Rewired glutamate metabolism diminishes cytostatic action of L-asparaginase

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F68378050%3A_____%2F24%3A00601829" target="_blank" >RIV/68378050:_____/24:00601829 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/00064203:_____/24:10485001 RIV/00216208:11130/24:10485001 RIV/00216208:11110/24:10485001

Výsledek na webu

<a href="https://www.sciencedirect.com/science/article/pii/S0304383524006372?via%3Dihub" target="_blank" >https://www.sciencedirect.com/science/article/pii/S0304383524006372?via%3Dihub</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.canlet.2024.217242" target="_blank" >10.1016/j.canlet.2024.217242</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Rewired glutamate metabolism diminishes cytostatic action of L-asparaginase

Popis výsledku v původním jazyce

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.

Název v anglickém jazyce

Rewired glutamate metabolism diminishes cytostatic action of L-asparaginase

Popis výsledku anglicky

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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30204 - Oncology

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2024

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Cancer letters

ISSN

0304-3835

e-ISSN

1872-7980

Svazek periodika

605

Číslo periodika v rámci svazku

Nov

Stát vydavatele periodika

IE - Irsko

Počet stran výsledku

13

Strana od-do

217242

Kód UT WoS článku

001344129200001

EID výsledku v databázi Scopus

2-s2.0-85206902024