Target Genes of Peroxisome Proliferator-activated Receptor γ in Colorectal Cancer Cells

Abstract

Activation of the nuclear hormone peroxisome proliferator-activated receptor γ (PPARγ) inhibits cell growth and promotes differentiation in a broad spectrum of epithelial derived tumor cell lines. Here we utilized microarray technology to identify PPARγ gene targets in intestinal epithelial cells. For each gene, the induction or repression was seen with two structurally distinct PPARγ agonists, and the change in expression could be blocked by co-treatment with a specific PPARγ antagonist. A majority of the genes could be regulated independently by a retinoid X receptor specific agonist. Genes implicated in lipid transport or storage (adipophilin and liver fatty acid-binding protein) were also activated by agonists of PPAR subtypes α and/or δ. In contrast, PPARγ-selective targets included genes linked to growth regulatory pathways (regenerating gene IA), colon epithelial cell maturation (GOB-4 and keratin 20), and immune modulation (neutrophil-gelatinase-associated lipocalin). Additionally, three different genes of the carcinoembryonic antigen family were induced by PPARγ. Cultured cells treated with PPARγ ligands demonstrated an increase in Ca2+-independent, carcinoembryonic antigen-dependent homotypic aggregation, suggesting a potential role for PPARγ in regulating intercellular adhesion. Collectively, these results will help define the mechanisms by which PPARγ regulates intestinal epithelial cell biology.