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Autophagy inhibition specifically promotes epithelial-mesenchymal transition and invasion in RAS-mutated cancer cells

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Title: Autophagy inhibition specifically promotes epithelial-mesenchymal transition and invasion in RAS-mutated cancer cells
Authors: Wang, Y
Xiong, H
Liu, D
Hill, C
Ertay, A
Li, J
Zou, Y
Miller, P
White, E
Downward, J
Goldin, RD
Yuan, X
Lu, X
Item Type: Journal Article
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.
Issue Date: 20-Feb-2019
Date of Acceptance: 28-Oct-2018
URI: http://hdl.handle.net/10044/1/71859
DOI: htttps://dx.doi.org/10.1080/15548627.2019.1569912
ISSN: 1554-8627
Publisher: Taylor & Francis
Start Page: 886
End Page: 899
Journal / Book Title: Autophagy
Volume: 15
Issue: 5
Copyright Statement: © 2019 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use,distribution, and reproduction in any medium, provided the original work is properly cited.
Keywords: Science & Technology
Life Sciences & Biomedicine
Cell Biology
Autophagy
EMT
NFKB
NF-0 kappa B
RAS
SQSTM1
p62
NF-KAPPA-B
METASTASIS
P62
PROGRESSION
MODULATION
ACTIVATION
EXPRESSION
PREDICTOR
ONCOGENES
Autophagy
EMT
NFKB/NF-0κB
RAS
SQSTM1/p62
Autophagy
EMT
NFKB/NF-0κB
RAS
SQSTM1/p62
0601 Biochemistry and Cell Biology
Biochemistry & Molecular Biology
Publication Status: Published
Conference Place: United States
Online Publication Date: 2019-02-20
Appears in Collections:Department of Medicine (up to 2019)