Phosphorylation of eukaryotic translation
initiation factor 2 alpha (eIF2alpha) is a critical convergence point of the integrated stress response (ISR), which supports eukaryotic cellular adaptation to diverse stressful conditions, including the endoplasmic reticulum (ER) stress by global
protein translational arrest and induction of numerous stress-triggered cytoprotective genes. Challenge with non-steroidal anti-inflammatory
drug (
NSAID) leads to ER perturbation that may sensitize
cancer cells to
drug-induced apoptosis. Here, we examined the ER stress signals in the context of
NSAID exposure and the induction of the critical
tumor suppressor,
NSAID-activated gene 1 (NAG-1), in the epithelial
cancer cells.
Sulindac sulfide, the active
sulindac metabolite, was shown to trigger the ISRs via eIF2alpha
kinase such as
RNA-dependent protein kinase-related endoplasmic reticulum
kinase (PERK) and
RNA-dependent protein kinase (PKR). ER stress markers such as
glucose-regulated
protein 78 (
GRP78),
C/EBP homologous protein (CHOP) and activating
transcription factor (ATF)-3 were enhanced by
sulindac sulfide in
colon cancer cells. In these cells, the PERK-activated ATF3-CHOP signaling pathway mediated the gene expression of pro-apoptotic NAG-1- and
NSAID-induced apoptosis. In contrast, PKR
protein was not involved in the signaling cascade for the gene expression of CHOP-linked NAG-1. Instead, PKR mediated activation of pro-survival
extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway, which was enhanced by NAG-1 suppression in response to cytotoxic
sulindac sulfide exposure. PKR-ERK1/2 activation may thus contribute to the defensive cellular response to cytotoxic
NSAIDs while
drug-mediated ER stress triggers the pro-apoptotic NAG-1 production in human
colon cancer cells.