Cyclooxygenase inhibitors induce colon cancer cell apoptosis Via PPARdelta --> 14-3-3epsilon pathway.

Non-steroidal anti-inflammatory drugs (NSAIDs) and selective cyclooxygenase-2 (COX-2) inhibitors (COXIBs) induce cancer cell apoptosis via several signaling pathways. There is evidence that they induce colon cancer cell apoptosis by suppressing peroxisome proliferator-activated receptor delta (PPARdelta) through inhibition of COX-2-derived prostacyclin (PGI2). PGI2 activates PPARdelta resulting in binding of PPARdelta to specific PPAR response elements (PPRE) of target genes. We have identified 14-3-3epsilon as one of the genes that are upregulated by PPARdelta. Elevated 14-3-3epsilon proteins in cytosol enhance sequestration of Bad and reduce mitochondrial damage by Bad and thereby control apoptosis. NSAIDs and COXIBs block PGI(2) production, thereby reducing PPARdelta DNA binding activity and abrogating 14-3-3e upregulation. Furthermore, the COX-2 inhibitors suppress PPARdelta expression. Suppression of PPARdelta leads to reduced 14-3-3e and hence a decline in Bad sequestration, resulting in an increased Bad-induced apoptosis via the mitochondrial death pathway.