Metabolomics analysis possibly identifies new therapeutic targets in treatment resistance by measuring changes in metabolites accompanying cancer progression. We previously conducted a global metabolomics (G-Met) study of renal cell carcinoma (RCC) and identified metabolites that may be involved in sunitinib resistance in RCC. Here, we aimed to elucidate possible mechanisms of sunitinib resistance in RCC through intracellular metabolites. We established sunitinib-resistant and control RCC cell lines from tumor tissues of RCC cell (786-O)-injected mice. We also quantified characteristic metabolites identified in our G-Met study to compare intracellular metabolism between the two cell lines using liquid chromatography-mass spectrometry. The established sunitinib-resistant RCC cell line demonstrated significantly desuppressed protein kinase B (Akt) and mesenchymal-to-epithelial transition (MET) phosphorylation compared with the control RCC cell line under sunitinib exposure. Among identified metabolites, glutamine, glutamic acid, and α-KG (involved in glutamine uptake into the tricarboxylic acid (TCA) cycle for energy metabolism); fructose 6-phosphate, D-sedoheptulose 7-phosphate, and glucose 1-phosphate (involved in increased glycolysis and its intermediate metabolites); and glutathione and myoinositol (antioxidant effects) were significantly increased in the sunitinib-resistant RCC cell line. Particularly, glutamine transporter (SLC1A5) expression was significantly increased in sunitinib-resistant RCC cells compared with control cells. In this study, we demonstrated energy metabolism with glutamine uptake and glycolysis upregulation, as well as antioxidant activity, was also associated with sunitinib resistance in RCC cells.

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代谢组学分析阐明肾细胞癌对舒尼替尼耐药的机制

代谢组学分析可能通过测量伴随癌症进展的代谢物变化来确定治疗耐药性的新治疗靶标。我们先前进行了肾细胞癌（RCC）的全球代谢组学（G-Met）研究，并确定了可能与RCC的舒尼替尼耐药相关的代谢物。在这里，我们旨在阐明通过细胞内代谢产物在RCC中舒尼替尼耐药的可能机制。我们从注射了RCC细胞（786-O）的小鼠的肿瘤组织中建立了耐舒尼替尼抗性和对照RCC细胞系。我们还对在G-Met研究中确定的特征代谢产物进行了定量分析，以使用液相色谱-质谱法比较两种细胞系之间的细胞内代谢。与暴露于舒尼替尼的对照RCC细胞系相比，已建立的耐舒尼替尼的RCC细胞系表现出显着去抑制的蛋白激酶B（Akt）和间充质上皮转换（MET）磷酸化。在鉴定出的代谢产物中，谷氨酰胺，谷氨酸和α-KG（参与谷氨酰胺摄入三羧酸（TCA）循环以进行能量代谢）；果糖6磷酸，D-七庚糖7磷酸和葡萄糖1磷酸（参与增加的糖酵解及其中间代谢产物）；在耐舒尼替尼的RCC细胞系中，谷胱甘肽和肌醇（抗氧化作用）显着增加。特别是，与对照组相比，耐舒尼替尼的RCC细胞的谷氨酰胺转运蛋白（SLC1A5）表达显着增加。在这个研究中，