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Pharmacological inhibition of fatty-acid oxidation synergistically enhances the effect of l-asparaginase in childhood ALL cells

Hermanova, I
Author Hermanova, I CLIP-Childhood Leukaemia Investigation Prague, Department of Pediatric Hematology/Oncology, Charles University Prague, Prague, Czech Republic
Arruabarrena-Aristorena, A
Author Arruabarrena-Aristorena, A CIC bioGUNE Technology Park of Bizkaia, Derio, Spain
Valis, K
Author Valis, K 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
Nuskova, H
Author Nuskova, H Department of Bioenergetics, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic
Alberich-Jorda, M
Author Alberich-Jorda, M Laboratory of Molecular Immunology, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic
Fiser, K
Author Fiser, K CLIP-Childhood Leukaemia Investigation Prague, Department of Pediatric Hematology/Oncology, Charles University Prague, Prague, Czech Republic
Fernandez-Ruiz, S
Author Fernandez-Ruiz, S CIC bioGUNE Technology Park of Bizkaia, Derio, Spain
Kavan, D
Author Kavan, D 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
Pecinova, A
Author Pecinova, A Department of Bioenergetics, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic
Niso-Santano, M
Author Niso-Santano, M 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
Zaliova, M
Author Zaliova, M CLIP-Childhood Leukaemia Investigation Prague, Department of Pediatric Hematology/Oncology, Charles University Prague, Prague, Czech Republic
Novak, P
Author Novak, P 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
Houstek, J
Author Houstek, J Department of Bioenergetics, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic
Mracek, T
Author Mracek, T Department of Bioenergetics, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic
Kroemer, G
Author Kroemer, G 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
Carracedo, A
Author Carracedo, A 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
Trka, J
Author Trka, J CLIP-Childhood Leukaemia Investigation Prague, Department of Pediatric Hematology/Oncology, Charles University Prague, Prague, Czech Republic University Hospital Motol, Prague, Czech Republic
Starkova, J
Author Starkova, J CLIP-Childhood Leukaemia Investigation Prague, Department of Pediatric Hematology/Oncology, Charles University Prague, Prague, Czech Republic

Leukemia. 2016 Jan ; 30 (1) : 209-18. [epub] 20150804

ISSN 1476-5551 | 0887-6924
Source

Language English Country Great Britain, England Media print-electronic

Document type Journal Article, Research Support, Non-U.S. Gov't

Persistent link https://www.medvik.cz/link/pmid26239197

PubMed 26239197
DOI 10.1038/leu.2015.213
PII: leu2015213
Knihovny.cz E-resources

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

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.

CIC bioGUNE Technology Park of Bizkaia Derio Spain

CLIP Childhood Leukaemia Investigation Prague Department of Pediatric Hematology Oncology Charles University Prague Prague Czech Republic

Department of Biochemistry and Molecular biology University of the Basque Country Leioa Spain

Department of Biochemistry Charles University Prague Czech Republic

Department of Bioenergetics Institute of Physiology of the Czech Academy of Sciences Prague Czech Republic

Equipe 11 labellisée par la Ligue Nationale Contre le Cancer; INSERM U1138; Centre de Recherche des Cordeliers Paris France

Ikerbasque Basque Foundation for Science Bilbao Spain

Laboratory of Molecular Immunology Institute of Molecular Genetics of the Czech Academy of Sciences Prague Czech Republic

Laboratory of Structural Biology and Cell Signaling Institute of Microbiology Academy of Sciences of the Czech Republic Prague Czech Republic

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