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
• Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy   metabolism   pathology   MeSH
• Asparaginase therapeutic use   MeSH
• Autophagy drug effects   MeSH
• Humans MeSH
• Fatty Acids metabolism   MeSH
• Monomeric GTP-Binding Proteins physiology   MeSH
• Mechanistic Target of Rapamycin Complex 1 MeSH
• Multiprotein Complexes physiology   MeSH
• Cell Line, Tumor MeSH
• Oxidation-Reduction MeSH
• Pyrimidines biosynthesis   MeSH
• TOR Serine-Threonine Kinases physiology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Asparaginase MeSH
• Fatty Acids MeSH
• Monomeric GTP-Binding Proteins MeSH
• Mechanistic Target of Rapamycin Complex 1 MeSH
• Multiprotein Complexes MeSH
• Pyrimidines MeSH
• TOR Serine-Threonine Kinases MeSH