Original articles
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. c-MYC-mediated TRIB3/P62+ aggresomes accumulation triggers paraptosis upon the combination of everolimus and ginsenoside Rh2[J]. Acta Pharmaceutica Sinica B, 2022, 12(3): 1240-1253

c-MYC-mediated TRIB3/P62+ aggresomes accumulation triggers paraptosis upon the combination of everolimus and ginsenoside Rh2
Min-Xia Sua, Yu-Lian Xua, Xiao-Ming Jianga, Mu-Yang Huanga, Le-Le Zhanga, Luo-Wei Yuana, Xiao-Huang Xua, Qi Zhua, Jian-Li Gaob, Jia-Hong Lua, Xiuping Chena, Ming-Qing Huangc, Yitao Wanga, Jin-Jian Lua,d
a. State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, China;
b. School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310000, China;
c. College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou 350000, China;
d. MoE Frontiers Science Center for Precision Oncology, University of Macau, Macao 999078, China
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 Panax ginseng C. A. Mey., enhanced the anti-cancer effect of the mTOR 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. 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.
Key words:    Everolimus    Ginsenoside Rh2    Paraptosis    Aggresomes    P62    TRIB3    c-MYC    Lung cancer   
Received: 2021-06-17     Revised: 2021-08-30
DOI: 10.1016/j.apsb.2021.09.014
Funds: We would like to appreciate Prof. Hua Li and Ms. Jing Guo (Huazhong University of Science and Technology, China), Prof. Su-Hong Chen and Dr. Bo Li (Zhejiang University of Technology, China) for their assistance in animal experiments, Prof. Cheng-Wei He (University of Macau, China) for sponsoring the P62 antibody, Prof. Jian-Bo Wan (University of Macau, China) for suggestions relating to hepatic fat accumulation, Ms. Xin-Ling He, Mr. Zi-Han Ye and Mr. Wei-Bang Yu (University of Macau, China) for their kind help in animal experiments, and Ms. Hai-Lu Su (China Academy of Art, China) for her assistance in drawing Fig. 7J. In addition, we thank the members of the SPF animal facility of Faculty of Health Sciences at the University of Macau for experimental and technical supports. This study was supported by the National Natural Science Foundation of China (No. 81973516) and partially supported by the Science and Technology Development Fund, Macao S.A.R, China (Nos. 024/2016/A1 and 0129/2019/A3), as well as University of Macau (No. CPG2021-00022-ICMS).
Corresponding author: Jin-Jian Lu,E-mai:jinjianlu@um.edu.mo     Email:jinjianlu@um.edu.mo
Author description:
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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

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