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.
Highlights
Endoplasmic reticulum (ER) is a main eukaryotic multifunctional organelle involved in calcium storage, lipid biosynthesis, and protein folding and protein transport [1]
Cells respond to ER stress by activating unfolded protein response (UPR), which activates downstream UPR related key components including PERK, IRE1α and ATF6 involved in maintaining and/ or restoring ER homeostasis [2]
We find that chemotherapeutic drug treatment including Gemcitabine, Doxorubicin and Cytarabine increase cell migration and invasion of lung adenocarcinoma cells
Summary
Endoplasmic reticulum (ER) is a main eukaryotic multifunctional organelle involved in calcium storage, lipid biosynthesis, and protein folding and protein transport [1]. Misfolded proteins in ER are transported to cytoplasm where they get degraded by the proteasome through an ER associated protein degradation pathway (ERAD). Disturbance in ER homeostasis through ERAD leads to ER stress. Cells respond to ER stress by activating unfolded protein response (UPR), which activates downstream UPR related key components including PERK, IRE1α and ATF6 involved in maintaining and/ or restoring ER homeostasis [2]. During EMT, cells undergo a phenotypic change which has been characterized by increased cellular motility and invasive properties. Cells lose their cell-tocell contacts and become more elongated and migratory. Several transcription factors including Snail, Slug, Zeb1/2 and SMAD-interacting protein 1 have been shown to be involved in EMT [5]
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