Pioglitazone and rosiglitazone decrease prostaglandin E2 in non-small-cell lung cancer cells by up-regulating 15-hydroxyprostaglandin dehydrogenase

Lung cancer cells elaborate the immunosuppressive and anti-apoptotic mediator prostaglandin E 2 (PGE 2), a product of cyclooxygenase-2 (COX-2) enzyme activity. Because peroxisome proliferator-activated receptor (PPAR) gamma ligands, such as thiazolidinediones (TZDs), inhibit lung cancer cell growth, we examined the effect of the TZDs pioglitazone and rosiglitazone on PGE 2 levels in non -small-cell lung cancer (NSCLC) A427 and A549 cells. Both TZDs inhibited PGE 2 production in NSCLC cells via a COX-2 independent pathway. To define the mechanism underlying COX-2 independent suppression of PGE 2 production, we focused on other enzymes responsible for the synthesis and degradation of PGE (2). 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 PGE 2, was induced by TZDs. The TZD-mediated suppression of PGE 2 concentration was significantly inhibited by small interfering RNA to 15-PGDH. Studies using dominant-negative PPAR gamma overexpression or 2-chloro-5-nitrobenzanilide (GW9662; a PPAR gamma antagonist) revealed that the suppressive effect of the TZDs on PGE 2 is PPAR gamma-independent. Together, these findings indicate that it is possible to use a clinically available pharmacological intervention to suppress tumor-derived PGE 2 by enhancing catabolism rather than blocking synthesis.