Targeting PFKL with penfluridol inhibits glycolysis and suppresses esophageal cancer tumorigenesis in an AMPK/FOXO3a/BIM-dependent manner

作     者：Cancan Zheng Xiaomei Yu Yiyao Liang Yidong Zhu Yan He Long Liao Dingkang Wang Yanming Yang Xingfeng Yin Ang Li Qingyu He Bin Li 

作者机构：MOE Key Laboratory of Tumor Molecular Biology and Key Laboratory of Functional Protein Research of Guangdong Higher Education InstitutesInstitute of Life and Health EngineeringJinan UniversityGuangzhou 510632China Guangdong Key Laboratory of Non-human Primate ResearchGuangdong-Hong Kong-Macao Institute of CNS RegenerationKey Laboratory of CNS RegenerationMinistry of EducationJinan UniversityGuangzhou 510632China MOE Key Laboratory of Tumor Molecular Biology and Guangdong Provincial Key Laboratory of Bioengineering MedicineNational Engineering Research Center of Genetic MedicineInstitute of BiomedicineCollege of Life Science and TechnologyJinan UniversityGuangzhou 510632China 

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

年 卷 期：2022年第12卷第3期

页      面：1271-1287页

核心收录：

学科分类：1007[医学-药学(可授医学、理学学位)] 1004[医学-公共卫生与预防医学(可授医学、理学学位)] 1002[医学-临床医学] 1001[医学-基础医学(可授医学、理学学位)] 100214[医学-肿瘤学] 10[医学] 

基　　金：supported by National Natural Science Foundation of China(31961160727,81773085,and 81973339) National Key Research and Development Program of China(2017YFA0505100) Guangdong Natural Science Research Grant International joint project(2021A0505030035,China) 

主　　题：Drug repurposing Metabolic reprogramming Glycolysis PFKL DARTS technology Esophageal cancer Penfluridol 

摘      要：As one of the hallmarks of cancer,metabolic reprogramming leads to cancer progression,and targeting glycolytic enzymes could be useful strategies for cancer *** screening a small molecule library consisting of 1320 FDA-approved drugs,we found that penfluridol,an antipsychotic drug used to treat schizophrenia,could inhibit glycolysis and induce apoptosis in esophageal squamous cell carcinoma(ESCC).Gene profiling and Ingenuity Pathway Analysis suggested the important role of AMPK in action mechanism of *** using drug affinity responsive target stability(DARTS)technology and proteomics,we identified phosphofructokinase,liver type(PFKL),a key enzyme in glycolysis,as a direct target of *** could not exhibit its anticancer property in PFKL-deficient cancer cells,illustrating that PFKL is essential for the bioactivity of *** PFKL expression is correlated with advanced stages and poor survival of ESCC patients,and silencing of PFKL significantly suppressed tumor ***,direct binding of penfluridol and PFKL inhibits glucose consumption,lactate and ATP production,leads to nuclear translocation of FOXO3a and subsequent transcriptional activation of BIM in an AMPK-dependent *** together,PFKL is a potential prognostic biomarker and therapeutic target in ESCC,and penfluridol may be a new therapeutic option for management of this lethal disease.