title: Imexon induces an oxidative endoplasmic reticulum stress response in pancreatic cancer cells.
abstract: Oxidative protein folding in the endoplasmic reticulum (ER) requires strict regulation of redox homeostasis. Disruption of the lumenal redox balance induces an integrated ER stress response that is associated with reduced protein translation, increased chaperone activity, and ultimately cell death. Imexon is a small-molecule chemotherapeutic agent that has been shown to bind glutathione (GSH) and induce oxidative stress in tumor cells; however, the mechanism of cytotoxicity is not well understood. In this report, we investigate the effects of imexon on the integrated ER stress response in pancreatic carcinoma cells. Acute exposure to imexon induces an ER stress response characterized by accumulation of the oxidized form of the oxidoreductase Ero1α, phosphorylation of eIF2α, and inhibition of protein synthesis. An RNA interference chemosensitization screen identified the eukaryotic translation initiation factor eIF2B5 as a target that enhanced imexon-induced growth inhibition of MiaPaCa-2 pancreatic cancer cells, but did not significantly augment the effects of imexon on protein synthesis. Concurrent reduction of intracellular thiols with N-acetyl cysteine reversed imexon activity, however cotreatment with superoxide scavengers had no effect, suggesting thiol binding may be a primary component of the oxidative effects of imexon. Moreover, the data suggest that disruption of the redox balance in the ER is a potential therapeutic target.
authors.affiliation: Arizona Cancer Center, University of Arizona, 1515 N. Campbell Avenue, Tucson, AZ 85724, USA.
authors.forename: Elena V
authors.initials: EV
authors.lastname: Sheveleva
authors.forename: Terry H
authors.initials: TH
authors.lastname: Landowski
authors.forename: Betty K
authors.initials: BK
authors.lastname: Samulitis
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Bartholomeusz
authors.forename: Garth
authors.initials: G
authors.lastname: Powis
authors.forename: Robert T
authors.initials: RT
authors.lastname: Dorr
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D020717:Eukaryotic Initiation Factor-2B / Q000378:metabolism; D020868:Gene Silencing / Q000187:drug effects; D006588:Hexanones / Q000494:pharmacology*; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D010088:Oxidoreductases / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D014176:Protein Biosynthesis / Q000187:drug effects
chemical_list: D020717:Eukaryotic Initiation Factor-2B; D006588:Hexanones; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; C014919:4-imino-1,3-diazabicyclo(3.1.0)hexan-2-one; C405327:ERO1A protein, human; D010088:Oxidoreductases