Inhibiting glutamine uptake represents an attractive new strategy for treating acute myeloid leukemia.

Publisher: Elsevier Country of Publication: United States NLM ID: 7603509 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1528-0020 (Electronic) Linking ISSN: 00064971 NLM ISO Abbreviation: Blood Subsets: MEDLINE

Publication: 2021- : [New York] : Elsevier
Original Publication: New York, Grune & Stratton [etc.]

Glutamine/*antagonists & inhibitors ; Leukemia, Myeloid, Acute/*drug therapy; Adult ; Aged ; Aged, 80 and over ; Amino Acid Transport System ASC/antagonists & inhibitors ; Amino Acid Transport System ASC/genetics ; Animals ; Apoptosis/drug effects ; Asparaginase/isolation & purification ; Asparaginase/pharmacology ; Autophagy/drug effects ; Bacterial Proteins/pharmacology ; Biological Transport/drug effects ; Cell Line, Tumor/drug effects ; Cell Line, Tumor/metabolism ; Dickeya chrysanthemi/enzymology ; Drug Screening Assays, Antitumor ; Escherichia coli Proteins/pharmacology ; Female ; Glutaminase/isolation & purification ; Glutaminase/pharmacology ; Glutamine/metabolism ; Humans ; Leukemia, Myeloid, Acute/metabolism ; Leukemia, Myeloid, Acute/pathology ; Leukemia, Myelomonocytic, Acute/drug therapy ; Leukemia, Myelomonocytic, Acute/metabolism ; Male ; Mechanistic Target of Rapamycin Complex 1 ; Mice ; Mice, Nude ; Middle Aged ; Minor Histocompatibility Antigens ; Multiprotein Complexes/antagonists & inhibitors ; Protein Biosynthesis/drug effects ; RNA Interference ; RNA, Small Interfering/pharmacology ; RNA, Small Interfering/therapeutic use ; Signal Transduction/drug effects ; TOR Serine-Threonine Kinases/antagonists & inhibitors ; Xenograft Model Antitumor Assays ; Young Adult

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.

Comment in: Blood. 2013 Nov 14;122(20):3398-400. (PMID: 24235130)

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0 (Amino Acid Transport System ASC)
0 (Bacterial Proteins)
0 (Escherichia coli Proteins)
0 (Minor Histocompatibility Antigens)
0 (Multiprotein Complexes)
0 (RNA, Small Interfering)
0 (SLC1A5 protein, human)
0RH81L854J (Glutamine)
EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
EC 2.7.11.1 (TOR Serine-Threonine Kinases)
EC 3.5.1.1 (Asparaginase)
EC 3.5.1.2 (Glutaminase)

Date Created: 20130910 Date Completed: 20140116 Latest Revision: 20220316

20221213

PMC3829119

10.1182/blood-2013-03-493163

24014241