Peroxisome Proliferator-Activated Receptor gamma (PPARg) is a Regulator of Colorectal Cancer Cell Growth and Differentiation

Abstract

Peroxisome prolferator-activated receptor g (PPARg) is a member of the nuclear hormone receptor superfamily and is ligand activated by polyunsaturated fatty acids, certain arachadonic acid metabolites, and class of synthetic compounds with insulin sensitizing activity known as thiazoidinediones. PPARg is strongly expressed in the post-mitotic epithelial compartment of the normal human large intestine. Exposure of a panel of human colorectal cancer cell lines to PPARg agonists leads to a decrease in cell growth that is associated with a partial G1 arrest and increased levels of the cyclin dependent kinase inhibitor p21. A subset of these cells lines were resistant to the growth inhibitory effects of PPARg ligands. All four of the resistant lines contained a point mutation at codon 422 of the ligand binding domain of PPARg. Further studies suggested this mutation leads to a loss of functional PPARg due to a defect in the ability of the receptor to repress the transcrption of some target genes in the absence of exogneous ligand. Microrray technology was used to understand the genomic response of intestinal epithelial cells exposed to PPARg agonists. PPARg selective target genes included proteins linked to regulation of cell growth, colon epithelial cell maturation, and immune modulation. One of these genes, Transforming Growth Factor b Clone-22 (TSC-22), is a leucine zipper containing transcription factor that is capable of repressing gene transcription. Inhibition of TSC-22 using a dominant-negative construct partially blocked the ability of PPARg to induce growth arrest. In summary, these studies collective demonstrate that PPARg is a regulator of colorectal cancer cell growth and differentiation.