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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

DC FieldValueLanguage
dc.contributor.author김세규-
dc.contributor.author김은영-
dc.contributor.author김형중-
dc.contributor.author장윤수-
dc.contributor.author장준-
dc.contributor.author안철민-
dc.date.accessioned2015-01-06T16:31:26Z-
dc.date.available2015-01-06T16:31:26Z-
dc.date.issued2014-
dc.identifier.issn1465-9921-
dc.identifier.urihttps://ir.ymlib.yonsei.ac.kr/handle/22282913/98267-
dc.description.abstractBACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.-
dc.description.statementOfResponsibilityopen-
dc.formatapplication/pdf-
dc.relation.isPartOfRESPIRATORY RESEARCH-
dc.rightsCC BY-NC-ND 2.0 KR-
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/2.0/kr/-
dc.subject.MESHCadherins/antagonists & inhibitors-
dc.subject.MESHCadherins/biosynthesis*-
dc.subject.MESHCadherins/genetics-
dc.subject.MESHCarcinoma, Non-Small-Cell Lung/genetics-
dc.subject.MESHCarcinoma, Non-Small-Cell Lung/metabolism*-
dc.subject.MESHCell Line, Tumor-
dc.subject.MESHEnzyme Inhibitors/pharmacology-
dc.subject.MESHEpithelial-Mesenchymal Transition/drug effects-
dc.subject.MESHEpithelial-Mesenchymal Transition/physiology-
dc.subject.MESHGene Silencing/physiology-
dc.subject.MESHGlycogen Synthase Kinase 3/antagonists & inhibitors-
dc.subject.MESHGlycogen Synthase Kinase 3/biosynthesis*-
dc.subject.MESHGlycogen Synthase Kinase 3/genetics-
dc.subject.MESHGlycogen Synthase Kinase 3 beta-
dc.subject.MESHHumans-
dc.subject.MESHLung Neoplasms/genetics-
dc.subject.MESHLung Neoplasms/metabolism*-
dc.subject.MESHMechanistic Target of Rapamycin Complex 1-
dc.subject.MESHMultiprotein Complexes/antagonists & inhibitors-
dc.subject.MESHMultiprotein Complexes/biosynthesis*-
dc.subject.MESHMultiprotein Complexes/genetics-
dc.subject.MESHProto-Oncogene Proteins c-akt/antagonists & inhibitors-
dc.subject.MESHProto-Oncogene Proteins c-akt/biosynthesis*-
dc.subject.MESHProto-Oncogene Proteins c-akt/genetics-
dc.subject.MESHRetrospective Studies-
dc.subject.MESHSignal Transduction/drug effects-
dc.subject.MESHSignal Transduction/physiology-
dc.subject.MESHTOR Serine-Threonine Kinases/antagonists & inhibitors-
dc.subject.MESHTOR Serine-Threonine Kinases/biosynthesis*-
dc.subject.MESHTOR Serine-Threonine Kinases/genetics-
dc.subject.MESHUp-Regulation/drug effects-
dc.subject.MESHUp-Regulation/physiology-
dc.titleInhibition 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-
dc.typeArticle-
dc.contributor.collegeCollege of Medicine (의과대학)-
dc.contributor.departmentDept. of Internal Medicine (내과학)-
dc.contributor.googleauthorEun Young Kim-
dc.contributor.googleauthorArum Kim-
dc.contributor.googleauthorSe Kyu Kim-
dc.contributor.googleauthorHyung Jung Kim-
dc.contributor.googleauthorJoon Chang-
dc.contributor.googleauthorChul Min Ahn-
dc.contributor.googleauthorYoon Soo Chang-
dc.identifier.doi10.1186/1465-9921-15-26-
dc.admin.authorfalse-
dc.admin.mappingfalse-
dc.contributor.localIdA00602-
dc.contributor.localIdA01158-
dc.contributor.localIdA02269-
dc.contributor.localIdA03456-
dc.contributor.localIdA03472-
dc.contributor.localIdA00811-
dc.relation.journalcodeJ02616-
dc.identifier.eissn1465-993X-
dc.identifier.pmid24571487-
dc.subject.keywordmTOR-
dc.subject.keywordmTORC1-
dc.subject.keywordmTORC2-
dc.subject.keywordE-Cadherin repressor complexes-
dc.subject.keywordRaptor-
dc.subject.keywordRictor-
dc.subject.keywordEMT-
dc.contributor.alternativeNameKim, Se Kyu-
dc.contributor.alternativeNameKim, Eun Young-
dc.contributor.alternativeNameKim, Hyung Jung-
dc.contributor.alternativeNameAhn, Chul Min-
dc.contributor.alternativeNameChang, Yoon Soo-
dc.contributor.alternativeNameChang, Joon-
dc.contributor.affiliatedAuthorKim, Se Kyu-
dc.contributor.affiliatedAuthorKim, Hyung Jung-
dc.contributor.affiliatedAuthorAhn, Chul Min-
dc.contributor.affiliatedAuthorChang, Yoon Soo-
dc.contributor.affiliatedAuthorChang, Joon-
dc.contributor.affiliatedAuthorKim, Eun Young-
dc.citation.volume15-
dc.citation.number26-
dc.citation.startPage1-
dc.citation.endPage9-
dc.identifier.bibliographicCitationRESPIRATORY RESEARCH, Vol.15(26) : 1-9, 2014-
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers

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