dc.contributor.author | Wang, Y | |
dc.contributor.author | Xiong, H | |
dc.contributor.author | Liu, D | |
dc.contributor.author | Hill, C | |
dc.contributor.author | Ertay, A | |
dc.contributor.author | Li, J | |
dc.contributor.author | Zou, Y | |
dc.contributor.author | Miller, P | |
dc.contributor.author | White, E | |
dc.contributor.author | Downward, J | |
dc.contributor.author | Goldin, RD | |
dc.contributor.author | Yuan, X | |
dc.contributor.author | Lu, X | |
dc.date.accessioned | 2020-06-08T14:33:53Z | |
dc.date.issued | 2019-05 | |
dc.identifier.citation | Autophagy, 2019, 15 (5), pp. 886 - 899 | |
dc.identifier.issn | 1554-8627 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/3699 | |
dc.identifier.eissn | 1554-8635 | |
dc.identifier.doi | 10.1080/15548627.2019.1569912 | |
dc.description.abstract | Macroautophagy/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.format | Print-Electronic | |
dc.format.extent | 886 - 899 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.subject | Cell Line, Tumor | |
dc.subject | HCT116 Cells | |
dc.subject | Humans | |
dc.subject | Neoplasms | |
dc.subject | Neoplasm Invasiveness | |
dc.subject | Ubiquitin-Conjugating Enzymes | |
dc.subject | RNA, Small Interfering | |
dc.subject | Antineoplastic Agents | |
dc.subject | Up-Regulation | |
dc.subject | Mutation | |
dc.subject | Genes, ras | |
dc.subject | Autophagy | |
dc.subject | Transcription Factor RelA | |
dc.subject | Epithelial-Mesenchymal Transition | |
dc.subject | Sequestosome-1 Protein | |
dc.subject | Autophagy-Related Protein 5 | |
dc.subject | Autophagy-Related Proteins | |
dc.title | Autophagy inhibition specifically promotes epithelial-mesenchymal transition and invasion in RAS-mutated cancer cells. | |
dc.type | Journal Article | |
rioxxterms.versionofrecord | 10.1080/15548627.2019.1569912 | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0 | |
rioxxterms.licenseref.startdate | 2019-05 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Autophagy | |
pubs.issue | 5 | |
pubs.notes | Not 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-status | Published | |
pubs.volume | 15 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Lung Cancer Group | en_US |
dc.contributor.icrauthor | Downward, Julian David Harry | |