Background: Metastasis is the most common cause of lethal outcome in various types of cancers. Although the cell proliferation related metabolism rewiring has been well characterized, less is known about the association of metabolic changes with tumor metastasis. Herein, we demonstrate that metastatic tumor obtained a mesenchymal phenotype, which is obtained by the loss of tumor suppressor NDRG2 triggered metabolic switch to glutamine metabolism./nMethods: mRNA-seq and gene expression profile analysis were performed to define the differential gene expressions in primary MEC1 and metastatic MC3 cells and the downstream pathways of NDRG2. NDRG2 regulation of Fbw7-dependent c-Myc stability were determined by immunoprecipitation and protein half-life assay. Luciferase reporter and ChIP assays were used to determine the roles of Akt and c-Myc in mediating NDRG2-dependent regulation of ASCT2 in in both tumor and NDRG2-knockout MEF cells. Finally, the effect of the NDRG2/Akt/c-Myc/ASCT2 signaling on glutaminolysis and tumor metastasis were evaluated by functional experiments and clinical samples./nResults: Based on the gene expression profile analysis, we identified metastatic tumor cells acquired the mesenchymal-like characteristics and displayed the increased dependency on glutamine utilization. Further, the gain of NDRG2 function blocked epithelial-mesenchymal transition (EMT) and glutaminolysis, potentially through suppression of glutamine transporter ASCT2 expression. The ASCT2 restoration reversed NDRG2 inhibitory effect on EMT program and tumor metastasis. Mechanistic study indicates that NDRG2 promoted Fbw7-dependent c-Myc degradation by inhibiting Akt activation, and subsequently decreased c-Myc-mediated ASCT2 transcription, in both tumor and NDRG2-knockout MEF cells. Supporting the biological significance, the reciprocal relationship between NDRG2 and ASCT2 were observed in multiple types of tumor tissues, and associated with tumor malignancy./nConclusions: NDRG2-dependent repression of ASCT2 presumably is the predominant route by which NDRG2 rewires glutaminolysis and blocks metastatic tumor survival. Targeting glutaminolytic pathway may provide a new strategy for the treatment of metastatic tumors.

中文翻译：

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NDRG2 消融通过诱导 ASCT2 将转移性癌细胞重新编程为谷氨酰胺依赖性

背景：转移是导致各种癌症致死结果的最常见原因。尽管与细胞增殖相关的代谢重新布线已得到很好的表征，但对代谢变化与肿瘤转移的关联知之甚少。在此，我们证明转移性肿瘤获得了间充质表型，这是通过失去肿瘤抑制因子 NDRG2 触发代谢转换为谷氨酰胺代谢而获得的。/n方法：进行 mRNA-seq 和基因表达谱分析以确定原代 MEC1 和转移性 MC3 细胞中的差异基因表达以及 NDRG2 的下游途径。通过免疫沉淀和蛋白质半衰期测定确定 NDRG2 对 Fbw7 依赖性 c-Myc 稳定性的调节。荧光素酶报告基因和 ChIP 测定用于确定 Akt 和 c-Myc 在介导肿瘤和 NDRG2 敲除 MEF 细胞中 ASCT2 的 NDRG2 依赖性调节中的作用。最后，通过功能实验和临床样本评估了 NDRG2/Akt/c-Myc/ASCT2 信号传导对谷氨酰胺溶解和肿瘤转移的影响。/n结果：基于基因表达谱分析，我们确定了转移性肿瘤细胞获得了间充质样特征，并显示出对谷氨酰胺利用的依赖性增加。此外，NDRG2 功能的获得可能通过抑制谷氨酰胺转运蛋白 ASCT2 的表达来阻断上皮间质转化 (EMT) 和谷氨酰胺分解。ASCT2 恢复逆转了 NDRG2 对 EMT 程序和肿瘤转移的抑制作用。机制研究表明，在肿瘤和 NDRG2 敲除 MEF 细胞中，NDRG2 通过抑制 Akt 激活促进 Fbw7 依赖性 c-Myc 降解，随后减少 c-Myc 介导的 ASCT2 转录。支持生物学意义，在多种类型的肿瘤组织中观察到 NDRG2 和 ASCT2 之间的相互关系，结论： NDRG2 对 ASCT2 的依赖性抑制可能是 NDRG2 重新连接谷氨酰胺分解和阻断转移性肿瘤存活的主要途径。靶向谷氨酰胺分解通路可能为转移性肿瘤的治疗提供新的策略。