α-Ketoglutarate promotes amino acid depletion and suppresses B-cell lymphoma growth and development Available to Purchase

• αKG induces leucine catabolism in a BCAT2–dependent manner, suppresses mTORC1, and displays antilymphoma properties in vitro and in vivo.

• Toxicity-free dietary supplementation of αKG hinders lymphoma development in vivo in association with suppression of energy metabolism.

Targeting metabolic dependencies and “starving” malignant cells have long been considered 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 α-ketoglutarate (αKG) as a nitrogen acceptor, and accumulation of the competitive inhibitor metabolite D-2-hydroxyglutarate 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 mammalian target of rapamycin complex 1 (mTORC1) subcellular 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 branched-chain amino acid transaminase 2 deletion, all blunted the antilymphoma 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 life span in mice, also encodes marked anticancer properties.