Common cytotoxic chemotherapeutics induce epithelial-mesenchymal transition (EMT) downstream of ER stress

// Parag P. Shah 1 , Tess V. Dupre 2 , Leah J. Siskind 2 , Levi J. Beverly 1, 2, 3 1 James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA 2 Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40202, USA 3 Department of Medicine, Division of Hematology and Oncology, University of Louisville School of Medicine, Louisville, KY 40202, USA Correspondence to: Levi J. Beverly, email: Levi.Beverly@Louisville.edu Keywords: ER stress, chemotherapeutics, EMT, migration, invasion Received: October 24, 2016      Accepted: January 24, 2017      Published: February 07, 2017 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.