2. Academic Validation
  3. Rewired glutamate metabolism diminishes cytostatic action of L-asparaginase

Rewired glutamate metabolism diminishes cytostatic action of L-asparaginase

  • Cancer Lett. 2024 Sep 11:605:217242. doi: 10.1016/j.canlet.2024.217242.
Katerina Hlozkova 1,  Maryna Vasylkivska 2,  Adam Boufersaoui 3,  Bryan Marzullo 3,  Matus Kolarik 4,  Natividad Alquezar-Artieda 2,  Mehak Shaikh 5,  Nadia Fatemeh Alaei 6,  Marketa Zaliova 7,  Martina Zwyrtkova 2,  Violeta Bakardijeva-Mihaylova 2,  Meritxell Alberich-Jorda 6,  Jan Trka 7,  Daniel A Tennant 3,  Julia Starkova 8
Affiliations

Affiliations

  • 1 Childhood Leukaemia Investigation Prague, Prague, Czech Republic; Second Faculty of Medicine, Department of Pediatric Hematology and Oncology, Charles University, Prague, Czech Republic. Electronic address: katerina.hlozkova@lfmotol.cuni.cz.
  • 2 Childhood Leukaemia Investigation Prague, Prague, Czech Republic; Second Faculty of Medicine, Department of Pediatric Hematology and Oncology, Charles University, Prague, Czech Republic.
  • 3 Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.
  • 4 Childhood Leukaemia Investigation Prague, Prague, Czech Republic; Second Faculty of Medicine, Department of Pediatric Hematology and Oncology, Charles University, Prague, Czech Republic; First Faculty of Medicine, Charles University, Prague, Czech Republic.
  • 5 Laboratory of Hemato-Oncology, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic.
  • 6 Childhood Leukaemia Investigation Prague, Prague, Czech Republic; Second Faculty of Medicine, Department of Pediatric Hematology and Oncology, Charles University, Prague, Czech Republic; Laboratory of Hemato-Oncology, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic.
  • 7 Childhood Leukaemia Investigation Prague, Prague, Czech Republic; Second Faculty of Medicine, Department of Pediatric Hematology and Oncology, Charles University, Prague, Czech Republic; University Hospital Motol, Prague, Czech Republic.
  • 8 Childhood Leukaemia Investigation Prague, Prague, Czech Republic; Second Faculty of Medicine, Department of Pediatric Hematology and Oncology, Charles University, Prague, Czech Republic; University Hospital Motol, Prague, Czech Republic. Electronic address: julia.starkova@lfmotol.cuni.cz.
PMID: 39270769 DOI: 10.1016/j.canlet.2024.217242
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.

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