Journal
AUTOPHAGY
Volume 15, Issue 5, Pages 886-899Publisher
TAYLOR & FRANCIS INC
DOI: 10.1080/15548627.2019.1569912
Keywords
Autophagy; EMT; NFKB; NF-0 kappa B; RAS; SQSTM1; p62
Categories
Funding
- Ludwig Institute for Cancer Research Ltd
- National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC)
- Academy of Medical Sciences/the Wellcome Trust Springboard Award [SBF002\1038]
- Royal Society Research Grant [RG160254]
- Ministry of Science and Technology of China National Key Research and Development Projects [2016YFC0904701]
- National Natural Science Foundation of China [81772827]
- Natural Science Foundation of Hubei [2016CKB711]
- Gerald Kerkut Charitable Trust
- University of Southampton Central VC Scholarship
- Wessex Medical Trust
- National Natural Science Youth Foundation [81502118]
- NIH [R01CA130893]
- Francis Crick Institute from Cancer Research UK [FC001070]
- UK Medical Research Council [FC001070]
- Wellcome Trust [FC001070]
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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-kappa B 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.
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