Mice deficient in the mitochondrial branched-chain aminotransferase (BCATm) respond with delayed tumour growth to a challenge with EL-4 lymphoma. Br J Cancer 2018 Oct;119(8):1009-1017
Date
10/16/2018Pubmed ID
30318512Pubmed Central ID
PMC6203766DOI
10.1038/s41416-018-0283-7Scopus ID
2-s2.0-85054920901 (requires institutional sign-in at Scopus site) 15 CitationsAbstract
BACKGROUND: 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). Next, the growth and metabolism of EL-4 cells were studied in the presence of different leucine concentrations in the growth medium.
RESULTS: BCATmKO 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.
CONCLUSIONS: Global 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.
Author List
Ananieva EA, Bostic JN, Torres AA, Glanz HR, McNitt SM, Brenner MK, Boyer MP, Addington AK, Hutson SMAuthor
Michelle Brenner in the CTSI department at Medical College of Wisconsin - CTSIMESH terms used to index this publication - Major topics in bold
AMP-Activated Protein KinasesAmino Acids, Branched-Chain
Animals
Disease Progression
Female
Lymphoma
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Mitochondria
Neoplasm Transplantation
Phosphorylation
Transaminases
