Blockade of NMT1 enzymatic activity inhibits N-myristoylation of VILIP3 protein and suppresses liver cancer progression  

作　　者：Xiang-Peng Tan Yan He Jing Yang Xian Wei You-Long Fan Guo-Geng Zhang Yi-Dong Zhu Zheng-Qiu Li Hua-Xin Liao Da-Jiang Qin Xin-Yuan Guan Bin Li 

机构地区：[1]The First Affiliated Hospital of Jinan University,Jinan University,Guangzhou,China [2]Key Laboratory of Biological Targeting Diagnosis,Therapy and Rehabilitation of Guangdong Higher Education Institutes and Key Laboratory of Protein Modification and Degradation,The Fifth Affiliated Hospital of Guangzhou Medical University,Guangzhou,China [3]MOE Key Laboratory of Tumor Molecular Biology and National Engineering Research Center of Genetic Medicine,College of Life Science and Technology,Jinan University,Guangzhou,China [4]School of Pharmacy,Jinan University,Guangzhou,China [5]Department of Clinical Oncology,The University of Hong Kong,Hong Kong,China

出　　处：《Signal Transduction and Targeted Therapy》2023年第2期716-729,共14页信号转导与靶向治疗（英文）

基　　金：This work was supported by National Natural Science Foundation of China(82273141,31961160727,81973339);National Key Research and Development Program of China(2021YFC2501000);Key Laboratory of Guangdong Higher Education Institutes(2021KSYS009).

摘　　要：Hepatocellular carcinoma(HCC)is one of the most common malignant tumors.Identification of the underlying mechanism of HCC progression and exploration of new therapeutic drugs are urgently needed.Here,a compound library consisting of 419 FDA-approved drugs was taken to screen potential anticancer drugs.A series of functional assays showed that desloratadine,an antiallergic drug,can repress proliferation in HCC cell lines,cell-derived xenograft(CDX),patient-derived organoid(PDO)and patient-derived xenograft(PDX)models.N-myristoyl transferase 1(NMT1)was identified as a target protein of desloratadine by drug affinity responsive target stability(DARTS)and surface plasmon resonance(SPR)assays.Upregulation of NMT1 expression enhanced but NMT1 knockdown suppressed tumor growth in vitro and in vivo.Metabolic labeling and mass spectrometry analyses revealed that Visinin-like protein 3(VILIP3)was a new substrate of NMT1 in protein N-myristoylation modification,and high NMT1 or VILIP3 expression was associated with advanced stages and poor survival in HCC.Mechanistically,desloratadine binds to Asn-246 in NMT1 and inhibits its enzymatic activity,disrupting the NMT1-mediated myristoylation of the VILIP3 protein and subsequent NFκB/Bcl-2 signaling.Conclusively,this study demonstrates that desloratadine may be a novel anticancer drug and that NMT1-mediated myristoylation contributes to HCC progression and is a potential biomarker and therapeutic target in HCC.

关 键 词：drugs VILI ALLERGIC 

分 类 号：R735.7[医药卫生—肿瘤]