Journal
AUTOPHAGY
Volume 9, Issue 2, Pages 196-207Publisher
LANDES BIOSCIENCE
DOI: 10.4161/auto.22805
Keywords
ursolic acid; MCF-7; ER stress; EIF2AK3; autophagy; MCL1; cytoprotection; apoptosis
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Funding
- Ministry of Science and Technology of China [2012BAD33B09]
- National Natural Science Foundation of China (NSFC) [31071533, 30972172]
- Chinese Universities Scientific Fund [2009-2-11]
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Ursolic acid (UA) is a pentacyclic triterpenoid with promising cancer chemopreventive properties. A better understanding of the mechanisms underlying anticancer activity of UA is needed for further development as a clinically useful chemopreventive agent. Here, we found that both endoplasmic reticulum (ER) stress and autophagy were induced by UA in MCF-7 human breast cancer cells. Surprisingly, ER stress was identified as an effect rather than a cause of UA-induced autophagy. Autophagy-dependent ER stress protected the cells from UA-induced apoptosis through EIF2AK3-mediated upregulation of MCL1. Activation of MAPK1/3 but not inhibition of MTOR pathway contributed to UA-induced cytoprotective autophagy in MCF-7 cells. Our findings uncovered a novel cellular mechanism involved in the anticancer activity of UA, and also provided a useful model to study biological significance and mechanisms of autophagy-mediated ER stress.
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