title: Autophagy-dependent EIF2AK3 activation compromises ursolic acid-induced apoptosis through upregulation of MCL1 in MCF-7 human breast cancer cells.
abstract: 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.
authors.affiliation: Department of Nutrition and Health, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China.
authors.forename: Chong
authors.initials: C
authors.lastname: Zhao
authors.forename: Shutao
authors.initials: S
authors.lastname: Yin
authors.forename: Yinhui
authors.initials: Y
authors.lastname: Dong
authors.forename: Xiao
authors.initials: X
authors.lastname: Guo
authors.forename: Lihong
authors.initials: L
authors.lastname: Fan
authors.forename: Min
authors.initials: M
authors.lastname: Ye
authors.forename: Hongbo
authors.initials: H
authors.lastname: Hu
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects*; D000071187:Autophagy-Related Protein 5; D000071186:Beclin-1; D001943:Breast Neoplasms / Q000201:enzymology* / Q000473:pathology* / Q000648:ultrastructure; D002470:Cell Survival / Q000187:drug effects; D019610:Cytoprotection / Q000187:drug effects; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D008565:Membrane Proteins / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008954:Models, Biological; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014315:Triterpenes / Q000494:pharmacology*; D056811:Unfolded Protein Response / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects; D014617:Vacuoles / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D019892:eIF-2 Kinase / Q000378:metabolism*; D000097245:Ursolic Acid
chemical_list: D051017:Apoptosis Regulatory Proteins; D000071187:Autophagy-Related Protein 5; D000071186:Beclin-1; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D020928:Mitogen-Activated Protein Kinases; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D058570:TOR Serine-Threonine Kinases; D014315:Triterpenes; D019892:eIF-2 Kinase; D000097245:Ursolic Acid; C502778:ATG5 protein, human; C491997:BECN1 protein, human; C460640:EIF2AK3 protein, human