Original articles
Zhaoming Lu, Xiaojing Shi, Fanghua Gong, Shenglei Li, Yang Wang, Yandan Ren, Mengyin Zhang, Bin Yu, Yan Li, Wen Zhao, Jianying Zhang, Guiqin Hou. RICTOR/mTORC2 affects tumorigenesis and therapeutic efficacy of mTOR inhibitors in esophageal squamous cell carcinoma[J]. Acta Pharmaceutica Sinica B, 2020, 10(6): 1004-1019

RICTOR/mTORC2 affects tumorigenesis and therapeutic efficacy of mTOR inhibitors in esophageal squamous cell carcinoma
Zhaoming Lua,b, Xiaojing Shia, Fanghua Gongc, Shenglei Lid, Yang Wanga, Yandan Rena, Mengyin Zhanga, Bin Yua, Yan Lie, Wen Zhaoa, Jianying Zhangf, Guiqin Houa
a School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China;
b Collaborative Innovation Center of Cancer Chemoprevention, Zhengzhou 450001, China;
c School of Pharmacy, Wenzhou Medical University, Wenzhou 325035, China;
d The First Affiliated Hospital, Zhengzhou University, Zhengzhou 450052, China;
e Center of Advanced Analysis & Gene Sequencing, Zhengzhou University, Zhengzhou 450001, China;
f Henan Academy of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450052, China
Dysregulation of mTORC1/mTORC2 pathway is observed in many cancers and mTORC1 inhibitors have been used clinically in many tumor types; however, the mechanism of mTORC2 in tumorigenesis is still obscure. Here, we mainly explored the potential role of mTORC2 in esophageal squamous cell carcinoma (ESCC) and its effects on the sensitivity of cells to mTOR inhibitors. We demonstrated that RICTOR, the key factor of mTORC2, and p-AKT (Ser473) were excessively activated in ESCC and their overexpression is related to lymph node metastasis and the tumor-node-metastasis (TNM) phase of ESCC patients. Furthermore, we found that mTORC1/mTORC2 inhibitor PP242 exhibited more efficacious anti-proliferative effect on ESCC cells than mTORC1 inhibitor RAD001 due to RAD001-triggered feedback activation of AKT signal. Another, we demonstrated that down-regulating expression of RICTOR in ECa109 and EC9706 cells inhibited proliferation and migration as well as induced cell ycle arrest and apoptosis. Noteworthy, knocking-down stably RICTOR significantly suppresses RAD001-induced feedback activation of AKT/PRAS40 signaling, and enhances inhibition efficacy of PP242 on the phosphorylation of AKT and PRAS40, thus potentiates the antitumor effect of RAD001 and PP242 both in vitro and in vivo. Our findings highlight that selective targeting mTORC2 could be a promising therapeutic strategy for future treatment of ESCC.
Key words:    RICTOR    AKT    RAD001    pp242    Esophageal squamous cell carcinoma   
Received: 2019-09-01     Revised: 2019-11-01
DOI: 10.1016/j.apsb.2020.01.010
Funds: This work was supported by the Open Foundation Project of Pharmacy in Zhejiang Province, China (Grant No.YKFJ2-010), the National Natural Science Foundation of Henan Province, China (Grant No.182300410312), Henan Provincial University Science and Technology Innovation Team, Department of Education of Henan Province (Grant No. 19IRTSTHN001, China), Key Research Project of University, Department of Education of Henan Province (Grant No. 20A350019, China) and the National Science and Technology Major Project of China (Grant No. 2018ZX10302205). The authors would like to thank all members of the study team, the patients involved in this study and Dr. Xuejian Feng from School of Pharmaceutical Sciences of Zhengzhou University (Zhengzhou, China).
Corresponding author: Guiqin Hou     Email:hougq@zzu.edu.cn
Author description:
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Zhaoming Lu
Xiaojing Shi
Fanghua Gong
Shenglei Li
Yang Wang
Yandan Ren
Mengyin Zhang
Bin Yu
Yan Li
Wen Zhao
Jianying Zhang
Guiqin Hou

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