Induction but not inhibition of COX-2 confers human lung cancer cell apoptosis by celecoxib

The antitumorigenic mechanism of the selective cyclooxygenase-2 (COX-2) inhibitor celecoxib is still a matter of debate. Among different structurally related COX-2 inhibitors, only celecoxib was found to cause apoptosis and cell death of human lung cancer cells (IC50 values of 19.96 mu M [A549], 12.48 mu M [H460], and 41.39 mu M [H358]) that was paralleled by a time-and concentration-dependent upregulation of COX-2 and peroxisome proliferator-activated receptor gamma (PPAR gamma) at mRNA and protein levels. Apoptotic death of celecoxib-treated cancer cells was suppressed by the PPAR gamma antagonist GW9662 and by siRNA targeting PPAR gamma and, surprisingly, also by the selective COX-2 inhibitor NS-398 and siRNA targeting COX-2. NS-398 (1 mu M) was shown to suppress celecoxib-induced COX-2 activity. Among the COX-2-dependent prostaglandins (PG) induced upon celecoxib treatment, PGD(2) and 15-deoxy-Delta(12,14)-PGJ(2) were found to induce a cytosol-to-nucleus translocation of PPAR gamma as well as a PPAR gamma-dependent apoptosis. Celecoxib-elicited PPAR gamma translocation was inhibited by NS-398. Finally, a COX-2-and PPAR gamma-dependent cytotoxic action of celecoxib was proven for primary human lung tumor cells. Together, our data demonstrate a proapoptotic mechanism of celecoxib involving initial upregulation of COX-2 and PPAR gamma and a subsequent nuclear translocation of PPAR gamma by COX2- dependent PGs.