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 a...
| Autori principali: | , , , , , , , , , , , , |
|---|---|
| Natura: | Journal article |
| Pubblicazione: |
Taylor and Francis
2019
|
| _version_ | 1826263457212661760 |
|---|---|
| author | Wang, Y Xiong, H Liu, D Hill, C Ertay, A Li, J Zou, Y Miller, P White, E Downward, J Goldin, R Yuan, X Lu, X |
| author_facet | Wang, Y Xiong, H Liu, D Hill, C Ertay, A Li, J Zou, Y Miller, P White, E Downward, J Goldin, R Yuan, X Lu, X |
| author_sort | Wang, Y |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-06T19:52:04Z |
| format | Journal article |
| id | oxford-uuid:244b1ff6-de0f-4537-91df-a667a5c483d0 |
| institution | University of Oxford |
| last_indexed | 2024-03-06T19:52:04Z |
| publishDate | 2019 |
| publisher | Taylor and Francis |
| record_format | dspace |
| spelling | oxford-uuid:244b1ff6-de0f-4537-91df-a667a5c483d02022-03-26T11:49:15ZAutophagy inhibition specifically promotes epithelial-mesenchymal transition and invasion in RAS-mutated cancer cellsJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:244b1ff6-de0f-4537-91df-a667a5c483d0Symplectic Elements at OxfordTaylor and Francis2019Wang, YXiong, HLiu, DHill, CErtay, ALi, JZou, YMiller, PWhite, EDownward, JGoldin, RYuan, XLu, XMacroautophagy/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. |
| spellingShingle | Wang, Y Xiong, H Liu, D Hill, C Ertay, A Li, J Zou, Y Miller, P White, E Downward, J Goldin, R Yuan, X Lu, X Autophagy inhibition specifically promotes epithelial-mesenchymal transition and invasion in RAS-mutated cancer cells |
| title | Autophagy inhibition specifically promotes epithelial-mesenchymal transition and invasion in RAS-mutated cancer cells |
| title_full | Autophagy inhibition specifically promotes epithelial-mesenchymal transition and invasion in RAS-mutated cancer cells |
| title_fullStr | Autophagy inhibition specifically promotes epithelial-mesenchymal transition and invasion in RAS-mutated cancer cells |
| title_full_unstemmed | Autophagy inhibition specifically promotes epithelial-mesenchymal transition and invasion in RAS-mutated cancer cells |
| title_short | Autophagy inhibition specifically promotes epithelial-mesenchymal transition and invasion in RAS-mutated cancer cells |
| title_sort | autophagy inhibition specifically promotes epithelial mesenchymal transition and invasion in ras mutated cancer cells |
| work_keys_str_mv | AT wangy autophagyinhibitionspecificallypromotesepithelialmesenchymaltransitionandinvasioninrasmutatedcancercells AT xiongh autophagyinhibitionspecificallypromotesepithelialmesenchymaltransitionandinvasioninrasmutatedcancercells AT liud autophagyinhibitionspecificallypromotesepithelialmesenchymaltransitionandinvasioninrasmutatedcancercells AT hillc autophagyinhibitionspecificallypromotesepithelialmesenchymaltransitionandinvasioninrasmutatedcancercells AT ertaya autophagyinhibitionspecificallypromotesepithelialmesenchymaltransitionandinvasioninrasmutatedcancercells AT lij autophagyinhibitionspecificallypromotesepithelialmesenchymaltransitionandinvasioninrasmutatedcancercells AT zouy autophagyinhibitionspecificallypromotesepithelialmesenchymaltransitionandinvasioninrasmutatedcancercells AT millerp autophagyinhibitionspecificallypromotesepithelialmesenchymaltransitionandinvasioninrasmutatedcancercells AT whitee autophagyinhibitionspecificallypromotesepithelialmesenchymaltransitionandinvasioninrasmutatedcancercells AT downwardj autophagyinhibitionspecificallypromotesepithelialmesenchymaltransitionandinvasioninrasmutatedcancercells AT goldinr autophagyinhibitionspecificallypromotesepithelialmesenchymaltransitionandinvasioninrasmutatedcancercells AT yuanx autophagyinhibitionspecificallypromotesepithelialmesenchymaltransitionandinvasioninrasmutatedcancercells AT lux autophagyinhibitionspecificallypromotesepithelialmesenchymaltransitionandinvasioninrasmutatedcancercells |