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c-MYC介导的TRIB3/P62聚集体积累在依维莫司和人参皂苷Rh2联合使用时引发副凋亡。

c-MYC-mediated TRIB3/P62 aggresomes accumulation triggers paraptosis upon the combination of everolimus and ginsenoside Rh2.

作者信息

Su Min-Xia, Xu Yu-Lian, Jiang Xiao-Ming, Huang Mu-Yang, Zhang Le-Le, Yuan Luo-Wei, Xu Xiao-Huang, Zhu Qi, Gao Jian-Li, Lu Jia-Hong, Chen Xiuping, Huang Ming-Qing, Wang Yitao, Lu Jin-Jian

机构信息

State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, China.

School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310000, China.

出版信息

Acta Pharm Sin B. 2022 Mar;12(3):1240-1253. doi: 10.1016/j.apsb.2021.09.014. Epub 2021 Sep 22.

DOI:10.1016/j.apsb.2021.09.014
PMID:35530150
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9072243/
Abstract

The mammalian target of rapamycin (mTOR) pathway is abnormally activated in lung cancer. However, the anti-lung cancer effect of mTOR inhibitors as monotherapy is modest. Here, we identified that ginsenoside Rh2, an active component of C. A. Mey., enhanced the anti-cancer effect of the mTOR inhibitor everolimus both and . Moreover, ginsenoside Rh2 alleviated the hepatic fat accumulation caused by everolimus in xenograft nude mice models. The combination of everolimus and ginsenoside Rh2 (labeled Eve-Rh2) induced caspase-independent cell death and cytoplasmic vacuolation in lung cancer cells, indicating that Eve-Rh2 prevented tumor progression by triggering paraptosis. Eve-Rh2 up-regulated the expression of c-MYC in cancer cells as well as tumor tissues. The increased c-MYC mediated the accumulation of tribbles homolog 3 (TRIB3)/P62 aggresomes and consequently triggered paraptosis, bypassing the classical c-MYC/MAX pathway. Our study offers a potential effective and safe strategy for the treatment of lung cancer. Moreover, we have identified a new mechanism of TRIB3/P62 aggresomes-triggered paraptosis and revealed a unique function of c-MYC.

摘要

雷帕霉素哺乳动物靶点（mTOR）信号通路在肺癌中异常激活。然而，mTOR抑制剂作为单一疗法的抗肺癌效果并不显著。在此，我们发现人参皂苷Rh2（五加科植物人参的活性成分）可增强mTOR抑制剂依维莫司的抗癌效果。此外，人参皂苷Rh2可减轻依维莫司在异种移植裸鼠模型中引起的肝脏脂肪堆积。依维莫司与人参皂苷Rh2联合用药（标记为Eve-Rh2）可诱导肺癌细胞发生非半胱天冬酶依赖性细胞死亡和细胞质空泡化，表明Eve-Rh2通过触发副凋亡来阻止肿瘤进展。Eve-Rh2可上调癌细胞以及肿瘤组织中c-MYC的表达。增加的c-MYC介导了 Tribbles 同源物3（TRIB3）/P62聚集体的积累，从而触发副凋亡，绕过了经典的c-MYC/MAX信号通路。我们的研究为肺癌治疗提供了一种潜在有效且安全的策略。此外，我们发现了TRIB3/P62聚集体触发副凋亡的新机制，并揭示了c-MYC的独特功能。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ace7/9072243/e345ae5b8cae/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ace7/9072243/ac80677cb653/ga1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ace7/9072243/fa9b662a02b4/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ace7/9072243/52fa15028840/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ace7/9072243/d9e36aae4ecb/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ace7/9072243/bfdb0fd8f347/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ace7/9072243/3b944df9d1bd/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ace7/9072243/198e5f9c0b67/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ace7/9072243/e345ae5b8cae/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ace7/9072243/ac80677cb653/ga1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ace7/9072243/fa9b662a02b4/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ace7/9072243/52fa15028840/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ace7/9072243/d9e36aae4ecb/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ace7/9072243/bfdb0fd8f347/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ace7/9072243/3b944df9d1bd/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ace7/9072243/198e5f9c0b67/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ace7/9072243/e345ae5b8cae/gr7.jpg

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