Antiproliferative effect of conjugated linoleic acid in caco-2 cells: involvement of PPARgamma and APC/beta-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 PPARgamma 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 PPARgamma 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 PPARgamma, which translocated into the nucleus, while PPARalpha and beta/delta protein levels were not affected. GW259662, a well known PPARgamma antagonist, blocked the increase in PPARgamma 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 down-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 PPARgamma expression by selectively acting as an agonist; however, the discrepancies in PPARgamma antagonist efficacy suggest the involvement of other pathways, independent of PPARgamma, in CLA antiproliferative activity.
Bozzo
Francesca
F
Department of Experimental Medicine and Oncology, University of Torino, C. Raffaello 30, 10125 Torino, Italy.
Bocca
Claudia
C
Colombatto
Sebastiano
S
Miglietta
Antonella
A
D015153:Blotting, Western; D018938:Caco-2 Cells; D015820:Cadherins / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D019084:Fluorescent Antibody Technique, Indirect; D017491:Genes, APC; D006801:Humans; D019787:Linoleic Acid / Q000494:pharmacology*; D047495:PPAR gamma / Q000502:physiology*; D010766:Phosphorylation; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism / Q000502:physiology*
D015820:Cadherins; D047495:PPAR gamma; D016271:Proto-Oncogene Proteins c-myc; D051176:beta Catenin; D019787:Linoleic Acid