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.