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Pioglitazone and Rosiglitazone Decrease Prostaglandin E₂ in Non–Small-Cell Lung Cancer Cells by Up-Regulating 15-Hydroxyprostaglandin Dehydrogenase

Department of Medicine (S.H., R.B., S.S., X.C., S.D.), Division of Pulmonary and Critical Care Medicine, Lung Cancer Research Program and Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California; Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California (R.B., S.S., S.D.); and Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky (H.T.).

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) 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 PPAR overexpression or 2-chloro-5-nitrobenzanilide (GW9662; a PPAR antagonist) revealed that the suppressive effect of the TZDs on PGE₂ is PPAR-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.

Address correspondence to: Saswati Hazra, UCLA Lung Cancer Research Program of the Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, 37-131 CHS, 10833 Le Conte Avenue, Los Angeles, CA 90095-1690. E-mail: shazra{at}mednet.ucla.edu

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