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 

作者机构：State Key Laboratory of Quality Research in Chinese MedicineInstitute of Chinese Medical SciencesUniversity of MacaoMacao 999078China School of Pharmaceutical SciencesZhejiang Chinese Medical UniversityHangzhou 310000China College of PharmacyFujian University of Traditional Chinese MedicineFuzhou 350000China Mo E Frontiers Science Center for Precision OncologyUniversity of MacaoMacao 999078China 

出 版 物：《Acta Pharmaceutica Sinica B》 (药学学报（英文版）)

年 卷 期：2022年第12卷第3期

页      面：1240-1253页

核心收录：

学科分类：1007[医学-药学(可授医学、理学学位)] 1006[医学-中西医结合] 10[医学] 100602[医学-中西医结合临床] 

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)。 

主　　题：Everolimus Ginsenoside Rh2 Paraptosis Aggresomes P62 TRIB3 c-MYC Lung cancer 

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.