Tetrandrine targeting SIRT5 exerts anti-melanoma properties via inducing ROS, ER stress, and blocked autophagy  

作　　者：Yacong Ji Chongyang Li Sicheng Wan Zhen Dong Chaolong Liu Leiyang Guo Shaomin Shi Mingxin Ci Minghao Xu Qian Li Huanrong Hu Hongjuan Cui Yaling Liu 

机构地区：[1]Department of Dermatology,The Third Hospital of Hebei Medical University,Shijiazhuang,050051,China [2]State Key Laboratory of Resource Insects,Medical Research Institute,Southwest University,Chongqing,400715,China [3]Department of Medical Oncology,Shanghai Pulmonary Hospital,School of Medicine,Tongji University,Shanghai,200433,China [4]JinFeng Laboratory,Chongqing,400715,China [5]Engineering Research Center for Cancer Biomedical and Translational Medicine,Southwest University,Chongqing,400715,China

出　　处：《Journal of Pharmaceutical Analysis》2024年第10期1468-1483,共16页药物分析学报（英文版）

基　　金：This work was supported by funding from Natural Science Foundation of China(Grant Nos.:82372519 and 81902664);the PostdoctoralFellowshipProgramof CPSF(GrantNo.:GZB20240544);the China Postdoctoral Science Foundation(Grant No.:2024M752432);the Natural Science Foundation of Hebei Province(Grant Nos.:H2022206368 and H2022206446);Medical Science Research Program of the Hebei Provincial Health Commission(Grant No.:20241603);Pilot Program of Southwest University(Program No.:SWU-XDZD22006)。

摘　　要：Tetrandrine(TET),a natural bisbenzyl isoquinoline alkaloid extracted from Stephania tetrandra S.Moore,has diverse pharmacological effects.However,its effects on melanoma remain unclear.Cellular prolif-eration assays,multi-omics analyses,and xenograft models were used to determine the effect of TET on melanoma.The direct target of TET was identified using biotin-TET pull-down liquid chromatograph-mass spectrometry(LC-MS),cellular thermal shift assays,and isothermal titration calorimetry(ITC)analysis.Our findings revealed that TET treatment induced robust cellular autophagy depending on activating transcription factor 6(ATF6)-mediated endoplasmic reticulum(ER)stress.Simultaneously,it hindered autophagic flux by inducing cytoskeletal protein depolymerization in melanoma cells.TET treatment resulted in excessive accumulation of reactive oxygen species(Ros)and simultaneously triggered mitophagy.Sirtuin 5(SIRT5)was ultimately found to be a direct target of TET.Mechanistically,TET led to the degradation of SIRT5 via the ubiquitin(Ub)-26S proteasome system.SIRT5 knockdown induced ROS accumulation,whereas SIRT5 overexpression attenuated the TET-induced ROS accumula-tion and autophagy.Importantly,TET exhibited anti-cancer effects in xenograft models depending on SIRT5 expression.This study highlights the potential of TET as an antimelanoma agent that targets SIRT5.These findings provide a promising avenue for the use of TET in melanoma treatment and underscore its potential as a therapeutic candidate.

关 键 词：MELANOMA TETRANDRINE Sirtuin 5(SIRT5) MITOPHAGY Cytoskeletal protein depolymerization Reactive oxygen species(ROS) 

分 类 号：R739.5[医药卫生—肿瘤]