CYP3A5 unexpectedly regulates glucose metabolism through the AKT-TXNIP-GLUT1 axis in pancreatic cancer  

作　　者：Ming Shao Qingfei Pan Haiyan Tan Jing Wu Ha Won Lee Andrew D.Huber William C.Wright Ji-Hoon Cho Jiyang Yu Junmin Peng Taosheng Chen 

机构地区：[1]Department of Chemical Biology and Therapeutics,St.Jude Children's Research Hospital,Memphis,TN 38105,USA [2]Department of Computational Biology,St.Jude Children's Research Hospital,Memphis,TN 38105,USA [3]Center for Proteomics and Metabolomics,St.Jude Children's Research Hospital,Memphis,TN 38105,USA [4]Department of Structural Biology,St.Jude Children's Research Hospital,Memphis,TN 38105,USA [5]Department of Developmental Neurobiology,St.Jude Children's Research Hospital,Memphis,TN 38105,USA

出　　处：《Genes & Diseases》2024年第4期381-399,共19页基因与疾病（英文）

基　　金：supported by the National Institute of General Medical Sciences of the National Institutes of Health under award number R35GM118041.

摘　　要：CYP3A5 is a cytochrome P450(CYP)enzyme that metabolizes drugs and contributes to drug resistance in cancer.However,it remains unclear whether CYP3A5 directly influences cancer progression.In this report,we demonstrate that CYP3A5 regulates glucose metabolism in pancreatic ductal adenocarcinoma.Multi-omics analysis showed that CYP3A5 knockdown re-sults in a decrease in various glucose-related metabolites through its effect on glucose trans-port.A mechanistic study revealed that CYP3A5 enriches the glucose transporter GLUT1 at the plasma membrane by restricting the translation of TXNIP,a negative regulator of GLUT1.Notably,CYP3A5-generated reactive oxygen species were proved to be responsible for atten-uating the AKT-4EBP1-TXNIP signaling pathway.CYP3A5 contributes to cell migration by maintaining high glucose uptake in pancreatic cancer.Taken together,our results,for the first time,reveal a role of CYP3A5 in glucose metabolism in pancreatic ductal adenocarcinoma and identify a novel mechanism that is a potential therapeutic target.

关 键 词：Cell migration CYP3A5 Glucose metabolism GLUT1 Pancreatic cancer TXNIP 

分 类 号：R96[医药卫生—药理学]