Antiproliferative effect of conjugated linoleic acid in caco-2 cells:: Involvement of PPARγ and APC/β-catenin pathways

Conjugated linoleic acid (CLA), a naturally occurring substance in food sources, occurs as mixtures of positional and geometrical isomers of octadecadienoate (18:2), and may inhibit colon tumorigenesis. It has been hypothesized that CLA can modulate cell proliferation and differentiation through the activation of peroxisome proliferator-activated receptors (PPARs), among which PPAR gamma is involved in growth inhibition of transformed cells. The aim of the present study was to investigate whether the antiproliferative effects of CLA are mediated by its interaction with PPAR gamma and APC/beta-catenin signalling pathway in human colon cancer cells. In CLA-treated caco-2 cells we found a remarkable increase in the expression of PPAR gamma, which translocated into the nucleus, while PPAR delta and beta/delta protein levels were not affected. GW259662, a well known PPAR gamma antagonist, blocked the increase in PPAR gamma protein rate and abrogated some biological effects of CLA, as it restored the proliferative capability of the cells and ERK1/2 phosphorylation level. We demonstrated that CLA treatment determined the clown-regulation of APC and c-myc proteins, but in this case the administration of the antagonist was not able to revert CLA effects. Furthermore, CLA induced a reorganization of E-cadherin and beta-catenin, as well as a redistribution of actin and tubulin filaments. Our data suggest that CLA may regulate PPAR gamma expression by selectively acting as an agonist; however, the discrepancies in PPAR gamma antagonist efficacy suggest the involvement of other pathways, independent of PPAR gamma, in CLA anti proliferative activity. (c) 2007 Elsevier Ireland Ltd. All rights reserved.