Nonsteroidal anti-inflammatory drugs induce colorectal cancer cell apoptosis by suppressing 14-3-3ε

Abstract

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 14-3-3ε protein expression in colorectal cancer cells. Sulindac sulfide inhibited 14-3-3ε proteins in HT-29 and DLD-1 cells in a time- and concentration-dependent manner. Sulindac sulfone at 600 μmol/L inhibited 14-3-3ε protein expression in HT-29. Indomethacin and SC-236, a selective cyclooxygenase-2 (COX-2) inhibitor, exerted a similar effect as sulindac. Sulindac suppressed 14-3-3ε promoter activity. As 14-3-3ε promoter activation is mediated by peroxisome proliferator-activated receptor δ (PPARδ), we determined the correlation between 14-3-3ε inhibition and PPARδ suppression by NSAIDs. Sulindac sulfide inhibited PPARδ protein expression and PPARδ transcriptional activity. Overexpression of PPARδ by adenoviral transfer rescued 14-3-3ε proteins from elimination by sulindac or indomethacin. NSAID-induced 14-3-3ε suppression was associated with reduced cytosolic Bad with elevation of mitochondrial Bad and increase in apoptosis which was rescued by Ad-PPARδ transduction. Stable expression of 14-3-3ε 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 PPARδ/14-3-3ε transcriptional pathway. These results suggest that 14-3-3ε is a target for the prevention and therapy of colorectal cancer. ©2007 American Association for Cancer Research.