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This study critically examined the role of PPARβ/δ in colon cancer models. Expression of PPARβ/δ 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 PPARβ/δ in normal colon tissue or colon tumors. Cleaved poly (ADP-ribose) polymerase (PARP) was either increased or unchanged, while expression of 14-3-3ε was not influenced in human colon cancer cell lines cultured with the PPARβ/δ ligand GW0742 under conditions known to increase apoptosis. While DLD1 cells exhibited fewer early apoptotic cells after ligand activation of PPARβ/δ 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 PPARβ/δ in human colon cancer cell lines enhanced ligand activation of PPARβ/δ and inhibition of clonogenicity in HT29 cells. These studies are the most quantitative to date to demonstrate that expression of PPARβ/δ 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 PPARβ/δ 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 PPARβ/δ-dependent modulation of apoptosis is required in the future., (Copyright © 2011 Wiley Periodicals, Inc.)

The purpose of this study was to determine whether the protective effect of fish oil against colon carcinogenesis is due to decreased proliferation, increased differentiation and/or increased apoptosis. Male Sprague Dawley rats (n = 260) were fed one of two oils (corn or fish) and two fibers (pectin or cellulose), plus or minus the carcinogen azoxymethane (AOM). Rats were killed at wk 18 (n = 80) or 36 (n = 180) for cytokinetic measurements. In vivo cell proliferation was measured by incorporation of bromodeoxyuridine into DNA, differentiation by binding of Dolichos biflorus agglutinin and apoptosis by immunoperoxidase detection of digoxigenin labeled genomic DNA. Fish oil resulted in a lower adenocarcinoma incidence (56.1 vs. 70.3%) compared with corn oil. There was no effect of fat or fiber on number of proliferative cells/crypt column in either the proximal or distal colon. In contrast, fish oil resulted in a greater degree of differentiation compared with corn oil in both colonic sites. In addition, fish oil resulted in a higher number of apoptotic cells/crypt column in both the proximal and distal colon as compared with corn oil. AOM treatment increased the ratio of proliferative cells/crypt column to apoptotic cells/crypt column in both the proximal and distal colon compared with saline controls. Fish oil, however, resulted in a lower ratio in both sites in the colon as compared with corn oil. These results suggest that an increase in apoptosis and differentiation, rather than a decrease in proliferation, accounts for the protective effect of fish oil against experimentally induced colon tumorigenesis. [ABSTRACT FROM AUTHOR]