Enhanced glutamine utilization mediated by SLC1A5 and GPT2 is an essential metabolic feature of colorectal signet ring cell carcinoma with therapeutic potential
Enhanced glutamine utilization mediated by SLC1A5 and GPT2 is an essential metabolic feature of colorectal signet ring cell carcinoma with therapeutic potential
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DOI：
10.21037/atm.2020.03.31
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发表时间：
2020-03
影响因子：
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通讯作者：
Renjie Wang;W. Xiang;Ye Xu;Lingyu Han;Qingguo Li;W. Dai;G. Cai
中科院分区：
文献类型：
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作者：
Renjie Wang;W. Xiang;Ye Xu;Lingyu Han;Qingguo Li;W. Dai;G. Cai
结直肠印戒细胞癌（SRCC）是结直肠癌的一个罕见亚群，预后极差，18 F-脱氧葡萄糖（18F-FDG）摄取率低或为阴性。由于缺乏可靠的研究模型，迄今为止尚未对结直肠SRCC的代谢特征进行深入研究。本研究的目的是探讨结直肠SRCC的能量利用的特点基于类器官模型。方法3个类器官来源于FDG摄取低或阴性的结直肠SRCC患者，3个类器官来源于结直肠腺癌（AC）患者。进行葡萄糖、脂肪酸和谷氨酰胺摄取测定以揭示SRCC类器官的不同代谢特征。采用免疫组化（IHC）、Western blotting和实时荧光定量PCR（real-time PCR）检测细胞内关键转运蛋白和能量代谢相关酶的表达。谷氨酰胺剥夺分析用于证实结直肠SRCC对谷氨酰胺的依赖性。结果葡萄糖、脂肪酸和谷氨酰胺摄取测定显示，与配对的正常类器官相比，结肠直肠SRCC类器官中仅谷氨酰胺摄取显著增加。比较SRCC类器官与AC类器官表明，AC类器官中葡萄糖和脂肪酸的摄取显著较高，而谷氨酰胺的摄取显著较低。基因表达分析证实，谷氨酰胺转运体SLC 1A 5和谷氨酰胺分解酶GPT 2在结直肠SRCC中显著失调。SLC 1A 5或GPT 2的沉默可以抑制SRCC类器官的增殖，但降低SRCC对谷氨酰胺剥夺的敏感性。SLC 1A 5或GPT 2抑制剂可抑制SRCC的生长，并显著增强SRCC对5-FU和L-OHP的敏感性。结论本研究强调了谷氨酰胺摄取和谷氨酰胺分解增加是结直肠SRCC的代谢特征和潜在的治疗靶点。
Background Colorectal signet-ring cell carcinoma (SRCC) is characterized as a rare subset of colorectal cancer with extremely poor prognosis and it is known to have low or negative 18F fluorodeoxyglucose (18F-FDG) uptake. To date, no in-depth study revealing the metabolic features of colorectal SRCC has been conducted for the lack of reliable study model. The aim of this study was to explore the distinct characteristics of energy utilization for colorectal SRCC based on organoid model. Methods Three organoids were derived from colorectal SRCC patients with low or negative FDG uptake and three organoids were derived from colorectal adenocarcinoma (AC) patients. Glucose, fatty acid and glutamine uptake assays were performed to reveal the different metabolic features of SRCC organoids. Immunohistochemistry (IHC), western blotting and real-time PCR were used to test the expression of critical transporters and enzymes of energy metabolism. Glutamine deprivation analyses were used to confirm the dependence of colorectal SRCC on glutamine. Results Glucose, fatty acid and glutamine uptake assays showed that only glutamine uptake was significantly increased in colorectal SRCC organoids compared with paired normal organoids. Comparing SRCC organoids with AC organoids indicated that glucose and fatty acid uptake were strikingly higher in AC organoids while glutamine uptake was notably lower. Gene expression analyses confirmed that the glutamine transporter SLC1A5 and glutaminolysis enzyme GPT2 were significantly unregulated in colorectal SRCC. Silencing of SLC1A5 or GPT2 could suppress the proliferation of SRCC organoids but attenuating the sensitivity of SRCC to glutamine deprivation. Administration of SLC1A5 or GPT2 inhibitor could prohibit SRCC growth and significantly enhance the sensitivity of SRCC to the treatment of 5-fu and L-OHP. Conclusions This study highlights enhanced glutamine uptake and glutaminolysis as a metabolic feature of colorectal SRCC and a potential therapeutic target.