c-MYC-mediated TRIB3/P62^(+) aggresomes accumulation triggers paraptosis upon the combination of everolimus and ginsenoside Rh2  

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

机构地区：[1]State Key Laboratory of Quality Research in Chinese Medicine,Institute of Chinese Medical Sciences,University of Macao,Macao 999078,China [2]School of Pharmaceutical Sciences,Zhejiang Chinese Medical University,Hangzhou 310000,China [3]College of Pharmacy,Fujian University of Traditional Chinese Medicine,Fuzhou 350000,China [4]Mo E Frontiers Science Center for Precision Oncology,University of Macao,Macao 999078,China

出　　处：《Acta Pharmaceutica Sinica B》2022年第3期1240-1253,共14页药学学报（英文版）

基　　金：supported by the National Natural Science Foundation of China(No.81973516);partially supported by the Science and Technology Development Fund,Macao S.A.R,China(Nos.024/2016/A1 and 0129/2019/A3);University of Macao(No.CPG2021-00022-ICMS)。

摘　　要：The mammalian target of rapamycin(m TOR) pathway is abnormally activated in lung cancer.However, the anti-lung cancer effect of m TOR inhibitors as monotherapy is modest. Here, we identified that ginsenoside Rh2, an active component of Panax ginseng C. A. Mey., enhanced the anti-cancer effect of the m TOR inhibitor everolimus both in vitro and in vivo. 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. EveRh2 up-regulated the expression of c-MYC in cancer cells as well as tumor tissues. The increased cMYC 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.

关 键 词：EVEROLIMUS Ginsenoside Rh2 Paraptosis AGGRESOMES P62 TRIB3 C-MYC Lung cancer 

分 类 号：R285[医药卫生—中药学]