Sato Tomonori, Kawasaki Yoshihide, Maekawa Masamitsu, Takasaki Shinya, Morozumi Kento, Sato Masahiko, Shimada Shuichi, Kawamorita Naoki, Yamashita Shinichi, Mitsuzuka Koji, Mano Nariyasu, Ito Akihiro
Department of Urology, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980-8574, Japan.
Department of Pharmaceutical Sciences, Tohoku University Hospital, Sendai, Miyagi 980-8574, Japan.
Metabolites. 2020 Dec 22;11(1):1. doi: 10.3390/metabo11010001.
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.
代谢组学分析通过测量伴随癌症进展的代谢物变化，可能识别出治疗耐药性中的新治疗靶点。我们之前对肾细胞癌（RCC）进行了一项全球代谢组学（G-Met）研究，并确定了可能与RCC中舒尼替尼耐药性有关的代谢物。在此，我们旨在通过细胞内代谢物阐明RCC中舒尼替尼耐药性的可能机制。我们从注射了RCC细胞（786-O）的小鼠肿瘤组织中建立了舒尼替尼耐药和对照RCC细胞系。我们还对在我们的G-Met研究中鉴定出的特征性代谢物进行了定量，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。与在舒尼替尼暴露下的对照RCC细胞系相比，建立的舒尼替尼耐药RCC细胞系显示出蛋白激酶B（Akt）和间充质-上皮转化（MET）磷酸化明显去抑制。在鉴定出的代谢物中，谷氨酰胺、谷氨酸和α-酮戊二酸（参与谷氨酰胺摄取进入三羧酸（TCA）循环以进行能量代谢）；6-磷酸果糖、D-景天庚酮糖7-磷酸和1-磷酸葡萄糖（参与糖酵解增加及其中间代谢物）；以及谷胱甘肽和肌醇（抗氧化作用）在舒尼替尼耐药RCC细胞系中显著增加。特别是，与对照细胞相比，舒尼替尼耐药RCC细胞中谷氨酰胺转运体（SLC1A5）的表达显著增加。在本研究中，我们证明了谷氨酰胺摄取和糖酵解上调的能量代谢以及抗氧化活性也与RCC细胞中的舒尼替尼耐药性有关。
