RICTOR/mTORC2 affects tumorigenesis and therapeutic efficacy of mTOR inhibitors in esophageal squamous cell carcinoma
| Autor: | Shenglei Li, Yandan Ren, Fanghua Gong, Mengyin Zhang, Wen Zhao, Xiao-Jing Shi, Guiqin Hou, Zhaoming Lu, Yang Wang, Bin Yu, Jianying Zhang, Yan Li |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Original article
Cell cycle checkpoint AKT protein kinase B (PKB) IC50 half maximal inhibitory concentration mTORC1 mTOR mammalian target of rapamycin pp242 medicine.disease_cause mTORC2 TUNEL terminal deoxynucleotidyl transferase dUTP nick end labeling 4EBP-1 E binding protein-1 03 medical and health sciences 0302 clinical medicine PI3K phosphatidylinositol 3 kinase In vivo Esophageal squamous cell carcinoma Medicine General Pharmacology Toxicology and Pharmaceutics Protein kinase B RAD001 030304 developmental biology 0303 health sciences business.industry H&E staining hematoxylin and eosin staining AKT lcsh:RM1-950 mTORC2 mTOR complex 2 rapalogs rapamycin and its analogs TNM tumor-node-metastasis FDA U.S. Food and Drug Administration lcsh:Therapeutics. Pharmacology RICTOR rapamycin-insensitive companion of mTOR Apoptosis 030220 oncology & carcinogenesis Cancer research Phosphorylation p70S6K p70 ribosomal S6 kinase-1 ESCC esophageal squamous cell carcinoma mTORC1 mTOR complex 1 business Carcinogenesis RICTOR |
| Zdroj: | Acta Pharmaceutica Sinica. B Acta Pharmaceutica Sinica B, Vol 10, Iss 6, Pp 1004-1019 (2020) |
| ISSN: | 2211-3835 |
| Popis: | 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 cycle 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. Graphical abstract This study demonstrated that mTORC2 subunit, RICTOR, and p-AKT (Ser473) have hyperactivity in esophageal squamous cell carcinoma (ESCC) and promotes its development. Moreover, down-regulation of RICTOR can improve the sensitivity of ESCC cells to the pan-mTOR inhibitor PP242 as well as mTORC1 inhibitor RAD001.Image 1 |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|