title: Common cytotoxic chemotherapeutics induce epithelial-mesenchymal transition (EMT) downstream of ER stress.
abstract: Endoplasmic reticulum (ER) in eukaryotes is a main organelle involved in a wide variety of functions including calcium storage, lipid biosynthesis, protein folding and protein transport. Disruption of ER homeostasis leads to ER stress and activation of the unfolded protein response (UPR). We and others have previously found that ER stress induces EMT in different cellular systems. Induction of ER stress with chemical modulators of ER homeostasis was sufficient to activate an EMT-like state in all cellular systems tested. Here, we provide evidence for the first time demonstrating that ER stress induces EMT that is neither cancer cell specific nor cell-type specific. In addition, we observed that chemotherapeutic drugs commonly used to treat patients also activate ER stress that is concomitant with activation of an EMT-like state. Interestingly, we find that following removal of ER stress, partial EMT characteristics still persist indicating that ER stress induced EMT is a long-term effect. Induction of mesenchymal characteristics, following chemotherapeutics treatment may be involved in providing cancer stemness and invasiveness in the cellular system. Interestingly, we find that mice treated with cisplatin have elevated level of ER stress and EMT markers in multiple tissues including lung, liver and kidneys. Furthermore, increased ER stress, as demonstrated by increased Bip, Chop, PDI, Ero1α and IRE1, and EMT, as demonstrated by increased Vimentin and Snail, is a hallmark of primary lung adenocarcinoma samples from patients. These observations have potential clinical relevance because overexpression of ER stress and EMT markers might contribute to chemoresistance and poor survival of lung adenocarcinoma patients.
authors.affiliation: James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA.
authors.forename: Parag P
authors.initials: PP
authors.lastname: Shah
authors.affiliation: Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40202, USA.
authors.forename: Tess V
authors.initials: TV
authors.lastname: Dupre
authors.affiliation: Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40202, USA.
authors.forename: Leah J
authors.initials: LJ
authors.lastname: Siskind
authors.affiliation: James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA.|Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40202, USA.|Department of Medicine, Division of Hematology and Oncology, University of Louisville School of Medicine, Louisville, KY 40202, USA.
authors.forename: Levi J
authors.initials: LJ
authors.lastname: Beverly
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004721:Endoplasmic Reticulum / Q000187:drug effects*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D011379:Prognosis; D014407:Tumor Cells, Cultured; D056811:Unfolded Protein Response / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor
keywords: EMT; ER stress; chemotherapeutics; invasion; migration