Imexon induces an oxidative endoplasmic reticulum stress response in pancreatic cancer cells

Elena V. Sheveleva, Terry H Landowski, Betty K. Samulitis, Geoffrey Bartholomeusz, Garth Powis, Robert T Dorr

Research output: Contribution to journalArticle

13 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)392-400
Number of pages9
JournalMolecular Cancer Research
Volume10
Issue number3
DOIs
StatePublished - Mar 2012

Fingerprint

Endoplasmic Reticulum Stress
Pancreatic Neoplasms
Oxidation-Reduction
Sulfhydryl Compounds
Endoplasmic Reticulum
Eukaryotic Initiation Factors
Protein Folding
Protein Biosynthesis
RNA Interference
4-imino-1,3-diazabicyclo(3.1.0)hexan-2-one
Superoxides
Glutathione
Cysteine
Oxidoreductases
Proteins
Oxidative Stress
Homeostasis
Cell Death
Phosphorylation
Growth

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Oncology

Cite this

Imexon induces an oxidative endoplasmic reticulum stress response in pancreatic cancer cells. / Sheveleva, Elena V.; Landowski, Terry H; Samulitis, Betty K.; Bartholomeusz, Geoffrey; Powis, Garth; Dorr, Robert T.

In: Molecular Cancer Research, Vol. 10, No. 3, 03.2012, p. 392-400.

Research output: Contribution to journalArticle

Sheveleva, Elena V. ; Landowski, Terry H ; Samulitis, Betty K. ; Bartholomeusz, Geoffrey ; Powis, Garth ; Dorr, Robert T. / Imexon induces an oxidative endoplasmic reticulum stress response in pancreatic cancer cells. In: Molecular Cancer Research. 2012 ; Vol. 10, No. 3. pp. 392-400.
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