title: Pharmacological inhibition of fatty-acid oxidation synergistically enhances the effect of l-asparaginase in childhood ALL cells.
abstract: 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.
authors.affiliation: CLIP-Childhood Leukaemia Investigation Prague, Department of Pediatric Hematology/Oncology, Charles University Prague, Prague, Czech Republic.
authors.forename: I
authors.initials: I
authors.lastname: Hermanova
authors.affiliation: CIC bioGUNE Technology Park of Bizkaia, Derio, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Arruabarrena-Aristorena
authors.affiliation: Laboratory of Structural Biology and Cell Signaling, Institute of Microbiology, Academy of Sciences of the Czech Republic, Prague, Czech Republic.|Department of Biochemistry, Charles University, Prague, Czech Republic.
authors.forename: K
authors.initials: K
authors.lastname: Valis
authors.affiliation: Department of Bioenergetics, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic.
authors.forename: H
authors.initials: H
authors.lastname: Nuskova
authors.affiliation: Laboratory of Molecular Immunology, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic.
authors.forename: M
authors.initials: M
authors.lastname: Alberich-Jorda
authors.affiliation: CLIP-Childhood Leukaemia Investigation Prague, Department of Pediatric Hematology/Oncology, Charles University Prague, Prague, Czech Republic.
authors.forename: K
authors.initials: K
authors.lastname: Fiser
authors.affiliation: CIC bioGUNE Technology Park of Bizkaia, Derio, Spain.
authors.forename: S
authors.initials: S
authors.lastname: Fernandez-Ruiz
authors.affiliation: Laboratory of Structural Biology and Cell Signaling, Institute of Microbiology, Academy of Sciences of the Czech Republic, Prague, Czech Republic.|Department of Biochemistry, Charles University, Prague, Czech Republic.
authors.forename: D
authors.initials: D
authors.lastname: Kavan
authors.affiliation: Department of Bioenergetics, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic.
authors.forename: A
authors.initials: A
authors.lastname: Pecinova
authors.affiliation: Equipe 11 labellisée par la Ligue Nationale Contre le Cancer; INSERM U1138; Centre de Recherche des Cordeliers, Paris, France.|Metabolomics and Molecular Cell Biology Platforms; Gustave Roussy, Villejuif, France.
authors.forename: M
authors.initials: M
authors.lastname: Niso-Santano
authors.affiliation: CLIP-Childhood Leukaemia Investigation Prague, Department of Pediatric Hematology/Oncology, Charles University Prague, Prague, Czech Republic.
authors.forename: M
authors.initials: M
authors.lastname: Zaliova
authors.affiliation: Laboratory of Structural Biology and Cell Signaling, Institute of Microbiology, Academy of Sciences of the Czech Republic, Prague, Czech Republic.|Department of Biochemistry, Charles University, Prague, Czech Republic.
authors.forename: P
authors.initials: P
authors.lastname: Novak
authors.affiliation: Department of Bioenergetics, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic.
authors.forename: J
authors.initials: J
authors.lastname: Houstek
authors.affiliation: Department of Bioenergetics, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic.
authors.forename: T
authors.initials: T
authors.lastname: Mracek
authors.affiliation: Equipe 11 labellisée par la Ligue Nationale Contre le Cancer; INSERM U1138; Centre de Recherche des Cordeliers, Paris, France.|Metabolomics and Molecular Cell Biology Platforms; Gustave Roussy, Villejuif, France.|Pôle de Biologie; Hôpital Européen Georges Pompidou; AP-HP, Paris, France.|Université Paris Descartes; Sorbonne Paris Cité, Paris, France.
authors.forename: G
authors.initials: G
authors.lastname: Kroemer
authors.affiliation: CIC bioGUNE Technology Park of Bizkaia, Derio, Spain.|Ikerbasque, Basque Foundation for Science, Bilbao, Spain.|Department of Biochemistry and Molecular biology, University of the Basque Country, Leioa, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Carracedo
authors.affiliation: CLIP-Childhood Leukaemia Investigation Prague, Department of Pediatric Hematology/Oncology, Charles University Prague, Prague, Czech Republic.|University Hospital Motol, Prague, Czech Republic.
authors.forename: J
authors.initials: J
authors.lastname: Trka
authors.affiliation: CLIP-Childhood Leukaemia Investigation Prague, Department of Pediatric Hematology/Oncology, Charles University Prague, Prague, Czech Republic.
authors.forename: J
authors.initials: J
authors.lastname: Starkova
mesh_terms: D001215:Asparaginase / Q000627:therapeutic use*; D001343:Autophagy / Q000187:drug effects; D045744:Cell Line, Tumor; D005227:Fatty Acids / Q000378:metabolism*; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D020559:Monomeric GTP-Binding Proteins / Q000502:physiology; D046912:Multiprotein Complexes / Q000502:physiology; D010084:Oxidation-Reduction; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011743:Pyrimidines / Q000096:biosynthesis; D058570:TOR Serine-Threonine Kinases / Q000502:physiology
chemical_list: D005227:Fatty Acids; D046912:Multiprotein Complexes; D011743:Pyrimidines; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D001215:Asparaginase; D020559:Monomeric GTP-Binding Proteins