Rewired glutamate metabolism diminishes cytostatic action of L-asparaginase
Language English Country Ireland Media print-electronic
Document type Journal Article
PubMed
39270769
DOI
10.1016/j.canlet.2024.217242
PII: S0304-3835(24)00637-2
Knihovny.cz E-resources
- MeSH
- Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy metabolism pathology MeSH
- Asparaginase * pharmacology metabolism MeSH
- Citric Acid Cycle drug effects MeSH
- Glutamine metabolism MeSH
- Glutathione * metabolism MeSH
- Glutamic Acid * metabolism MeSH
- Humans MeSH
- Mice MeSH
- Cell Line, Tumor MeSH
- Antineoplastic Agents pharmacology MeSH
- Xenograft Model Antitumor Assays MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Asparaginase * MeSH
- Glutamine MeSH
- Glutathione * MeSH
- Glutamic Acid * MeSH
- Antineoplastic Agents MeSH
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.
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