Functional characterization of peroxisome proliferator-activated receptor-?/? expression in colon cancer.

ABSTRACT: This study critically examined the role of PPAR?/? in colon cancer models. Expression of PPAR?/? 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?/? in normal colon tissue or colon tumors. Cleaved poly (ADP-ribose) polymerase (PARP) was either increased or unchanged, while expression of 14-3-3? was not influenced in human colon cancer cell lines cultured with the PPAR?/? ligand GW0742 under conditions known to increase apoptosis. While DLD1 cells exhibited fewer early apoptotic cells after ligand activation of PPAR?/? 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?/? in human colon cancer cell lines enhanced ligand activation of PPAR?/? and inhibition of clonogenicity in HT29 cells. These studies are the most quantitative to date to demonstrate that expression of PPAR?/? 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?/? 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?/?-dependent modulation of apoptosis is required in the future.

SUBMITTER: Foreman JE 

PROVIDER: S-EPMC3482838 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature