glutaminase and Leukemia--Myelomonocytic--Acute

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.

Topics: Adult; Aged; Aged, 80 and over; Amino Acid Transport System ASC; Animals; Apoptosis; Asparaginase; Autophagy; Bacterial Proteins; Biological Transport; Cell Line, Tumor; Dickeya chrysanthemi; Drug Screening Assays, Antitumor; Escherichia coli Proteins; Female; Glutaminase; Glutamine; Humans; Leukemia, Myeloid, Acute; Leukemia, Myelomonocytic, Acute; Male; Mechanistic Target of Rapamycin Complex 1; Mice; Mice, Nude; Middle Aged; Minor Histocompatibility Antigens; Multiprotein Complexes; Protein Biosynthesis; RNA Interference; RNA, Small Interfering; Signal Transduction; TOR Serine-Threonine Kinases; Xenograft Model Antitumor Assays; Young Adult