Tumor suppressor NDRG2 inhibits glycolysis and glutaminolysis in colorectal cancer cells by repressing c-Myc expression.
Tumor suppressor NDRG2 inhibits glycolysis and glutaminolysis in colorectal cancer cells by repressing c-Myc expression.
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肿瘤抑制因子 NDRG2 通过抑制 c-Myc 表达来抑制结直肠癌细胞中的糖酵解和谷氨酰胺分解
DOI：
10.18632/oncotarget.4544
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发表时间：
2015-09-22
期刊：
影响因子：
--
通讯作者：
Shen L
中科院分区：
文献类型：
--
作者：
Xu X;Li J;Sun X;Guo Y;Chu D;Wei L;Li X;Yang G;Liu X;Yao L;Zhang J;Shen L
癌细胞使用葡萄糖和谷氨酰胺作为主要的能量来源和前体中间体，而糖酵解和谷氨酰胺溶解的增强是癌症代谢重编程的主要标志。癌基因激活和肿瘤抑制基因失活改变影响糖酵解和谷氨酰胺解的多种细胞内信号通路。N-Myc下游调控基因2 （NDRG2）是抑制肿瘤生长、转移和侵袭的肿瘤抑制基因。然而，NDRG2在肿瘤代谢中的作用和分子机制尚不清楚。在本研究中，我们发现肿瘤抑制基因NDRG2在癌细胞有氧糖酵解和谷氨酰胺溶解中的作用。NDRG2抑制结直肠癌细胞的葡萄糖消耗和乳酸产生、谷氨酰胺消耗和谷氨酸产生。葡萄糖转运蛋白和参与糖酵解的催化酶分析显示，葡萄糖转运蛋白1 （GLUT1）、己糖激酶2 （HK2）、丙酮酸激酶M2异构体（PKM2）和乳酸脱氢酶A （LDHA）被NDRG2显著抑制。对谷氨酰胺转运蛋白和参与谷氨酰胺水解的催化酶的分析发现，NDRG2也显著抑制了谷氨酰胺转运蛋白ASC -氨基酸转运蛋白2 （ASCT2）和谷氨酰胺酶1 （GLS1）。转录因子c-Myc介导的NDRG2对糖酵解和谷氨酰胺解的抑制。更重要的是，NDRG2通过抑制β-catenin的表达来抑制c-Myc的表达，β-catenin可以转录激活细胞核中的c-Myc基因。此外，NDRG2通过抑制糖酵解和谷氨酰胺解作用，显著抑制结直肠癌细胞的生长和增殖。综上所述，这些研究结果表明，NDRG2通过抑制c-Myc在糖酵解和谷氨酰胺解中发挥重要的调节作用，并通过协调靶向葡萄糖和谷氨酰胺转运蛋白、参与糖酵解和谷氨酰胺解的多种催化酶来抑制癌症的发生，从而为癌症的增殖和进展提供所需的生物能量和生物材料。
Cancer cells use glucose and glutamine as the major sources of energy and precursor intermediates, and enhanced glycolysis and glutamimolysis are the major hallmarks of metabolic reprogramming in cancer. Oncogene activation and tumor suppressor gene inactivation alter multiple intracellular signaling pathways that affect glycolysis and glutaminolysis. N-Myc downstream regulated gene 2 (NDRG2) is a tumor suppressor gene inhibiting cancer growth, metastasis and invasion. However, the role and molecular mechanism of NDRG2 in cancer metabolism remains unclear. In this study, we discovered the role of the tumor suppressor gene NDRG2 in aerobic glycolysis and glutaminolysis of cancer cells. NDRG2 inhibited glucose consumption and lactate production, glutamine consumption and glutamate production in colorectal cancer cells. Analysis of glucose transporters and the catalytic enzymes involved in glycolysis revealed that glucose transporter 1 (GLUT1), hexokinase 2 (HK2), pyruvate kinase M2 isoform (PKM2) and lactate dehydrogenase A (LDHA) was significantly suppressed by NDRG2. Analysis of glutamine transporter and the catalytic enzymes involved in glutaminolysis revealed that glutamine transporter ASC amino-acid transporter 2 (ASCT2) and glutaminase 1 (GLS1) was also significantly suppressed by NDRG2. Transcription factor c-Myc mediated inhibition of glycolysis and glutaminolysis by NDRG2. More importantly, NDRG2 inhibited the expression of c-Myc by suppressing the expression of β-catenin, which can transcriptionally activate C-MYC gene in nucleus. In addition, the growth and proliferation of colorectal cancer cells were suppressed significantly by NDRG2 through inhibition of glycolysis and glutaminolysis. Taken together, these findings indicate that NDRG2 functions as an essential regulator in glycolysis and glutaminolysis via repression of c-Myc, and acts as a suppressor of carcinogenesis through coordinately targeting glucose and glutamine transporter, multiple catalytic enzymes involved in glycolysis and glutaminolysis, which fuels the bioenergy and biomaterials needed for cancer proliferation and progress.