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

Yihua Wang, Hua Xiong, Dian Liu, Charlotte Hill, Ayse Ertay, Juanjuan Li, Yanmei Zou, Paul Miller, Eileen White, Julian Downward, Robert D. Goldin, Xianglin Yuan, Xin Lu

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)886-899
Number of pages14
JournalAutophagy
Volume15
Issue number5
DOIs
StatePublished - May 4 2019

Fingerprint

Epithelial-Mesenchymal Transition
Autophagy
TNF Receptor-Associated Factor 6
Neoplasms
RNA Interference
Dacarbazine
1-Phosphatidylinositol 4-Kinase
Cadherins
Mitogen-Activated Protein Kinases
Phosphatidylinositol 3-Kinases
Transforming Growth Factor beta
Estrogen Receptors
Adenocarcinoma
Tumor Necrosis Factor-alpha
Epithelial Cells
Kidney
Proteins

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

Keywords

  • Autophagy
  • EMT
  • NFKB/NF-0κB
  • RAS
  • SQSTM1/p62

Cite this

Wang, Yihua ; Xiong, Hua ; Liu, Dian ; Hill, Charlotte ; Ertay, Ayse ; Li, Juanjuan ; Zou, Yanmei ; Miller, Paul ; White, Eileen ; Downward, Julian ; Goldin, Robert D. ; Yuan, Xianglin ; Lu, Xin. / Autophagy inhibition specifically promotes epithelial-mesenchymal transition and invasion in RAS-mutated cancer cells. In: Autophagy. 2019 ; Vol. 15, No. 5. pp. 886-899.
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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 2019, 'Autophagy inhibition specifically promotes epithelial-mesenchymal transition and invasion in RAS-mutated cancer cells', Autophagy, vol. 15, no. 5, pp. 886-899. https://doi.org/10.1080/15548627.2019.1569912

Autophagy inhibition specifically promotes epithelial-mesenchymal transition and invasion in RAS-mutated cancer cells. / Wang, Yihua; Xiong, Hua; Liu, Dian; Hill, Charlotte; Ertay, Ayse; Li, Juanjuan; Zou, Yanmei; Miller, Paul; White, Eileen; Downward, Julian; Goldin, Robert D.; Yuan, Xianglin; Lu, Xin.

In: Autophagy, Vol. 15, No. 5, 04.05.2019, p. 886-899.

Research output: Contribution to journalArticle

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T1 - Autophagy inhibition specifically promotes epithelial-mesenchymal transition and invasion in RAS-mutated cancer cells

AU - Wang, Yihua

AU - Xiong, Hua

AU - Liu, Dian

AU - Hill, Charlotte

AU - Ertay, Ayse

AU - Li, Juanjuan

AU - Zou, Yanmei

AU - Miller, Paul

AU - White, Eileen

AU - Downward, Julian

AU - Goldin, Robert D.

AU - Yuan, Xianglin

AU - Lu, Xin

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N2 - 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.

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