Targeting glutamine utilization to block metabolic adaptation of tumor cells under the stress of carboxyamidotriazole-induced nutrients unavailability

作     者：Jing Shi Rui Ju Hongting Gao Yuqing Huang Lei Guo Dechang Zhang Jing Shi;Rui Ju;Hongting Gao;Yuqing Huang;Lei Guo;Dechang Zhang

作者机构：Department of PharmacologyInstitute of Basic Medical SciencesChinese Academy of Medical Sciences and School of Basic MedicinePeking Union Medical CollegeBeijing 100005China Department of PharmacyPeking University Third HospitalBeijing 100191China 

出 版 物：《Acta Pharmaceutica Sinica B》 (药学学报（英文版）)

年 卷 期：2022年第12卷第2期

页      面：759-773页

核心收录：

学科分类：1007[医学-药学(可授医学、理学学位)] 1006[医学-中西医结合] 100706[医学-药理学] 100602[医学-中西医结合临床] 10[医学] 

基　　金：supported by the National Natural Science Foundation of China(grants 81872897 and 81672966) the CAMS Major Collaborative Innovation Project 2016-I2 M-1-011(China) 

主　　题：CAI Glutaminolysis Glutamine metabolism AhR Colorectal cancer metabolism Mitochondrial oxidative stress Redox homeostasis Metabolic reprogramming 

摘      要：Tumor cells have unique metabolic programming that is biologically distinct from that of corresponding normal *** tumor metabolic programming is a promising strategy to ameliorate drug resistance and improve the tumor ***,we show that carboxyamidotriazole(CAI),an anticancer drug,can function as a metabolic modulator that decreases glucose and lipid metabolism and increases the dependency of colon cancer cells on glutamine *** suppressed glucose and lipid metabolism utilization,causing inhibition of mitochondrial respiratory chain complex I,thus producing reactive oxygen species(ROS).In parallel,activation of the aryl hydrocarbon receptor(Ah R)increased glutamine uptake via the transporter SLC1A5,which could activate the ROS-scavenging enzyme glutathione *** a result,combined use of inhibitors of GLS/GDH1,CAI could effectively restrict colorectal cancer(CRC)energy *** data illuminate a new antitumor mechanism of CAI,suggesting a new strategy for CRC metabolic reprogramming treatment.