Pecina 2015 Abstract MiP2015

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

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Hermanova I, Arruabarrena-Aristorena A, Valis K, Nuskova H, Jorda MA, Fiser K, Fernandez-Ruiz S, Kavan D, Pecinova A, Niso-Santano M, Zaliova M, Pecina P, Novak P, Houstek J, Mracek T, Kroemer G, Carracedo A, Trka J, Starkova J (2015)

Event: MiP2015

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.


O2k-Network Lab: CZ Prague Houstek J


Labels: MiParea: Respiration, Instruments;methods, nDNA;cell genetics, Pharmacology;toxicology  Pathology: Cancer  Stress:Cell death  Organism: Human 




Event: A2  MiP2015 

Affiliations

1-CLIP-Childhood Leukaemia Investigation Prague, Dept Pediatric Hematology/Oncology, Charles Univ Prague and Univ Hospital Motol, Prague; 2-CIC bioGUNE Technology Park Bizkaia, Derio, Spain; 3-Lab Structural Biol Cell Signaling, Inst Microbiol, CAS, Prague; 4-Dept Biochem, Charles Univ, Prague; 5-Dept Bioenergetics, Inst Physiology CAS, Prague; 6-Lab Molecular Immunology, Inst Molecular Genetics CAS, Prague; 7-Equipe 11 labellisée par la Ligue Nat Contre le Cancer; INSERM; Centre Recherche Cordeliers, Paris, France; 8-Metabolomics Mol Cell Biol Platforms, Gustave Roussy, Villejuif, France; 9-Pôle Biologie; Hôpital Européen Georges Pompidou, AP-HP, Paris, France; 10-Univ Paris Descartes; Sorbonne Paris Cité, Paris, France; 11-Ikerbasque, Basque Foundation Sc, Bilbao, Spain; 12-Dept Biochem Mol Bio, Univ Basque Country, Leioa, Spain; 13-Univ Hospital Motol, Prague, Czech Republic. - petr.pecina@fgu.cas.cz

Acknowledgements

This work was recently published: Heřmanová I, et al., Pharmacological inhibition of fatty acid oxidation synergistically enhances the effect of L-asparaginase in childhood ALL cells. Leukemia. 2015 Aug 4. PMID: 26239197. Research relating to this abstract was funded by the Grant Agency of the Ministry of Health of the Czech Republic (NT12370-5) and the Grant Agency of the Czech Republic (14-36804G).