α-Ketoglutarate promotes amino acid depletion and suppresses B-cell lymphoma growth and development.

Targeting metabolic dependencies and "starving" malignant cells have long been considered as potential strategies to treat cancer. However, with rare exceptions, the implementation of these maneuvers has been fraught with limited activity and lack of specificity. Multiple cytoplasmic and mitochondrial transaminases catalyze reactions that lead to amino acid catabolism. These enzymes use alpha-ketoglutarate (αKG) as a nitrogen acceptor, and accumulation of the competitive inhibitor metabolite D-2-HG perturbs their function. We postulated that exogenous αKG supplementation would influence the directionality of these reactions and deplete amino acids in cancer cells. Using B cell lymphoma as a model system, we found that αKG mediates a rapid and sustained amino acid depletion, principally of aspartate and branched-chain leucine, valine and isoleucine. The decrease in leucine levels influenced MTORC1 sub-cellular movement, suppressed its activity and associated with inhibition of B cell lymphoma growth in vitro and in vivo Increasing import of aspartate or leucine levels in the lymphoma cells, genetically forcing MTORC1 lysosomal localization or blocking leucine catabolism through BCAT2 deletion, all blunted the anti-lymphoma effects of αKG. In addition, long term dietary supplementation of αKG, a toxicity free strategy, significantly hindered lymphoma development in Eµ-Myc mice, in association with amino acid perturbation and impaired energy generation. We posit that αKG supplementation, which has been shown to improve health and lifespan in mice, also encodes marked anti-cancer properties.