Inhibiting glutamine uptake represents an attractive new strategy for treating acute myeloid leukemia
Menée in vitro et in vivo, cette étude suggère l'intérêt de la L-asparaginase, qui inhibe notamment l'absorption de la glutamine, pour le traitement d'une leucémie myéloïde aiguë
Cancer cells require nutrients and energy to adapt to increased biosynthetic activity and protein synthesis inhibition downstream of 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 anti-cancer agent also harboring glutaminase activity. We show that L-ases from both E. coli and E. 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 anti-cancer activity and glutamine uptake inhibition are promising new therapeutic strategies for AML.