Lee Naeun, Jang Won-Jun, Seo Ji Hae, Lee Sooyeun, Jeong Chul-Ho
College of Pharmacy, Keimyung University, Daegu 42601, Korea.
Department of Biochemistry, Keimyung University School of Medicine, Daegu 42601, Korea.
Metabolites. 2019 Sep 17;9(9):188. doi: 10.3390/metabo9090188.
One of the most prominent hallmarks of cancer cells is their dependency on the glycolytic pathway for energy production. As a potent inhibitor of glycolysis, 2-deoxy-d-glucose (2DG) has been proposed for cancer treatment and extensively investigated in clinical studies. Moreover, 2DG has been reported to interfere with other biological processes including glycosylation. To further understand the overall effect of and metabolic alteration by 2DG, we performed biochemical and metabolomics analyses on oral squamous cell carcinoma cell lines. In this study, we found that 2DG more effectively reduced glucose consumption and lactate level in SCC15 cells than in SCC4 cells, which are less dependent on glycolysis. Coincidentally, 2DG impaired N-linked glycosylation of the key oncogenic receptors Axl and Met in SCC15 cells, thereby reducing the cell viability and colony formation ability. The impaired processes of glycolysis and N-linked glycosylation were restored by exogenous addition of pyruvate and mannose, respectively. Additionally, our targeted metabolomics analysis revealed significant alterations in the metabolites, including amino acids, biogenic amines, glycerophospholipids, and sphingolipids, caused by the impairment of glycolysis and N-linked glycosylation. These observations suggest that alterations of these metabolites may be responsible for the phenotypic and metabolic changes in SCC15 cells induced by 2DG. Moreover, our data suggest that N-linked glycosylation of Axl and Met may contribute to the maintenance of cancer properties in SCC15 cells. Further studies are needed to elucidate the roles of these altered metabolites to provide novel therapeutic targets for treating human oral cancer.
癌细胞最显著的特征之一是它们在能量产生方面对糖酵解途径的依赖性。作为一种有效的糖酵解抑制剂，2-脱氧-D-葡萄糖（2DG）已被提出用于癌症治疗，并在临床研究中得到广泛研究。此外，据报道2DG会干扰包括糖基化在内的其他生物过程。为了进一步了解2DG的总体作用和代谢改变，我们对口腔鳞状细胞癌细胞系进行了生化和代谢组学分析。在本研究中，我们发现2DG在SCC15细胞中比在对糖酵解依赖性较小的SCC4细胞中更有效地降低了葡萄糖消耗和乳酸水平。巧合的是，2DG损害了SCC15细胞中关键致癌受体Axl和Met的N-糖基化，从而降低了细胞活力和集落形成能力。糖酵解和N-糖基化受损的过程分别通过外源添加丙酮酸和甘露糖得以恢复。此外，我们的靶向代谢组学分析揭示了由糖酵解和N-糖基化受损引起的代谢物显著变化，包括氨基酸、生物胺、甘油磷脂和鞘脂。这些观察结果表明这些代谢物的改变可能是2DG诱导的SCC15细胞表型和代谢变化的原因。此外，我们的数据表明Axl和Met的N-糖基化可能有助于维持SCC15细胞的癌症特性。需要进一步研究以阐明这些改变的代谢物的作用，为治疗人类口腔癌提供新的治疗靶点。
