Depletion of squalene epoxidase in synergy with glutathione peroxidase 4 inhibitor RSL3 overcomes oxidative stress resistance in lung squamous cell carcinoma  

作　　者：Guo Li Lu Chen Hua Bai Li Zhang Jie Wang Weimin Li 

机构地区：[1]CAMS Key Laboratory of Translational Research on Lung Cancer,State Key Laboratory of Molecular Oncology,Department of Medical Oncology,National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital,Chinese Academy of Medical Sciences Peking Union Medical College,Beijing 100021,China [2]Department of Pulmonary and Critical Care Medicine,West China Hospital,Sichuan University,Chengdu 610041,China [3]Institute of Respiratory Health,Frontiers Science Center for Disease-related Molecular Network,West China Hospital,Sichuan University,Chengdu 610041,China [4]Precision Medicine Center,Precision Medicine Key Laboratory of Sichuan Province,West China Hospital,Sichuan University,Chengdu 610041,China [5]State Key Laboratory of Respiratory Health and Multimorbidity,West China Hospital,Chengdu 610041,China [6]The Research Units of West China,Chinese Academy of Medical Sciences,West China Hospital,Chengdu 610041,China

出　　处：《Precision Clinical Medicine》2024年第2期109-121,共13页精准临床医学（英文）

基　　金：the National Natural Science Foundation of China(Grant No.92159302,W.L.);Science and Technology Project of Sichuan(Grant No.2022ZDZX0018,W.L.);1.3.5 project for disciplines of excellence,West China Hospital,Sichuan University(Grant No.ZYGD22009,W.L.);National Key R&D program of China(Grant No.2022YFC2505000);NSFC general program(Grant No.82272796);NSFC special program(Grant No.82241229);CAMS Innovation Fund for Medical Sciences(Grant No.CIFMS 2022-I2M-1-009);CAMS Key Laboratory of Translational Research on Lung Cancer(Grant No.2018PT31035);the Aiyou foundation(Grant No.KY201701).

摘　　要：Background:Lung squamous cell carcinoma(Lusc)lacks effective targeted therapies and has a poor prognosis.Disruption of squalene epoxidase(SQLE)has been implicated in metabolic disorders and cancer.However,the role of SQLE as a monooxygenase involved in oxidativestressremainsunclear.Methods:We analyzed the expression and prognosis of lung adenocarcinoma(LUAD)and LUSC samples from GEO and TCGA databases.The proliferative activity of the tumors after intervention of SQLE was verified by cell and animal experiments.JC-1 assay,flow cytometry,and Western blot were used to show changes in apoptosis after intervention of sQLE.Flow cytometry and fluorescence assay of ROs levels were used to indicate oxidative stress status.Results:We investigated the unique role of SQLE expression in the diagnosis and prognosis prediction of LUSC.Knockdown of SQLE or treatment with the SQLE inhibitor terbinafine can suppress the proliferation of LUsC cells by inducing apoptosis and reactive oxygen species accumulation.However,depletion of SQLE also results in the impairment of lipid peroxidation and ferroptosis resistance such as upregulation of glutathione peroxidase 4.Therefore,prevention of SQLE in synergy with glutathione peroxidase 4 inhibitor RSL3 effectively mitigates the proliferation and growth of LUSC.Conclusion:Our study indicates that the low expression of sQLE employs adaptive survival through regulating the balance of apoptosis and ferroptosis resistance.In future,the combinational therapy of targeting sQLE and ferroptosis could be a promising approach in treating LUSC.

关 键 词：lung squamous cell carcinoma squalene epoxidase TERBINAFINE ROS ferroptosis 

分 类 号：R734.2[医药卫生—肿瘤]