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Inhibition of mTORC1 induces loss of E-cadherin through AKT/GSK-3β signaling-mediated upregulation of E-cadherin repressor complexes in non-small cell lung cancer cells

 Eun Young Kim  ;  Arum Kim  ;  Se Kyu Kim  ;  Hyung Jung Kim  ;  Joon Chang  ;  Chul Min Ahn  ;  Yoon Soo Chang 
 RESPIRATORY RESEARCH, Vol.15(26) : 1-9, 2014 
Journal Title
Issue Date
Cadherins/antagonists & inhibitors ; Cadherins/biosynthesis* ; Cadherins/genetics ; Carcinoma, Non-Small-Cell Lung/genetics ; Carcinoma, Non-Small-Cell Lung/metabolism* ; Cell Line, Tumor ; Enzyme Inhibitors/pharmacology ; Epithelial-Mesenchymal Transition/drug effects ; Epithelial-Mesenchymal Transition/physiology ; Gene Silencing/physiology ; Glycogen Synthase Kinase 3/antagonists & inhibitors ; Glycogen Synthase Kinase 3/biosynthesis* ; Glycogen Synthase Kinase 3/genetics ; Glycogen Synthase Kinase 3 beta ; Humans ; Lung Neoplasms/genetics ; Lung Neoplasms/metabolism* ; Mechanistic Target of Rapamycin Complex 1 ; Multiprotein Complexes/antagonists & inhibitors ; Multiprotein Complexes/biosynthesis* ; Multiprotein Complexes/genetics ; Proto-Oncogene Proteins c-akt/antagonists & inhibitors ; Proto-Oncogene Proteins c-akt/biosynthesis* ; Proto-Oncogene Proteins c-akt/genetics ; Retrospective Studies ; Signal Transduction/drug effects ; Signal Transduction/physiology ; TOR Serine-Threonine Kinases/antagonists & inhibitors ; TOR Serine-Threonine Kinases/biosynthesis* ; TOR Serine-Threonine Kinases/genetics ; Up-Regulation/drug effects ; Up-Regulation/physiology
mTOR ; mTORC1 ; mTORC2 ; E-Cadherin repressor complexes ; Raptor ; Rictor ; EMT
mTOR, which can form mTOR Complex 1 (mTORC1) or mTOR Complex 2 (mTORC2) depending on its binding partners, is frequently deregulated in the pulmonary neoplastic conditions and interstitial lung diseases of the patients treated with rapalogs. In this study, we investigated the relationship between mTOR signaling and epithelial mesenchymal transition (EMT) by dissecting mTOR pathways.
Components of mTOR signaling pathway were silenced by shRNA in a panel of non-small cell lung cancer cell lines and protein expression of epithelial and mesenchymal markers were evaluated by immunoblotting and immunocytochemistry. mRNA level of the E-cadherin repressor complexes were evaluated by qRT-PCR.
IGF-1 treatment decreased expression of the E-cadherin and rapamycin increased its expression, suggesting hyperactivation of mTOR signaling relates to the loss of E-cadherin. Genetic ablation of rapamycin-insensitive companion of mTOR (Rictor), a component of mTORC2, did not influence E-cadherin expression, whereas genetic ablation of regulatory-associated protein of mTOR (Raptor), a component of mTORC1, led to a decrease in E-cadherin expression at the mRNA level. Increased phosphorylation of AKT at Ser473 and GSK-3β at Ser9 were observed in the Raptor-silenced NSCLC cells. Of the E-cadherin repressor complexes tested, Snail, Zeb2, and Twist1 mRNAs were elevated in raptor-silenced A549 cells, and Zeb2 and Twist1 mRNAs were elevated in Raptor-silenced H2009 cells. These findings were recapitulated by treatment with the GSK-3β inhibitor, LiCl. Raptor knockdown A549 cells showed increased expression of N-cadherin and vimentin with mesenchymal phenotypic changes.
In conclusion, selective inhibition of mTORC1 leads to hyperactivation of the AKT/GSK-3β pathway, inducing E-cadherin repressor complexes and EMT. These findings imply the existence of a feedback inhibition loop of mTORC1 onto mTORC2 that plays a role in the homeostasis of E-cadherin expression and EMT, requiring caution in the clinical use of rapalog and selective mTORC1 inhibitors.
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1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Se Kyu(김세규)
Kim, Eun Young(김은영) ORCID logo https://orcid.org/0000-0002-3281-5744
Kim, Hyung Jung(김형중) ORCID logo https://orcid.org/0000-0003-2498-0683
Ahn, Chul Min(안철민)
Chang, Yoon Soo(장윤수) ORCID logo https://orcid.org/0000-0003-3340-4223
Chang, Joon(장준) ORCID logo https://orcid.org/0000-0003-4542-6841
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