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
• 来源期刊: 药学学报（英文版）
• 年，卷（期）: 2022,（2）
• 所属期刊栏目: Original articles
• 页码范围: 759-773
• 页数: 15页
• 语种: 英文

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 amelio-rate 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 meta-bolism 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(AhR)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.