%0 Journal Article %A Wang, Yihua %A Xiong, Hua %A Liu, Dian %A Hill, Charlotte %A Ertay, Ayse %A Li, Juanjuan %A Zou, Yanmei %A Miller, Paul %A White, Eileen %A Downward, Julian %A Goldin, Robert D %A Yuan, Xianglin %A Lu, Xin %D 2019 %T Autophagy inhibition specifically promotes epithelial-mesenchymal transition and invasion in RAS-mutated cancer cells %U https://crick.figshare.com/articles/journal_contribution/Autophagy_inhibition_specifically_promotes_epithelial-mesenchymal_transition_and_invasion_in_RAS-mutated_cancer_cells/11410068 %2 https://crick.figshare.com/ndownloader/files/20297250 %K Autophagy %K EMT %K NFKB/NF-0κB %K RAS %K SQSTM1/p62 %K Downward FC001070 %K Biochemistry & Molecular Biology %K 0601 Biochemistry and Cell Biology %X 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. %I The Francis Crick Institute