The integrated stress response-associated signals modulates intestinal tumor cell growth by NSAID-activated gene 1 (NAG-1/MIC-1/PTGF-beta).
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.
Department of Microbiology and Immunology and Medical Research Institute, Pusan National University School of Medicine, Yangsan 626-813, Korea.
Hyun
H
Yang
Seong Hwan
SH
Park
Hye Jin
HJ
Choi
Yuseok
Y
Moon
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D017209:Apoptosis; D003110:Colonic Neoplasms / Q000473:pathology*; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D055436:Growth Differentiation Factor 15 / Q000235:genetics*; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D013312:Stress, Physiological / Q000187:drug effects*; D013467:Sulindac / Q000031:analogs & derivatives / Q000494:pharmacology; D051742:Transcription Factor CHOP / Q000235:genetics; D019892:eIF-2 Kinase / Q000502:physiology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000091342:Endoplasmic Reticulum Chaperone BiP; D048049:Extracellular Signal-Regulated MAP Kinases; D055436:Growth Differentiation Factor 15; D013467:Sulindac; D051742:Transcription Factor CHOP; D019892:eIF-2 Kinase; C497249:DDIT3 protein, human; C526140:GDF15 protein, human; C000717247:HSPA5 protein, human; C025462:sulindac sulfide