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 

机构地区：[1]Department of Pharmacology,Institute of Basic Medical Sciences,Chinese Academy of Medical Sciences and School of Basic Medicine,Peking Union Medical College,Beijing 100005,China [2]Department of Pharmacy,Peking University Third Hospital,Beijing 100191,China

出　　处：《Acta Pharmaceutica Sinica B》2022年第2期759-773,共15页药学学报（英文版）

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)。

摘　　要：Tumor cells have unique metabolic programming that is biologically distinct from that of corresponding normal cells.Resetting tumor metabolic programming is a promising strategy to ameliorate drug resistance and improve the tumor microenvironment.Here,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 metabolism.CAI 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 peroxidase.As a result,combined use of inhibitors of GLS/GDH1,CAI could effectively restrict colorectal cancer(CRC)energy metabolism.These data illuminate a new antitumor mechanism of CAI,suggesting a new strategy for CRC metabolic reprogramming treatment.

关 键 词：CAI GLUTAMINOLYSIS Glutamine metabolism AHR Colorectal cancer metabolism Mitochondrial oxidative stress Redox homeostasis Metabolic reprogramming 

分 类 号：R96[医药卫生—药理学]