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Leukemia. 2016 Jan;30(1):209-18. doi: 10.1038/leu.2015.213. Epub 2015 Aug 4.

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

Author information

1
CLIP-Childhood Leukaemia Investigation Prague, Department of Pediatric Hematology/Oncology, Charles University Prague, Prague, Czech Republic.
2
CIC bioGUNE Technology Park of Bizkaia, Derio, Spain.
3
Laboratory of Structural Biology and Cell Signaling, Institute of Microbiology, Academy of Sciences of the Czech Republic, Prague, Czech Republic.
4
Department of Biochemistry, Charles University, Prague, Czech Republic.
5
Department of Bioenergetics, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic.
6
Laboratory of Molecular Immunology, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic.
7
Equipe 11 labellisée par la Ligue Nationale Contre le Cancer; INSERM U1138; Centre de Recherche des Cordeliers, Paris, France.
8
Metabolomics and Molecular Cell Biology Platforms; Gustave Roussy, Villejuif, France.
9
Pôle de Biologie; Hôpital Européen Georges Pompidou; AP-HP, Paris, France.
10
Université Paris Descartes; Sorbonne Paris Cité, Paris, France.
11
Ikerbasque, Basque Foundation for Science, Bilbao, Spain.
12
Department of Biochemistry and Molecular biology, University of the Basque Country, Leioa, Spain.
13
University Hospital Motol, Prague, Czech Republic.

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.

PMID:
26239197
DOI:
10.1038/leu.2015.213
[Indexed for MEDLINE]

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