title: Inhibiting glutamine uptake represents an attractive new strategy for treating acute myeloid leukemia.
abstract: Cancer cells require nutrients and energy to adapt to increased biosynthetic activity, and protein synthesis inhibition downstream of mammalian target of rapamycin complex 1 (mTORC1) has shown promise as a possible therapy for acute myeloid leukemia (AML). Glutamine contributes to leucine import into cells, which controls the amino acid/Rag/mTORC1 signaling pathway. We show in our current study that glutamine removal inhibits mTORC1 and induces apoptosis in AML cells. The knockdown of the SLC1A5 high-affinity transporter for glutamine induces apoptosis and inhibits tumor formation in a mouse AML xenotransplantation model. l-asparaginase (l-ase) is an anticancer agent also harboring glutaminase activity. We show that l-ases from both Escherichia coli and Erwinia chrysanthemi profoundly inhibit mTORC1 and protein synthesis and that this inhibition correlates with their glutaminase activity levels and produces a strong apoptotic response in primary AML cells. We further show that l-ases upregulate glutamine synthase (GS) expression in leukemic cells and that a GS knockdown enhances l-ase-induced apoptosis in some AML cells. Finally, we observe a strong autophagic process upon l-ase treatment. These results suggest that l-ase anticancer activity and glutamine uptake inhibition are promising new therapeutic strategies for AML.
authors.affiliation: Unité Fonctionnelle d'Hématologie, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, Paris, France;
authors.forename: Lise
authors.initials: L
authors.lastname: Willems
authors.forename: Nathalie
authors.initials: N
authors.lastname: Jacque
authors.forename: Arnaud
authors.initials: A
authors.lastname: Jacquel
authors.forename: Nathalie
authors.initials: N
authors.lastname: Neveux
authors.forename: Thiago Trovati
authors.initials: TT
authors.lastname: Maciel
authors.forename: Mireille
authors.initials: M
authors.lastname: Lambert
authors.forename: Alain
authors.initials: A
authors.lastname: Schmitt
authors.forename: Laury
authors.initials: L
authors.lastname: Poulain
authors.forename: Alexa S
authors.initials: AS
authors.lastname: Green
authors.forename: Madalina
authors.initials: M
authors.lastname: Uzunov
authors.forename: Olivier
authors.initials: O
authors.lastname: Kosmider
authors.forename: Isabelle
authors.initials: I
authors.lastname: Radford-Weiss
authors.forename: Ivan Cruz
authors.initials: IC
authors.lastname: Moura
authors.forename: Patrick
authors.initials: P
authors.lastname: Auberger
authors.forename: Norbert
authors.initials: N
authors.lastname: Ifrah
authors.forename: Valérie
authors.initials: V
authors.lastname: Bardet
authors.forename: Nicolas
authors.initials: N
authors.lastname: Chapuis
authors.forename: Catherine
authors.initials: C
authors.lastname: Lacombe
authors.forename: Patrick
authors.initials: P
authors.lastname: Mayeux
authors.forename: Jérôme
authors.initials: J
authors.lastname: Tamburini
authors.forename: Didier
authors.initials: D
authors.lastname: Bouscary
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D026962:Amino Acid Transport System ASC / Q000037:antagonists & inhibitors / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001215:Asparaginase / Q000302:isolation & purification / Q000494:pharmacology; D001343:Autophagy / Q000187:drug effects; D001426:Bacterial Proteins / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects; D045744:Cell Line, Tumor / Q000187:drug effects / Q000378:metabolism; D016974:Dickeya chrysanthemi / Q000201:enzymology; D004354:Drug Screening Assays, Antitumor; D029968:Escherichia coli Proteins / Q000494:pharmacology; D005260:Female; D005972:Glutaminase / Q000302:isolation & purification / Q000494:pharmacology; D005973:Glutamine / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015479:Leukemia, Myelomonocytic, Acute / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D015778:Minor Histocompatibility Antigens; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors; D014176:Protein Biosynthesis / Q000187:drug effects; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D023041:Xenograft Model Antitumor Assays; D055815:Young Adult
chemical_list: D026962:Amino Acid Transport System ASC; D001426:Bacterial Proteins; D029968:Escherichia coli Proteins; D015778:Minor Histocompatibility Antigens; D046912:Multiprotein Complexes; D034741:RNA, Small Interfering; C420506:SLC1A5 protein, human; D005973:Glutamine; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D001215:Asparaginase; D005972:Glutaminase