Key Points• Glutamine removal and knockdown of the glutamine transporter SLC1A5 have antileukemic activity in AML.• The glutaminase activity of L-asparaginase inhibits mTORC1 and protein synthesis and induces a strong autophagy in AML.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. (Blood. 2013;122(20):3521-3532)
The deregulation of translation markedly contributes to the malignant phenotype in cancers, and the assembly of the translation initiating complex eIF4F is the limiting step of this process. The mammalian Target of Rapamycin Complex 1 (mTORC1) is thought to positively regulate eIF4F assembly and subsequent oncogenic protein synthesis through 4E-BP1 phosphorylation. We showed here that the translation inhibitor 4EGI-1 decreased the clonogenic growth of leukemic progenitors and induced apoptosis of blast cells, with limited toxicity against normal hematopoiesis, which emphasize the importance of translation deregulation in acute myeloid leukemia (AML) biology. However, the mTORC1 inhibitor RAD001 (a rapamycin derivate) did not induce AML blast cell apoptosis. We herein demonstrated that mTORC1 disruption using raptor siRNA or RAD001 failed to inhibit 4E-BP1 phosphorylation in AML. Moreover, RAD001 failed to inhibit eIF4F assembly, to decrease the proportion of polysome-bound c-Myc mRNA, and to reduce the translation-dependent accumulation of oncogenic proteins. We identified the Pim-2 serine/threonine kinase as mainly responsible for 4E-BP1 phosphorylation on the S 65 residue and subsequent translation control in AML. Our results strongly implicate an mTORC1-independent deregulation of oncogenic proteins synthesis in human myeloid leukemogenesis. Di IntroductionAcute myeloid leukemia (AML) is a clonal hematologic disease characterized by differentiation arrest and by the proliferation of immature myeloid progenitors, both sustained by the deregulation of multiple signaling pathways. 1 Despite recent advances in the understanding of AML biology, the prognosis of this disease remains poor and new therapeutic perspectives are therefore under active investigation. 2 In most cancer models, the activity of mammalian Target of Rapamycin Complex 1 (mTORC1) is dependent on the activation of Akt, an oncoprotein that operates downstream of class IA phosphoinositide 3-kinase (PI3K). 3 In AML, mTORC1 is frequently activated, 4 but recent evidence has suggested that this activity does not rely on PI3K/Akt. These findings have shown that the p110␦ isoform of PI3K is principally responsible for PI3K activity 5 and that a specific p110␦ inhibitor, IC87114, fully inhibits Akt phosphorylation without affecting mTORC1 activity. 6 Moreover, the Src kinase Lyn has recently been shown to control mTORC1 activity but not Akt phosphorylation in primary AML cells. 7 The mTORC1 complex consists of mTOR, raptor, mLST8, and PRAS40. 8 It governs cell growth and regulates the cap-dependent translation of mRNAs. 9 Rapamycin and derivates, referred to as rapalogs (eg, RAD001), are closely related molecules demonstrating similar biologic activities by specifically repressing mTORC1 activity. 10,11 These compounds have recently been developed as anticancer therapeutics because of the frequent activation of mTORC1 in cancers and approved for clinical use. 12 Despite their seemingly clear mechanism of action and the rationale for their use as a canc...
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