Abstract
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.
Highlights
Malignant growth and proliferation of cancer cells consume large quantities of bioenergy and biomaterials, which enhance the carbon flux through glycolysis and glutaminolysis to fulfill energetic and biosynthetic demands of cancer cells [1, 2]
We discovered that tumor suppressor N-v-myc myelocytomatosis viral oncogene homolog (Myc) downstream regulated gene 2 (NDRG2) participates in tumor metabolism, especially in glycolysis and glutaminolysis
Our current experiments demonstrate for the first time that NDRG2, which is downregulated in colorectal cancer, inhibits glycolysis and glutaminolysis in addition to inhibiting cancer cell proliferation and invasion
Summary
Malignant growth and proliferation of cancer cells consume large quantities of bioenergy and biomaterials, which enhance the carbon flux through glycolysis and glutaminolysis to fulfill energetic and biosynthetic demands of cancer cells [1, 2]. The expression and activation of glucose transporters are always regulated by several oncogenes and tumor suppressor genes including c-Myc, hypoxia inducible factor-1 (HIF-1), and p53 in cancer cells [9]. The M2 isoform of pyruvate kinase (PKM2), the last rate-limiting enzyme in the glycolytic pathway, is upregulated in colorectal cancer cells and plays an important role in the regulation of cancer metabolism [12, 13]. Lactate dehydrogenase A (LDHA), which can catalyze pyruvate into lactate, is directly transactivated by Myc and HIF-1 [6, 14] These metabolic enzymes are important for the dynamic regulation of enhanced glycolytic flux in cancer cells
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