RGD Reference Report - RICTOR/mTORC2 affects tumorigenesis and therapeutic efficacy of mTOR inhibitors in esophageal squamous cell carcinoma. - Rat Genome Database

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RICTOR/mTORC2 affects tumorigenesis and therapeutic efficacy of mTOR inhibitors in esophageal squamous cell carcinoma.

Authors: Lu, Zhaoming  Shi, Xiaojing  Gong, Fanghua  Li, Shenglei  Wang, Yang  Ren, Yandan  Zhang, Mengyin  Yu, Bin  Li, Yan  Zhao, Wen  Zhang, Jianying  Hou, Guiqin 
Citation: Lu Z, etal., Acta Pharm Sin B. 2020 Jun;10(6):1004-1019. doi: 10.1016/j.apsb.2020.01.010. Epub 2020 Jan 26.
RGD ID: 152995512
Pubmed: PMID:32642408   (View Abstract at PubMed)
PMCID: PMC7332809   (View Article at PubMed Central)
DOI: DOI:10.1016/j.apsb.2020.01.010   (Journal Full-text)

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.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
AKT1Humanesophagus squamous cell carcinoma disease_progressionIEP protein:increased expression:esophagus (human)RGD 
Akt1Ratesophagus squamous cell carcinoma disease_progressionISOAKT1 (Homo sapiens)protein:increased expression:esophagus (human)RGD 
Akt1Mouseesophagus squamous cell carcinoma disease_progressionISOAKT1 (Homo sapiens)protein:increased expression:esophagus (human)RGD 
RICTORHumanesophagus squamous cell carcinoma disease_progressionIEP protein:increased expression:esophagus (human)RGD 
RictorRatesophagus squamous cell carcinoma disease_progressionISORICTOR (Homo sapiens)protein:increased expression:esophagus (human)RGD 
RictorMouseesophagus squamous cell carcinoma disease_progressionISORICTOR (Homo sapiens)protein:increased expression:esophagus (human)RGD 

Objects Annotated

Genes (Rattus norvegicus)
Akt1  (AKT serine/threonine kinase 1)
Rictor  (RPTOR independent companion of MTOR, complex 2)

Genes (Mus musculus)
Akt1  (thymoma viral proto-oncogene 1)
Rictor  (RPTOR independent companion of MTOR, complex 2)

Genes (Homo sapiens)
AKT1  (AKT serine/threonine kinase 1)
RICTOR  (RPTOR independent companion of MTOR complex 2)


Additional Information