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

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

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  • 国家科技期刊平台
  • NETL
  • NSTL
  • 万方数据
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.

MelanomaTetrandrineSirtuin 5(SIRT5)MitophagyCytoskeletal protein depolymerizationReactive oxygen species(ROS)

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

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Department of Dermatology,The Third Hospital of Hebei Medical University,Shijiazhuang,050051,China

State Key Laboratory of Resource Insects,Medical Research Institute,Southwest University,Chongqing,400715,China

Department of Medical Oncology,Shanghai Pulmonary Hospital,School of Medicine,Tongji University,Shanghai 200433,China

State Key Laboratory of Resource Insects,Medical Research Institute,Southwest University,Chongqing 400715,China

Department of Dermatology,the Third Hospital of Hebei Medical University,Shijiazhuang 050051,China

JinFeng Laboratory,Chongqing,400715,China

Engineering Research Center for Cancer Biomedical and Translational Medicine,Southwest University,Chongqing,400715,China

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2024

10.1016/j.jpha.2024.101036

药物分析学报(英文)
西安交通大学

药物分析学报(英文)

影响因子：0.244
ISSN：2095-1779
年,卷(期)：2024.14(10)