TZDs suppress PGE2 via COX-2 dependent and independent pathways in NSCLC.

A122

Lung cancer cells elaborate the immunosuppressive and anti-apoptotic mediator PGE2, a product of COX-2 enzyme activity. Because PPARγ ligands, such as thiazolidinediones (TZDs) inhibit lung cancer cell growth, we examined the effect of TZDs (pioglitazone, rosiglitazone and ciglitazone) on PGE2 levels in NSCLC (A427 and A549 cells).In NSCLC, pioglitazone and rosiglitazone inhibited PGE2 production via a COX-2 independent pathway and in contrast ciglitazone inhibited COX-2. In order to define the mechanism underlying COX-2 independent suppression of PGE2 production by pioglitazone and rosiglitazone, we focused on other enzymes responsible for the synthesis and the degradation of PGE2. The expression of all three prostaglandin synthases (mPGES1, cPGES and mPGES2) were not upregulated by the pioglitazone and rosiglitazones. In contrast, 15-hydroxyprostaglandin dehydrogenase (15-PGDH), an enzyme that catalyzes the formation of biologically inactive 15-keto-prostaglandins from active PGE2, was induced by these two drugs. The suppression of PGE2 concentration by pioglitazone and rosiglitazone was significantly inhibited by si-RNA to 15-PGDH. The TZD mediated induction of 15-PGDH was blocked by inhibitors of the MEK/ERK1/2 pathway. COX-2 ELISA assay and western blot analysis suggested that ciglitazone-dependent inhibition of PGE₂ occurs through the suppression of COX-2. Ciglitazone treatment suppressed COX-2 promoter and COX-2 mRNA expression while upregulating peroxisome proliferator-response element (PPRE) promoter activity. Ciglitazone, like pioglitazone and rosiglitazone, did not modify the expression of enzymes downstream of COX-2 including PGE synthase (PGES) and 15-hydroxyprostaglandin dehydrogenase (15-PGDH). Utilization of a dn. PPARγ showed that the suppression of PGE2 by all three drugs is mediated via non-PPAR pathways. Taken together, our findings suggest that TZDs suppress PGE2 in NSCLC by operating via distinct COX-2 dependent and independent pathways. The mechanism of PGE2 suppression is dependent upon the individual TZD under investigation.