Tumor suppressor NDRG2 inhibits glycolysis and glutaminolysis in colorectal cancer cells by repressing c-Myc expression
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Xinyuan Xu1,*, Jianying Li1,*, Xiang Sun2,*, Yan Guo1,*, Dake Chu3, Li Wei4, Xia Li1, Guodong Yang1, Xinping Liu1, Libo Yao1, Jian Zhang1, Lan Shen1
1The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, Shaanxi, China
2Department of Prosthodontics, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, China
3The State Key Laboratory of Cancer Biology, Department of Gastrointestinal Surgery, Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, Xi'an, Shaanxi, China
4Department of Obstetrics and Gynecology, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, China
*These authors have contributed equally to this work
Jian Zhang, e-mail: [email protected]
Lan Shen, e-mail: [email protected]
Keywords: NDRG2, tumor metabolism, aerobic glycolysis, glutaminolysis, colorectal cancer
Received: March 13, 2015 Accepted: July 08, 2015 Published: July 20, 2015
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.
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