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

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

doi:10.1016/j.jpha.2024.101036

Volume 14 Issue 10

Oct. 2024

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Article Navigation > Journal of Pharmaceutical Analysis > 2024 > 14(10): 101036

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. Tetrandrine targeting SIRT5 exerts anti-melanoma properties via inducing ROS, ER stress, and blocked autophagy[J]. Journal of Pharmaceutical Analysis, 2024, 14(10): 101036. doi: 10.1016/j.jpha.2024.101036

Citation:

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. Tetrandrine targeting SIRT5 exerts anti-melanoma properties via inducing ROS, ER stress, and blocked autophagy[J]. Journal of Pharmaceutical Analysis, 2024, 14(10): 101036. doi: 10.1016/j.jpha.2024.101036

Citation:

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. Tetrandrine targeting SIRT5 exerts anti-melanoma properties via inducing ROS, ER stress, and blocked autophagy[J]. Journal of Pharmaceutical Analysis, 2024, 14(10): 101036. doi: 10.1016/j.jpha.2024.101036

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

doi: 10.1016/j.jpha.2024.101036

a. Department of Dermatology, The Third Hospital of Hebei Medical University, Shijiazhuang, 050051, China;
b. State Key Laboratory of Resource Insects, Medical Research Institute, Southwest University, Chongqing, 400715, China;
c. Department of Medical Oncology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, 200433, China;
d. JinFeng Laboratory, Chongqing, 400715, China;
e. Engineering Research Center for Cancer Biomedical and Translational Medicine, Southwest University, Chongqing, 400715, China

Funds:

This work was supported by funding fromNatural Science Foundation of China (Grant Nos.:82372519 and 81902664), the Postdoctoral Fellowship Program of CPSF (Grant No.: 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), and Pilot Program of Southwest University (Program No.:SWU-XDZD22006). We also thanked Jifu Li from the College of Sericulture and Textile and Biomass Science of Southwest University for the assistance during the use of the confocal fluorescence microscope (FV1000, Olympus, Japan).

Received Date: Jan. 13, 2024
Accepted Date: Jul. 01, 2024
Rev Recd Date: Jun. 10, 2024
Publish Date: Jul. 02, 2024

Abstract

Abstract

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 proliferation 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 accumulation 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.
- Melanoma,
- Tetrandrine,
- Sirtuin 5 (SIRT5),
- Mitophagy,
- Cytoskeletal protein depolymerization,
- Reactive oxygen species (ROS)

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References(50)

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