title: Regulation of VCP/p97 demonstrates the critical balance between cell death and epithelial-mesenchymal transition (EMT) downstream of ER stress.
abstract: Valosin-containing protein (VCP), also called p97, is a AAA+ ATPase that has been shown to be involved in endoplasmic reticulum-associated protein degradation (ERAD), mitochondria quality control and vesicle transport. We and others have previously found that disruption of VCP is sufficient to cause endoplasmic reticulum (ER) stress. We observed that induction of ER stress either following siRNA mediated loss of VCP or inhibition of VCP with eeyarestatin I potently activates an EMT-like state in cells. Interestingly, both ER stress and EMT are reversible events. Further, brief treatment of cells with eeyarestatin I increases EMT markers, and migratory and invasive properties of lung cancer cells. By examining primary lung adenocarcinoma patient samples we find that the VCP locus is heterozygously lost in nearly half of lung adenocarcinomas and VCP protein expression is decreased in nearly all primary lung tumors. Further, primary lung adenocarcinomas have increased ER stress and EMT markers. These observations have potential clinical relevance because increased ER stress and EMT markers are known to contribute to chemoresistance and poor survival of patients with lung adenocarcinoma.
authors.affiliation: James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA.
authors.forename: Parag P
authors.initials: PP
authors.lastname: Shah
authors.affiliation: James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA.|Department of Medicine, Division of Hematology and Oncology, University of Louisville School of Medicine, Louisville, KY, USA.|Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY, USA.
authors.forename: Levi J
authors.initials: LJ
authors.lastname: Beverly
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology*; D000251:Adenosine Triphosphatases / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D016923:Cell Death / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology*; D016133:Polymerase Chain Reaction; D034741:RNA, Small Interfering; D014162:Transfection; D000074405:Valosin Containing Protein
chemical_list: D018797:Cell Cycle Proteins; D034741:RNA, Small Interfering; D000251:Adenosine Triphosphatases; C000614178:VCP protein, human; D000074405:Valosin Containing Protein
keywords: EMT; ER stress; ERAD; invasion; metastasis; migration; p97