Abstract

Lung cancer cells elaborate the immunosuppressive and antiapoptotic mediator prostaglandin E₂ (PGE₂), a product of cyclooxygenase-2 (COX-2) enzyme activity. Because peroxisome proliferator-activated receptor (PPAR)γ ligands, such as thiazolidinediones (TZDs), inhibit lung cancer cell growth, we examined the effect of the TZDs pioglitazone and rosiglitazone on PGE₂ levels in non–small-cell lung cancer (NSCLC) A427 and A549 cells. Both TZDs inhibited PGE₂ production in NSCLC cells via a COX-2 independent pathway. To define the mechanism underlying COX-2 independent suppression of PGE₂ production, we focused on other enzymes responsible for the synthesis and degradation of PGE₂. The expression of none of the three prostaglandin synthases (microsomal PGES1, PGES2 and cystosolic PGES) was down-regulated by the TZDs. It is noteworthy that 15-hydroxyprostaglandin dehydrogenase (15-PGDH), an enzyme that produces biologically inactive 15-ketoprostaglandins from active PGE₂, was induced by TZDs. The TZD-mediated suppression of PGE₂ concentration was significantly inhibited by small interfering RNA to 15-PGDH. Studies using dominant-negative PPARγ overexpression or 2-chloro-5-nitrobenzanilide (GW9662; a PPARγ antagonist) revealed that the suppressive effect of the TZDs on PGE₂ is PPARγ-independent. Together, these findings indicate that it is possible to use a clinically available pharmacological intervention to suppress tumor-derived PGE₂ by enhancing catabolism rather than blocking synthesis.