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.
Publication types
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Adult
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Aged
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Aged, 80 and over
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Amino Acid Transport System ASC / antagonists & inhibitors
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Amino Acid Transport System ASC / genetics
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Animals
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Apoptosis / drug effects
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Asparaginase / isolation & purification
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Asparaginase / pharmacology
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Autophagy / drug effects
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Bacterial Proteins / pharmacology
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Biological Transport / drug effects
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Cell Line, Tumor / drug effects
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Cell Line, Tumor / metabolism
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Dickeya chrysanthemi / enzymology
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Drug Screening Assays, Antitumor
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Escherichia coli Proteins / pharmacology
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Female
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Glutaminase / isolation & purification
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Glutaminase / pharmacology
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Glutamine / antagonists & inhibitors*
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Glutamine / metabolism
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Humans
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Leukemia, Myeloid, Acute / drug therapy*
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Leukemia, Myeloid, Acute / metabolism
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Leukemia, Myeloid, Acute / pathology
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Leukemia, Myelomonocytic, Acute / drug therapy
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Leukemia, Myelomonocytic, Acute / metabolism
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Male
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Mechanistic Target of Rapamycin Complex 1
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Mice
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Mice, Nude
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Middle Aged
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Minor Histocompatibility Antigens
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Multiprotein Complexes / antagonists & inhibitors
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Protein Biosynthesis / drug effects
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RNA Interference
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RNA, Small Interfering / pharmacology
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RNA, Small Interfering / therapeutic use
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Signal Transduction / drug effects
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TOR Serine-Threonine Kinases / antagonists & inhibitors
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Xenograft Model Antitumor Assays
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Young Adult
Substances
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Amino Acid Transport System ASC
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Bacterial Proteins
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Escherichia coli Proteins
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Minor Histocompatibility Antigens
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Multiprotein Complexes
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RNA, Small Interfering
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SLC1A5 protein, human
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Glutamine
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Mechanistic Target of Rapamycin Complex 1
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TOR Serine-Threonine Kinases
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Asparaginase
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Glutaminase