Mice deficient in the mitochondrial branched-chain aminotransferase (BCATm) respond with delayed tumour growth to a challenge with EL-4 lymphoma

Abstract

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.

An amino acid-defined diet impairs tumour growth in mice by promoting endoplasmic reticulum stress and mTOR inhibition

“…For example, Ananieva et al. showed that BCATm knock-out mice, which display high levels of circulating BCAAs, have a reduced tumour growth; of note, in their animals, mTORC1 was not upregulated [ 82 ]. On the contrary, elevated concentrations of BCAAs have led to increased tumour growth when associated with upregulation of mTORC1 activity [ 83 ].…”

Amino acid sensor GCN2 promotes SARS-CoV-2 receptor ACE2 expression in response to amino acid deprivation

“…1 ). However, incubation with three-fold amounts of EAAs 26 had no effect on the ACE2 or p-EIF2A expression levels (Supplementary Fig. 2 ), indicating that ACE2 responded particularly to amino acid deficiency.…”

The emerging role of the branched chain aminotransferases, BCATc and BCATm, for anti-tumor T-cell immunity

“… Comparison of leucine catabolism in immune and cancer cells . The two reactions in leucine catabolism, transamination, and irreversible oxidation, were compared as a percent distribution in T cells, microphages, and cancer cells based on unpublished and published reports [ 54 , 69 , 70 ] . co-Stim: anti-CD3 and anti-CD28 co-stimulated mouse CD4 + T cells; EL4: murine T-cell lymphoma; LPS: lipopolysaccharide stimulated Raw 264.7 macrophages; SCLC: murine small-cell lung cancer; TCR, anti-CD3 stimulated CD4 + mouse T cells; un-stim: unstimulated murine CD4 + T cells or Raw 264.7 macrophages.…”

“…Some published data and ongoing research suggest that the BCAT isoenzymes may exert immunosuppressive functions in the TME [ 12 – 14 , 48 , 54 , 70 ] . As described in Ananieva’s reports, the BCAT isoenzymes might be a part of a critical resistance mechanism that involves a BCAT-dependent negative feedback regulation of mTORC1 signaling during T-cell activation and may serve as an essential metabolic checkpoint of T-cell function in TME [ 48 , 54 ] .…”

“…In contrast to the increasing interest of BCATc in immunity, the only study that provides experimental findings regarding the role of BCATm in immune cells dates to 2014 where BCATm is described as a constitutively expressed transaminase supporting mitochondrial BCAA catabolism in CD4 + T cells [ 54 ] . Oppositely, there is a well-established experimental evidence on BCATm being expressed in cancers of different origins and its role as a prognostic cancer marker [ 16 , 17 , 70 ] . A report by Conway and co-authors [ 92 ] shows that the protein expression of BCATm, along with that of BCATc, is increased in human specimens isolated from IDH-WT gliomas compared to normal brain tissues.…”