Work

Rewired glutamate metabolism diminishes cytostatic action of L-asparaginase

Year: 2024

Type: article

Abstract: Tumor cells often adapt to amino acid deprivation through metabolic rewiring, compensating for the loss with alternative amino acids/substrates. We have described such a scenario in leukemic cells treated with L-asparaginase (ASNase). Clinical effect of ASNase is based on nutrient stress achieved by its dual enzymatic action which leads to depletion of asparagine and glutamine and is accompanied with elevated aspartate and glutamate concentrations in serum of acute lymphoblastic leukemia patients. We showed that in these limited conditions glutamate uptake compensates for the loss of glutamine availability. Extracellular glutamate flux detection confirms its integration into the TCA cycle and its participation in nucleotide and glutathione synthesis. Importantly, it is glutamate-driven de novo synthesis of glutathione which is the essential metabolic pathway necessary for glutamate's pro-survival effect. In vivo findings support this effect by showing that inhibition of glutamate transporters enhances the therapeutic effect of ASNase. In summary, ASNase induces elevated extracellular glutamate levels under nutrient stress, which leads to a rewiring of intracellular glutamate metabolism and has a negative impact on ASNase treatment. • A novel mechanism of action involving the by-product glutamate in the anti-leukemic effect of L-asparaginase. • Glutamate compensates for glutamine loss after L-asparaginase treatment. • Transported glutamate boosts TCA cycle, enhances nucleotide and de novo glutathione synthesis.

Source: Cancer Letters

DOI: 10.1016/j.canlet.2024.217242