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.