The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, 710032, China.
State Key Laboratory of Military Stomatology &National Clinical Research Center for Oral Diseases&Shaanxi Clinical Research Center for Oral Diseases, Department of Oral and Maxillofacial Surgery, School of Stomatology, The Fourth Military Medical University, No. 145 Changle Xi Road, Xi'an, 710032, China.
Int J Biol Sci. 2020 Oct 16;16(16):3100-3115. doi: 10.7150/ijbs.48066. eCollection 2020.
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. 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. 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. 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.
转移是各种类型癌症导致致命后果的最常见原因。虽然细胞增殖相关的代谢重编程已经得到很好的描述，但代谢变化与肿瘤转移之间的联系知之甚少。在此，我们证明转移性肿瘤获得了间充质表型，这是由肿瘤抑制因子 NDRG2 缺失触发的代谢开关到谷氨酰胺代谢引起的。进行了 mRNA-seq 和基因表达谱分析，以确定原发性 MEC1 和转移性 MC3 细胞中的差异基因表达和 NDRG2 的下游途径。通过免疫沉淀和蛋白质半衰期测定来确定 NDRG2 对 Fbw7 依赖性 c-Myc 稳定性的调节作用。使用荧光素酶报告基因和 ChIP 测定来确定 Akt 和 c-Myc 在介导 NDRG2 依赖性调节 ASCT2 在肿瘤和 NDRG2 敲除 MEF 细胞中的作用。最后，通过功能实验和临床样本评估 NDRG2/Akt/c-Myc/ASCT2 信号对谷氨酰胺分解和肿瘤转移的影响。基于基因表达谱分析，我们发现转移性肿瘤细胞获得了间充质样特征，并表现出对谷氨酰胺利用的依赖性增加。此外，NDRG2 功能的获得阻止了上皮-间充质转化 (EMT) 和谷氨酰胺分解，可能是通过抑制谷氨酰胺转运体 ASCT2 的表达。ASCT2 的恢复逆转了 NDRG2 对 EMT 程序和肿瘤转移的抑制作用。机制研究表明，NDRG2 通过抑制 Akt 激活促进 Fbw7 依赖性 c-Myc 降解，随后降低 c-Myc 介导的 ASCT2 转录，这在肿瘤和 NDRG2 敲除 MEF 细胞中均如此。支持生物学意义的是，在多种类型的肿瘤组织中观察到 NDRG2 和 ASCT2 之间的相互关系，并与肿瘤恶性程度相关。NDRG2 依赖的 ASCT2 抑制可能是 NDRG2 重编程谷氨酰胺分解并阻断转移性肿瘤存活的主要途径。靶向谷氨酰胺分解途径可能为转移性肿瘤的治疗提供新策略。
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