Functional Characterization of Peroxisome Proliferator-Activated Receptor-β/δ Expression in Colon Cancer

This study critically examined the role of PPAR beta/delta in colon cancer models. Expression of PPAR beta/delta mRNA and protein was lower and expression of CYCLIN D1 protein higher in human colon adenocarcinomas compared to matched non-transformed tissue. Similar results were observed in colon tumors from Apc(+/Min-FCCC) mice compared to control tissue. Dietary administration of sulindac to Apc(+/Min-FCCC) mice had no influence on expression of PPAR beta/delta in normal colon tissue or colon tumors. Cleaved poly (ADP-ribose) polymerase (PARP) was either increased or unchanged, while expression of 14-3-3 epsilon was not influenced in human colon cancer cell lines cultured with the PPAR beta/delta ligand GW0742 under conditions known to increase apoptosis. While DLD1 cells exhibited fewer early apoptotic cells after ligand activation of PPAR beta/delta following treatment with hydrogen peroxide, this change was associated with an increase in late apoptotic/necrotic cells, but not an increase in viable cells. Stable over-expression of PPAR beta/delta in human colon cancer cell lines enhanced ligand activation of PPAR beta/delta and inhibition of clonogenicity in HT29 cells. These studies are the most quantitative to date to demonstrate that expression of PPAR beta/delta is lower in human and Apc(+/Min-FCCC) mouse colon tumors than in corresponding normal tissue, consistent with the finding that increasing expression and activation of PPAR beta/delta in human colon cancer cell lines inhibits clonogenicity. Because ligand-induced attenuation of early apoptosis can be associated with more late, apoptotic/necrotic cells, but not more viable cells, these studies illustrate why more comprehensive analysis of PPAR beta/delta-dependent modulation of apoptosis is required in the future. (C) 2011 Wiley Periodicals, Inc.