Involvement of PPARγ and E‐cadherin/β‐catenin pathway in the antiproliferative effect of conjugated linoleic acid in MCF‐7 cells

Abstract

Conjugated linoleic acid (CLA) is a naturally occurring fatty acid, which has been shown to exert beneficial effects against breast carcinogenesis. It has been reported that CLA could modulate cellular proliferation and differentiation through the activation of peroxisome proliferator-activated receptors (PPARs). Among different PPAR isotypes, PPARc is involved in growth inhibition of transformed cells. Ligands of PPARc are considered as potential anticancer drugs, so CLA was tested for its ability to induce PPARc expression in MCF-7 breast cancer cells. The effects of CLA and of a specific synthetic PPARc antagonist were evaluated on cell growth as well as on parameters responsible for cell growth regulation. We demonstrated here that CLA stimulated the expression of PPARc to levels up to control and caused PPARc translocation into the nucleus. Furthermore, the overexpression of PPARc positively correlates with the inhibition of cell proliferation and with the modulation of ERK signaling induced by CLA; in all cases the administration of the antagonist reverted CLA effects. The PPAR-signaling pathway is connected with the b-catenin/Ecadherin pathway, thus we evaluated CLA effects on the expression and cellular distribution of these proteins, which are involved in cell adhesion and responsible for invasive behavior. The treatment with CLA determined the up-regulation and the redistribution of b-catenin and E-cadherin and the antagonist reverted only the effect on b-catenin. These studies indicate that CLA regulates PPARc expression by selectively acting as an agonist and may influence cell-cell adhesion and invasiveness of MCF-7 cells. ' 2007 Wiley-Liss, Inc.

Induction but not inhibition of COX-2 confers human lung cancer cell apoptosis by celecoxib

“…Third, inhibition of COX-2 and PPAR ␥ by knockdown and smallmolecule approaches was demonstrated to suppress celecoxib-induced apoptotic cell death. Fourth, celecoxibinduced translocation of PPAR ␥ from cytosol to nucleus, an established marker of PPAR ␥ activation (43)(44)(45), was inhibited by NS-398, suggesting that COX-2-dependent PGs generated upon celecoxib treatment confer the observed activation of PPAR ␥ . In line with this notion, exogenously added PGD 2 and 15d-PGJ 2 elicited PPAR ␥ translocation and PPAR ␥ -dependent apoptosis, which is in agreement with other studies demonstrating that anticancerogenic effects of PGD 2 and 15d-PGJ 2 occur via PPAR ␥ ( 27,28,(31)(32)(33).…”

The Role of Conjugated Linoleic Acid in Breast Cancer Growth and Development

“…CLA treatment of MCF-7 breast cancer cells was shown to increase protein levels of the anti-proliferative PPARγ and decrease protein levels of the anti-apoptotic PPARβ/δ [67,68]. CLA also increased the localization of PPARγ from the cytosol to the nucleus, and increased PPAR response element activation [68,69]. Use of a PPARγ antagonist abolished the growth inhibitory effects of CLA [68].…”

“…CLA also increased the localization of PPARγ from the cytosol to the nucleus, and increased PPAR response element activation [68,69]. Use of a PPARγ antagonist abolished the growth inhibitory effects of CLA [68]. CLA exerted different effects on the estrogen receptor-negative MDA-MB-231 cell line [67].…”

Hereditary breast cancer: new genetic developments, new therapeutic avenues

“…However, in individuals with lobular breast cancer and a family history of breast cancer but not gastric cancer, mutations in CDH1 are found at a low frequency (Masciari et al 2007). Upregulation of E-cadherin by various drugs (Bocca et al 2007;Gapter et al 2008;Wang et al 2008) might be beneWcial for breast cancer treatment as it can act as an invasion suppressor (Frixen et al 1991).…”