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First published on November 30, 2007; DOI: 10.1124/mol.107.042002

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Received for publication September 20, 2007.
Revised November 27, 2007.
Accepted for publication November 30, 2007.

Antitumorigenic Effects of Peroxisome Proliferator-Activated Receptor-{gamma} (PPAR{gamma}) in Non-small Cell Lung Cancer Cells (NSCLC) are Mediated by Suppression of COX-2 via Inhibition of NF-{kappa}B

Yvette Bren-Mattison 1, Amy M Meyer 2, Vicki Van Putten 2, Howard Li 2, Katherine Kuhn 2, Robert Stearman 2, Mary Weiser-Evans 2, Robert A Winn 2, Lynn E Heasley 2, Raphael Nemenoff 3*

1 Sporian Corportaion 2 University of Colorado Health Sciences Center 3 University Colorado Health Sciences Center

* Address correspondence to: E-mail: raphael.nemenoff{at}uchsc.edu

Abstract

Pharamacological activators of peroxisome proliferator-activated receptor-{gamma} (PPAR{gamma}) inhibit growth of non-small cell lung cancer (NSCLC) cell lines in vitro and in xenograft models. Since these agents engage off-target pathways, we have assessed the effects of PPAR{gamma} by overexpressing the protein in NSCLC cells. We previously reported that increased PPAR{gamma} inhibits transformed growth and invasiveness, and promotes epithelial differentiation in a panel of NSCLC expressing oncogenic K-Ras. These cells express high levels of COX-2 and produce high levels of PGE2. The goal of these studies was to identify the molecular mechanisms whereby PPAR{gamma} inhibits tumorigenesis. Increased PPAR{gamma} inhibited expression of COX-2 protein and promoter activity, resulting in decreased PGE2 production. Suppression of COX-2 was mediated through increased activity of the tumor suppressor PTEN, leading to decreased levels of phospho-Akt and inhibition of NF-{kappa}B activity. Pharmacological inhibition of PGE2 production mimicked the effects of PPAR{gamma} on epithelial differentiation in 3-dimensional culture, and exogenous PGE2 reversed the effects of increased PPAR{gamma} activity. Transgenic mice overexpressing PPAR{gamma} under the control of the surfactant protein C promoter had reduced expression of COX-2 in Type II cells, and were protected against developing lung tumors in a chemical carcinogenesis model. These data indicate that high levels of PGE2 as a result of elevated COX-2 expression are critical for promoting lung tumorigenesis, and that the antitumorigenic effects of PPAR{gamma} are mediated in part through blocking this pathway.


Key words: Prostanoid, Interleukins, PPARs, NFkappaB, Regulation - transcriptional, Cyclooxygenases, Eicosanoids, Oncogenes, Transcription targets




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