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Received for publication December 12, 2006.
Revised April 4, 2007.
Accepted for publication April 5, 2007.
Lung cancer cells elaborate the immunosuppressive and anti-apoptotic mediator PGE2, a product of COX-2 enzyme activity. Because PPAR
ligands, such as thiazolidinediones (TZDs) inhibit lung cancer cell growth, we examined the effect of TZDs (pioglitazone and rosiglitazone) on PGE2 levels in NSCLC (A427 and A549 cells). Both TZDs inhibited PGE2 production in NSCLC cells via a COX-2 independent pathway. In order to define the mechanism underlying COX-2 independent suppression of PGE2 production, 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 downregulated by the TZDs. Importantly, 15-hydroxyprostaglandin dehydrogenase (15-PGDH), an enzyme that produces biologically inactive 15-keto-prostaglandins from active PGE2, was induced by TZDs. The TZD-mediated suppression of PGE2 concentration was significantly inhibited by si-RNA to 15-PGDH. Studies utilizing dominant-negative PPAR overexpression or GW9662 (a PPAR antagonist) revealed that the suppressive effect of the TZDs on PGE2 is PPAR independent. Collectively, these findings indicate that it is possible to utilize a clinically available pharmacological intervention to suppress tumor-derived PGE2 by enhancing catabolism rather than blocking synthesis.
Key words:
PPARs, Signaling network analyses
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