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Antitumorigenic Effects of Peroxisome Proliferator-Activated Receptor- in Non-Small-Cell Lung Cancer Cells Are Mediated by Suppression of Cyclooxygenase-2 via Inhibition of Nuclear Factor-B

Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado

Pharmacological activators of peroxisome proliferator-activated receptor- (PPAR) inhibit growth of non-small-cell lung cancer (NSCLC) cell lines in vitro and in xenograft models. Because these agents engage off-target pathways, we have assessed the effects of PPAR by overexpressing the protein in NSCLC cells. We reported previously that increased PPAR inhibits transformed growth and invasiveness and promotes epithelial differentiation in a panel of NSCLC expressing oncogenic K-Ras. These cells express high levels of cyclooxygenase-2 (COX-2) and produce high levels of prostaglandin E₂ (PGE₂). The goal of these studies was to identify the molecular mechanisms whereby PPAR inhibits tumorigenesis. Increased PPAR 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 phosphatase and tensin homolog, leading to decreased levels of phospho-Akt and inhibition of nuclear factor-B activity. Pharmacological inhibition of PGE₂ production mimicked the effects of PPAR on epithelial differentiation in three-dimensional culture, and exogenous PGE₂ reversed the effects of increased PPAR activity. Transgenic mice overexpressing PPAR 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 are mediated in part through blocking this pathway.

Address correspondence to: Dr. Raphael Nemenoff, Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado Health Sciences Center, Box C-281, 4200 East 9th Avenue, Denver, CO 80262. E-mail: raphael.nemenoff{at}uchsc.edu