutarate to form glutamate and the respective branched-chain α-keto-acid (BCKA).[12,13] Extraction of nitrogen from BCAAs for the synthesis of glutamine and nucleotides was reported in lung and pancreatic tumours, as well as, glioblastomas.[7,14,15] The release of BCKAs, on the other hand, had antiproliferative effects on blast crisis chronic myeloid leukaemia.[16]
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