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

Autophagy inhibition specifically promotes epithelial-mesenchymal transition and invasion in RAS-mutated cancer cells
Autophagy inhibition specifically promotes epithelial-mesenchymal transition and invasion in RAS-mutated cancer cells
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 NFKBpathway 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 RASmutated cancer.
1554-8627
886-899
Wang, Yihua
f5044a95-60a7-42d2-87d6-5f1f789e3a7e
Xiong, Hua
2521cfab-f603-4fe2-b038-7a508b866d65
Liu, Dian
4ea8ec16-006a-48bc-89d3-40c0c69d896a
Hill, Charlotte
6d1cfed3-11b1-48af-b171-b8726ab673eb
Ertay, Ayse
fdd0c5cb-cfb2-4e25-9343-cdc462035531
Li, Juanjuan
7888cf96-2102-4b8c-b719-5dd71f4c359d
Zou, Yanmei
9e9728e2-ec84-4691-a78c-44bb3625c9a1
Miller, Paul
6fb15d56-ceb8-499d-aa86-a6a9c954c875
White, Eileen
ef32ccf7-8bc4-4608-983a-97cc1bd4f6e0
Downward, Julian
8c5ea429-4763-4010-be2e-94eed542dd57
Goldin, Robert
236b8cd1-f43d-4fae-8d55-77cb1704c9c1
Yuan, Xianglin
69ed23ce-4774-480c-b2d6-1447e1ade2ae
Lu, Xin
23803ccb-4f47-433f-8285-76e3dee950b7
Wang, Yihua
f5044a95-60a7-42d2-87d6-5f1f789e3a7e
Xiong, Hua
2521cfab-f603-4fe2-b038-7a508b866d65
Liu, Dian
4ea8ec16-006a-48bc-89d3-40c0c69d896a
Hill, Charlotte
6d1cfed3-11b1-48af-b171-b8726ab673eb
Ertay, Ayse
fdd0c5cb-cfb2-4e25-9343-cdc462035531
Li, Juanjuan
7888cf96-2102-4b8c-b719-5dd71f4c359d
Zou, Yanmei
9e9728e2-ec84-4691-a78c-44bb3625c9a1
Miller, Paul
6fb15d56-ceb8-499d-aa86-a6a9c954c875
White, Eileen
ef32ccf7-8bc4-4608-983a-97cc1bd4f6e0
Downward, Julian
8c5ea429-4763-4010-be2e-94eed542dd57
Goldin, Robert
236b8cd1-f43d-4fae-8d55-77cb1704c9c1
Yuan, Xianglin
69ed23ce-4774-480c-b2d6-1447e1ade2ae
Lu, Xin
23803ccb-4f47-433f-8285-76e3dee950b7

Wang, Yihua, Xiong, Hua, Liu, Dian, Hill, Charlotte, Ertay, Ayse, Li, Juanjuan, Zou, Yanmei, Miller, Paul, White, Eileen, Downward, Julian, Goldin, Robert, Yuan, Xianglin and Lu, Xin (2019) Autophagy inhibition specifically promotes epithelial-mesenchymal transition and invasion in RAS-mutated cancer cells. Autophagy, 15 (5), 886-899. (doi:10.1080/15548627.2019.1569912).

Record type: 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 NFKBpathway 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 RASmutated cancer.

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More information

Accepted/In Press date: 28 October 2018
e-pub ahead of print date: 20 February 2019
Published date: 4 May 2019

Identifiers

Local EPrints ID: 425712
URI: http://eprints.soton.ac.uk/id/eprint/425712
ISSN: 1554-8627
PURE UUID: 76663917-6892-4095-8f28-d957d8e1150a
ORCID for Yihua Wang: ORCID iD orcid.org/0000-0001-5561-0648

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Date deposited: 01 Nov 2018 17:30
Last modified: 15 Sep 2021 05:22

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