Induction but not inhibition of COX-2 confers human lung cancer cell apoptosis by celecoxib.
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Ramer R, Walther U, Borchert P, Laufer S, Linnebacher M, Hinz B
Induction but not inhibition of COX-2 confers human lung cancer cell apoptosis by celecoxib.
J Lipid Res. 2013 Nov;54(11):3116-29. doi: 10.1194/jlr.M042283. Epub 2013 Aug 12.
- PubMed ID
- 23943857 [ View in PubMed]
- Abstract
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 (IC(5)(0) values of 19.96 microM [A549], 12.48 microM [H460], and 41.39 microM [H358]) that was paralleled by a time- and concentration-dependent upregulation of COX-2 and peroxisome proliferator-activated receptor gamma (PPARgamma) at mRNA and protein levels. Apoptotic death of celecoxib-treated cancer cells was suppressed by the PPARgamma antagonist GW9662 and by siRNA targeting PPARgamma and, surprisingly, also by the selective COX-2 inhibitor NS-398 and siRNA targeting COX-2. NS-398 (1 microM) 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(1)(2),(1)(4)-PGJ(2) were found to induce a cytosol-to-nucleus translocation of PPARgamma as well as a PPARgamma-dependent apoptosis. Celecoxib-elicited PPARgamma translocation was inhibited by NS-398. Finally, a COX-2- and PPARgamma-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 PPARgamma and a subsequent nuclear translocation of PPARgamma by COX-2-dependent PGs.