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Abstract
Glycolysis and glutaminolysis are heavily involved in the metabolic reprogramming of cancer cells. The activation of oncogenes and inactivation of tumor suppressor genes has a marked effect on the cellular metabolic processes glycolysis and glutaminolysis. N-Myc downstream-regulated gene 2 (NDRG2) is a tumor suppressor gene that previous studies have demonstrated can inhibit the growth, proliferation and metastasis of clear cell renal cell carcinoma (ccRCC) cells. However, the function of NDRG2 in ccRCC metabolism remains unknown. In the present study, NDRG2 significantly inhibited the consumption of glucose and glutamine, as well as the production of lactate and glutamate in ccRCC. NDRG2 significantly suppressed the expression of glucose transporter 1, hexokinase 2, pyruvate kinase M2, lactate dehydrogenase A, glutamine transporter ASC amino acid transporter 2 and glutaminase 1 at the mRNA (by quantitative polymerase chain reaction) and protein level (by western blot analysis), all of which are key regulators and enzymes in glycolysis and glutaminolysis. Data from the present study also revealed that overexpression of NDRG2 suppressed cell proliferation in ccRCC in vitro and in vivo, demonstrated by colony formation assays, wound healing assay and nude mouse transplantation tumor experiment. The present findings demonstrate for the first time that NDRG2 acts as a key inhibitor of glycolysis and glutaminolysis in ccRCC and could be a promising target for the metabolic treatment of ccRCC.
Highlights
Altered metabolism is considered to be a hallmark of cancer cells, aiding the maintenance of uncontrolled growth and proliferation by providing sufficient biomass and energy [1]
The results of the present study reveal that N‐Myc downstream‐regulated gene 2 (NDRG2) inhibits aerobic glycolysis, as indicated by the decrease in glucose consumption and lactate production in 786‐O and Caki‐1 cells (Fig. 1B)
To identify the molecular targets involved in NDRG2‐regulated aerobic glycolysis, the expression of glucose transporters and enzymes in glycolysis, and glutamine transporters and glutaminolysis pathway enzymes was assessed in NDRG2‐overexpressing 786‐O and Caki‐1 cells
Summary
Altered metabolism is considered to be a hallmark of cancer cells, aiding the maintenance of uncontrolled growth and proliferation by providing sufficient biomass and energy [1]. Since the altered metabolism of transformed cells significantly contributes to cellular proliferation, targeting metabolic pathways of cancer cells is a promising area in cancer therapeutics [2]. A key metabolic alteration exhibited by the majority of cancer cells is enhanced aerobic glycolysis, a phenomenon known as the Warburg effect, which provides several metabolic benefits to proliferating cancer cells [3]. To meet the unique energetic requirements of cancer cells, changes in glycolysis and glutaminolysis alter the intracellular carbon flux [7,8]. During the initiation and progression of cancer, the inactivation of tumor suppressor genes and the activation of oncogenes results in multiple intracellular signaling shifts, affecting glycolytic flux and glutaminolysis in cancer cells [9,10,11,12]. An improved understanding of the molecular mechanisms involved in tumor metabolism may facilitate the identification of novel diagnostic approaches and treatment strategies for targeted cancer therapy
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