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Inhibiting glutamine uptake represents an attractive new strategy for treating acute myeloid leukemia
Lise Willems1, Nathalie Jacque, Arnaud Jacquel
1Unité Fonctionnelle d'Hématologie, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, Paris, France;
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.
Insights
Inhibition of glutamine uptake and protein synthesis shows promise for treating acute myeloid leukemia (AML). L-asparaginase (l-ase) effectively targets cancer cells by blocking glutamine, inducing apoptosis in AML.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Acute myeloid leukemia (AML) cells rely on nutrients for growth and proliferation.
- Mammalian target of rapamycin complex 1 (mTORC1) signaling is crucial for cancer cell adaptation.
- Glutamine uptake influences leucine import and the mTORC1 pathway.
Purpose of the Study:
- To investigate the role of glutamine in AML cell survival and proliferation.
- To evaluate the therapeutic potential of glutamine deprivation and l-asparaginase (l-ase) in AML.
Main Methods:
- Studied the effects of glutamine removal and SLC1A5 transporter knockdown on AML cells.
- Assessed the impact of bacterial l-asparaginase (from E. coli and E. chrysanthemi) on mTORC1 signaling, protein synthesis, and apoptosis in AML.
- Investigated the role of glutamine synthase (GS) and autophagy in l-ase-treated AML cells.
Main Results:
- Glutamine removal and SLC1A5 knockdown inhibited mTORC1 signaling and induced apoptosis in AML cells.
- L-asparaginase demonstrated potent inhibition of mTORC1 and protein synthesis, correlating with glutaminase activity and inducing apoptosis.
- L-ase treatment upregulated GS expression and triggered autophagy in leukemic cells, with GS knockdown enhancing l-ase-induced apoptosis in some cases.
Conclusions:
- Targeting glutamine uptake and inhibiting protein synthesis are viable therapeutic strategies for AML.
- L-asparaginase exhibits significant anticancer activity against AML by disrupting glutamine metabolism and inducing apoptosis.
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