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原薯蓣皂苷通过引发内质网应激介导的IP3R靶向Mfn1/Bak表达诱导人肝癌细胞的线粒体凋亡。

Protodioscin Induces Mitochondrial Apoptosis of Human Hepatocellular Carcinoma Cells Through Eliciting ER Stress-Mediated IP3R Targeting Mfn1/Bak Expression.

作者信息

Yu Chen-Lin, Lee Hsiang-Lin, Yang Shun-Fa, Wang Shih-Wei, Lin Ching-Pin, Hsieh Yi-Hsien, Chiou Hui-Ling

机构信息

Institute of Biomedical Science, Mackay Medical College, New Taipei City, Taiwan.

Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.

出版信息

J Hepatocell Carcinoma. 2022 Apr 24;9:327-341. doi: 10.2147/JHC.S355027. eCollection 2022.

DOI:10.2147/JHC.S355027
PMID:35496076
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9049873/
Abstract

OBJECTIVE

Protodioscin (PD), a steroidal saponin, has a diverse pharmacological activity including neuroprotection, male fertility improvement, and cytotoxicity against various cancers cell lines of different origins. However, the effect of PD on hepatocellular carcinoma (HCC) is still unclear.

METHODS

Cell viability, colony formation and flow cytometry analysis for apoptosis profile, mitochondrial membrane potential endoplasmic reticulum (ER) expansion were employed to determine the effect of PD against HCC cells. Transient transfection of siRNA, immunofluorescent imaging and immunoprecipitation were used to elucidate the anti-cancer mechanism of PD. The in vivo toxicity and efficacy of PD were assessed by a xenograft mouse model.

RESULTS

PD induced apoptosis, loss of mitochondrial membrane potential and ER expansion in HCC cells. Either downregulation of Mfn1 or Bak reversed PD-induced apoptosis and loss of mitochondrial membrane potential. Further analysis revealed that Mfn1 and Bak will form a complex with IP3R to facilitate the transfer of Ca from ER to mitochondria and apoptosis. In addition, our tumour xenograft model further verifies the in vivo anti-tumour effect of PD.

CONCLUSION

Our study sheds light on the understanding of the anti-HCC effects of PD and may open new aspects for the development of novel treatment for human hepatocellular carcinoma.

摘要

目的

原薯蓣皂苷（PD）是一种甾体皂苷，具有多种药理活性，包括神经保护、改善男性生育能力以及对不同来源的各种癌细胞系具有细胞毒性。然而，PD对肝细胞癌（HCC）的作用仍不清楚。

方法

采用细胞活力、集落形成以及凋亡谱、线粒体膜电位、内质网（ER）扩张的流式细胞术分析来确定PD对肝癌细胞的作用。通过小干扰RNA（siRNA）的瞬时转染、免疫荧光成像和免疫沉淀来阐明PD的抗癌机制。通过异种移植小鼠模型评估PD的体内毒性和疗效。

结果

PD诱导肝癌细胞凋亡、线粒体膜电位丧失和内质网扩张。Mfn1或Bak的下调均可逆转PD诱导的凋亡和线粒体膜电位丧失。进一步分析表明，Mfn1和Bak将与肌醇三磷酸受体（IP3R）形成复合物，以促进钙从内质网转移到线粒体并引发凋亡。此外，我们的肿瘤异种移植模型进一步验证了PD的体内抗肿瘤作用。

结论

我们的研究有助于理解PD对肝癌的作用，并可能为人类肝细胞癌新治疗方法的开发开辟新的方向。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3232/9049873/551c8b1ac06b/JHC-9-327-g0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3232/9049873/1c1b26d80a13/JHC-9-327-g0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3232/9049873/9f4a1594216f/JHC-9-327-g0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3232/9049873/b42f74df6494/JHC-9-327-g0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3232/9049873/af938c3851b7/JHC-9-327-g0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3232/9049873/7a54c1dbe55b/JHC-9-327-g0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3232/9049873/828f1b2a9672/JHC-9-327-g0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3232/9049873/98065e7e9f3e/JHC-9-327-g0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3232/9049873/551c8b1ac06b/JHC-9-327-g0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3232/9049873/1c1b26d80a13/JHC-9-327-g0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3232/9049873/9f4a1594216f/JHC-9-327-g0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3232/9049873/b42f74df6494/JHC-9-327-g0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3232/9049873/af938c3851b7/JHC-9-327-g0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3232/9049873/7a54c1dbe55b/JHC-9-327-g0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3232/9049873/828f1b2a9672/JHC-9-327-g0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3232/9049873/98065e7e9f3e/JHC-9-327-g0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3232/9049873/551c8b1ac06b/JHC-9-327-g0008.jpg

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