Cyclooxygenase Inhibitors Induce Colon Cancer Cell Apoptosis Via PPAR 14-3-3 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 δ (PPARδ) through inhibition of COX-2-derived prostacyclin (PGI2). PGI2 activates PPARδ resulting in binding of PPARδ to specific PPAR response elements (PPRE) of target genes. We have identified 14-3-3ε as one of the genes that are upregulated by PPARδ. Elevated 14-3-3ε proteins in cytosol enhance sequestration of Bad and reduce mitochondrial damage by Bad and thereby control apoptosis. NSAIDs and COXIBs block PGI2 production, thereby reducing PPARδ DNA binding activity and abrogating 14-3-3e upregulation. Furthermore, the COX-2 inhibitors suppress PPARδ expression. Suppression of PPARδ 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.