Enhanced glutamine utilization mediated by SLC1A5 and GPT2 is an essential metabolic feature of colorectal signet ring cell carcinoma with therapeutic potential

Abstract

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 18 F fluorodeoxyglucose (18 F-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.