PT  - JOURNAL ARTICLE
AU  - Saswati Hazra
AU  - Raj K. Batra
AU  - Hsin H. Tai
AU  - Sherven Sharma
AU  - Xiaoyan Cui
AU  - Steven M. Dubinett
TI  - Pioglitazone and Rosiglitazone Decrease Prostaglandin E<sub>2</sub> in Non–Small-Cell Lung Cancer Cells by Up-Regulating 15-Hydroxyprostaglandin Dehydrogenase
AID  - 10.1124/mol.106.033357
DP  - 2007 Jun 01
TA  - Molecular Pharmacology
PG  - 1715--1720
VI  - 71
IP  - 6
4099  - http://molpharm.aspetjournals.org/content/71/6/1715.short
4100  - http://molpharm.aspetjournals.org/content/71/6/1715.full
SO  - Mol Pharmacol2007 Jun 01; 71
AB  - 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. The American Society for Pharmacology and Experimental Therapeutics