Inhibiting glutamine uptake represents an attractive new strategy for treating acute myeloid leukemia
Inhibiting glutamine uptake represents an attractive new strategy for treating acute myeloid leukemia
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DOI：
10.1182/blood-2013-03-493163
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发表时间：
2013-11-14
期刊：
影响因子：
20.3
通讯作者：
Bouscary, Didier
中科院分区：
文献类型：
--
作者：
Willems, Lise;Jacque, Nathalie;Bouscary, Didier
癌细胞需要营养和能量来适应增加的生物合成活性，而哺乳动物雷帕霉素靶点复合物1 （mTORC1）下游的蛋白质合成抑制有望成为急性髓性白血病（AML）的一种可能治疗方法。谷氨酰胺有助于亮氨酸进入细胞，从而控制氨基酸/Rag/mTORC1信号通路。在我们目前的研究中，我们表明谷氨酰胺去除抑制mTORC1并诱导AML细胞凋亡。在小鼠AML异种移植模型中，谷氨酰胺高亲和转运体SLC1A5的敲除可诱导细胞凋亡并抑制肿瘤形成。l -天冬酰胺酶（L-ase）是一种具有谷氨酰胺酶活性的抗癌剂。我们发现，来自大肠杆菌和菊花Erwinia的l酶都能深刻抑制mTORC1和蛋白质合成，这种抑制与它们的谷氨酰胺酶活性水平相关，并在原发性AML细胞中产生强烈的凋亡反应。我们进一步表明，l -酶上调白血病细胞中谷氨酰胺合成酶（GS）的表达，GS敲低可增强l -酶诱导的一些AML细胞凋亡。最后，我们观察到L-ase处理后的强自噬过程。这些结果表明，l -酶抗癌活性和谷氨酰胺摄取抑制是治疗AML的新策略。
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.