To determine the role of 14-3-3 in colorectal cancer apoptosis induced by nonsteroidal anti-inflammatory drugs (NSAIDs), we evaluated the effects of sulindac on 14-3-3 epsilon protein expression in colorectal cancer cells. Sulindac sulfide inhibited 14-3-3 epsilon proteins in HT-29 and DLD-1 cells in a time- and concentration-dependent manner. Sulindac sulfone at 600 mu mol/L inhibited 14-3-3 epsilon protein expression in HT-29. Indomethacin and SC-236, a selective cyclooxygenase-2 (COX-2) inhibitor, exerted a similar effect as sulindac. Sulindac suppressed 14-3-3 epsilon promoter activity. As 14-3-3 epsilon promoter activation is mediated by peroxisome proliferator-activated receptor delta (PPAR delta), we determined the correlation between 14-3-3 epsilon inhibition and PPAR delta suppression by NSAIDs. Sulindac sulfide inhibited PPAR delta protein expression and PPAR delta transcriptional activity. Overexpression of PPAR delta by adenoviral transfer rescued 14-3-3 epsilon proteins from elimination by sulindac or indomethacin. NSAID-induced 14-3-3e suppression was associated with reduced cytosolic Bad with elevation of mitochondrial Bad and increase in apoptosis which was rescued by Ad-PPAR8 transduction. Stable expression of 14-3-3 epsilon in HT-29 significantly protected cells from apoptosis. Our findings shed light on a novel mechanism by which NSAIDs induce colorectal cancer apoptosis via the PPAR delta/14-3-3 epsilon transcriptional pathway. These results suggest that 14-3-3 epsilon is a target for the prevention and therapy of colorectal cancer.
