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dc.contributor.authorWang, Y
dc.contributor.authorXiong, H
dc.contributor.authorLiu, D
dc.contributor.authorHill, C
dc.contributor.authorErtay, A
dc.contributor.authorLi, J
dc.contributor.authorZou, Y
dc.contributor.authorMiller, P
dc.contributor.authorWhite, E
dc.contributor.authorDownward, J
dc.contributor.authorGoldin, RD
dc.contributor.authorYuan, X
dc.contributor.authorLu, X
dc.date.accessioned2020-06-08T14:33:53Z
dc.date.issued2019-05
dc.identifier.citationAutophagy, 2019, 15 (5), pp. 886 - 899
dc.identifier.issn1554-8627
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3699
dc.identifier.eissn1554-8635
dc.identifier.doi10.1080/15548627.2019.1569912
dc.description.abstractMacroautophagy/autophagy inhibition is a novel anticancer therapeutic strategy, especially for tumors driven by mutant RAS. Here, we demonstrate that autophagy inhibition in RAS-mutated cells induces epithelial-mesenchymal transition (EMT), which is associated with enhanced tumor invasion. This is at least partially achieved by triggering the NFKB/NF-κB pathway via SQSTM1/p62. Knockdown of ATG3 or ATG5 increases oncogenic RAS-induced expression of ZEB1 and SNAI2/Snail2, and activates NFKB activity. Depletion of SQSTM1 abolishes the activation of the NFKB pathway induced by autophagy inhibition in RAS-mutated cells. NFKB pathway inhibition by depletion of RELA/p65 blocks this EMT induction. Finally, accumulation of SQSTM1 protein correlates with loss of CDH1/E-cadherin expression in pancreatic adenocarcinoma. Together, we suggest that combining autophagy inhibition with NFKB inhibitors may therefore be necessary to treat RAS-mutated cancer. Abbreviations: 4-OHT: 4-hydroxytamoxifen; DIC: differential interference contrast; EMT: epithelial-mesenchymal transition; ESR: estrogen receptor; MAPK/ERK: mitogen-activated protein kinase; iBMK: immortalized baby mouse kidney epithelial cells; MET: mesenchymal-epithelial transition; PI3K: phosphoinositide 3-kinase; RNAi: RNA interference; TGFB/TGF-β: transforming growth factor beta; TNF: tumor necrosis factor; TRAF6: TNF receptor associated factor 6.
dc.formatPrint-Electronic
dc.format.extent886 - 899
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.subjectCell Line, Tumor
dc.subjectHCT116 Cells
dc.subjectHumans
dc.subjectNeoplasms
dc.subjectNeoplasm Invasiveness
dc.subjectUbiquitin-Conjugating Enzymes
dc.subjectRNA, Small Interfering
dc.subjectAntineoplastic Agents
dc.subjectUp-Regulation
dc.subjectMutation
dc.subjectGenes, ras
dc.subjectAutophagy
dc.subjectTranscription Factor RelA
dc.subjectEpithelial-Mesenchymal Transition
dc.subjectSequestosome-1 Protein
dc.subjectAutophagy-Related Protein 5
dc.subjectAutophagy-Related Proteins
dc.titleAutophagy inhibition specifically promotes epithelial-mesenchymal transition and invasion in RAS-mutated cancer cells.
dc.typeJournal Article
rioxxterms.versionofrecord10.1080/15548627.2019.1569912
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2019-05
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfAutophagy
pubs.issue5
pubs.notesNot known
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Biology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Biology/Lung Cancer Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Lung Cancer Group
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Biology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Biology/Lung Cancer Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Lung Cancer Group
pubs.publication-statusPublished
pubs.volume15
pubs.embargo.termsNot known
icr.researchteamLung Cancer Groupen_US
dc.contributor.icrauthorDownward, Julian David Harryen


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