l-asparaginase (ASNase), a key component in the treatment of childhood acute lymphoblastic leukemia (ALL), hydrolyzes plasma asparagine and glutamine and thereby disturbs metabolic homeostasis of leukemic cells. The efficacy of such therapeutic strategy will depend on the capacity of cancer cells to adapt to the metabolic challenge, which could relate to the activation of compensatory metabolic routes. Therefore, we studied the impact of ASNase on the main metabolic pathways in leukemic cells. Treating leukemic cells with ASNase increased fatty-acid oxidation (FAO) and cell respiration and inhibited glycolysis. FAO, together with the decrease in protein translation and pyrimidine synthesis, was positively regulated through inhibition of the RagB-mTORC1 pathway, whereas the effect on glycolysis was RagB-mTORC1 independent. As FAO has been suggested to have a pro-survival function in leukemic cells, we tested its contribution to cell survival following ASNase treatment. Pharmacological inhibition of FAO significantly increased the sensitivity of ALL cells to ASNase. Moreover, constitutive activation of the mammalian target of rapamycin pathway increased apoptosis in leukemic cells treated with ASNase, but did not increase FAO. Our study uncovers a novel therapeutic option based on the combination of ASNase and FAO inhibitors.

• MeSH
• akutní lymfatická leukemie farmakoterapie   metabolismus   patologie   MeSH
• asparaginasa terapeutické užití   MeSH
• autofagie účinky léků   MeSH
• lidé MeSH
• mastné kyseliny metabolismus   MeSH
• monomerní proteiny vázající GTP fyziologie   MeSH
• mTORC1 MeSH
• multiproteinové komplexy fyziologie   MeSH
• nádorové buněčné linie MeSH
• oxidace-redukce MeSH
• pyrimidiny biosyntéza   MeSH
• TOR serin-threoninkinasy fyziologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• asparaginasa MeSH
• mastné kyseliny MeSH
• monomerní proteiny vázající GTP MeSH
• mTORC1 MeSH
• multiproteinové komplexy MeSH
• pyrimidiny MeSH
• TOR serin-threoninkinasy MeSH