Inhibiting glutamine uptake represents an attractive new strategy for treating acute myeloid leukemia
Lise Willems, Nathalie Jacque, Arnaud Jacquel, Nathalie Neveux, Thiago Trovati Maciel, Mireille Lambert, Alain Schmitt, Laury Poulain, Alexa S Green, Madalina Uzunov, Olivier Kosmider, Isabelle Radford-Weiss, Ivan Cruz Moura, Patrick Auberger, Norbert Ifrah, Valérie Bardet, Nicolas Chapuis, Catherine Lacombe, Patrick Mayeux, Jérôme Tamburini, Didier Bouscary, Lise Willems, Nathalie Jacque, Arnaud Jacquel, Nathalie Neveux, Thiago Trovati Maciel, Mireille Lambert, Alain Schmitt, Laury Poulain, Alexa S Green, Madalina Uzunov, Olivier Kosmider, Isabelle Radford-Weiss, Ivan Cruz Moura, Patrick Auberger, Norbert Ifrah, Valérie Bardet, Nicolas Chapuis, Catherine Lacombe, Patrick Mayeux, Jérôme Tamburini, Didier Bouscary
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.
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Source: PubMed