Involvement of PPARγ and E-cadherin/β-catenin pathway in the antiproliferative effect of conjugated linoleic acid in MCF-7 cells (original) (raw)
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Chemico-Biological Interactions, 2007
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␥ 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␥ and APC/-catenin signalling pathway in human colon cancer cells. In CLA-treated caco-2 cells we found a remarkable increase in the expression of PPAR␥, which translocated into the nucleus, while PPAR␣ and /␦ protein levels were not affected. GW259662, a well known PPAR␥ antagonist, blocked the increase in PPAR␥ 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 -catenin, as well as a redistribution of actin and tubulin filaments. Our data suggest that CLA may regulate PPAR␥ expression by selectively acting as an agonist; however, the discrepancies in PPAR␥ antagonist efficacy suggest the involvement of other pathways, independent of PPAR␥, in CLA antiproliferative activity.
CLA reduces breast cancer cell growth and invasion through ERα and PI3K/Akt pathways
Chemico-Biological Interactions, 2010
Keywords: CLA MCF-7 MDA-MB-231 ER␣ PI3K/Akt -Catenin/E-cadherin a b s t r a c t We previously reported that conjugated linoleic acid (CLA), a naturally occurring fatty acid, inhibits the growth of ER␣(+) MCF-7 and ER␣(−) MDA-MB-231 human breast cancer cells by negative modulation of the ERK/MAPK pathway and apoptosis induction. Here we show that in these cell lines CLA also downregulates the PI3K/Akt cascade. In MCF-7 cells CLA also triggers ER␣/PP2A complex formation reducing the phosphorylation state and transcriptional activity of Er␣ whereas in MDA-MB-231 cells CLA does not induce PP2A activation.
CLA reduces breast cancer cell growth and invasion through ERa and PI3K/Akt pathways
Chem Biol Inter, 2010
Keywords: CLA MCF-7 MDA-MB-231 ER␣ PI3K/Akt -Catenin/E-cadherin a b s t r a c t We previously reported that conjugated linoleic acid (CLA), a naturally occurring fatty acid, inhibits the growth of ER␣(+) MCF-7 and ER␣(−) MDA-MB-231 human breast cancer cells by negative modulation of the ERK/MAPK pathway and apoptosis induction. Here we show that in these cell lines CLA also downregulates the PI3K/Akt cascade. In MCF-7 cells CLA also triggers ER␣/PP2A complex formation reducing the phosphorylation state and transcriptional activity of Er␣ whereas in MDA-MB-231 cells CLA does not induce PP2A activation.
Journal of Functional Foods, 2016
The n-3 fatty acid α-linolenic acid (ALA) inhibits oestrogen receptor (ER) positive MCF-7 cell growth in vitro and in vivo. Our objective was to explore potential mechanisms. MCF-7 cells were treated with 100 µM ALA and 1 nM oestradiol (E2) then analysed for fatty acid profile, mRNA and protein biomarkers compared to an E2-containing control. The independent and combined effects of ALA, ER activator (E2) and antagonist (ICI-182,780, fulvestrant) on cell growth were determined. ALA was incorporated into cells but not further metabolized. ALA modulated the mRNA expression of targets regulated by or that regulate the ER including caveolin-1, survivin and progesterone receptor (PGR). Lower cyclin-D1, PGR, caveolin-1 and higher ERα protein expression were seen in ALA-treated cells. Co-incubation with ICI-182,780 negated the growth-reducing effect of ALA. In conclusion, ALA may reduce MCF-7 growth by modulating ER-related signalling, thus suggesting a plausible mechanism for ALA independent of its metabolites.
2002
The goal of the present study was to elucidate the extent that CLA binds to and activates PPAR␥. All of the isomers of CLA tested activated PPAR␥ in a manner similar to the polyunsaturated fatty acid, linoleic acid (18:2n6). When the binding affinity of CLA to PPAR␥ was determined using a scintillation proximity assay (SPA), isomers of CLA were ligands for PPAR␥ with micromolar affinity. To determine the extent that metabolism of CLA via ⌬6 desaturase could alter activation of PPAR␥, we used a ⌬6 desaturase inhibitor, SC-26,196, to block ⌬6 desaturase metabolism. Blocking ⌬6 desaturase significantly reduced activation of PPAR␥ by c9t11-CLA. These data suggest that the ability of CLA to induce PPAR-responsive genes may be via both direct binding of CLA to the nuclear hormone receptor, PPAR␥, as well as active metabolites of CLA via ⌬6 desaturase. Further work is needed to determine the ability of ⌬6 desaturase metabolites of CLA to bind and activate PPAR␥.
Conjugated linoleic acid is a potent naturally occurring ligand and activator of PPARα
Journal of Lipid Research, 1999
We have previously shown that a mixture of dietary conjugated derivatives of linoleic acid (conjugated linoleic acid, CLA) induces peroxisome proliferator-responsive enzymes and modulates hepatic lipid metabolism in vivo. The present studies demonstrate that CLA is a high affinity ligand and activator of peroxisome proliferator-activated receptor ␣ (PPAR ␣) and induces accumulation of PPARresponsive mRNAs in a rat hepatoma cell line. Using a scintillation proximity assay (SPA), CLA isomers were shown to be ligands for human PPAR ␣ with a rank order of potency of (9Z,11E) Ͼ (10E,12Z) Ͼ (9E,11E) Ͼ furan-CLA (IC 50 values from 140 n M to 400 n M). Levels of acyl-CoA oxidase (ACO), liver fatty acid-binding protein (L-FABP), and cytochrome P450IVA1 (CYP4A1) mRNA were induced by CLA in FaO hepatoma cells. Even though linoleate and CLA were incorporated into lipids of hepatoma cells to the same extent, linoleate had little or no effect on ACO, CYP4A1, or L-FABP mRNA. In agreement with its binding potency, (9Z,11E)-CLA was the most efficacious PPAR ␣ activator in the mouse PPAR ␣-GAL4(UAS) 5-CAT reporter system. These data indicate that CLA is a ligand and activator of PPAR ␣ and its effects on lipid metabolism may be attributed to transcriptional events associated with this nuclear receptor. Also, (9Z,11E)-CLA is one of the most avid fatty acids yet described as a PPAR ␣ ligand.-Moya-Camarena, S.
Conjugated linoleic acid inhibits peritoneal metastasis in human gastrointestinal cancer cells
International Journal of Cancer, 2005
The effect of conjugated linoleic acid (CLA) on peritoneal metastasis was examined by in vitro treatment of cancer cells and mouse peritoneal metastasis models. First, cell growth of MKN28 human gastric cancer cells and Colo320 human colon cancer cells was suppressed by CLA in a dose-dependent manner with an increment in apoptosis. CLA significantly inhibited invasion into type IV collagen-coated membrane of MKN28 and Colo320 cells (p < 0.05). CLA-induced growth inhibition was recovered by the exposure to antisense S-oligodeoxynucleotide for peroxisome proliferator-activated receptor (PPAR)-c in both cell lines. BALB/c nu-nu mice were inoculated with MKN28 and Colo320 cells into their peritoneal cavity, and administrated with CLA intraperitoneally (weekly, 4 times). CLA treatment did not affect food intake or weight gain of mice. CLA treatment significantly decreased metastatic foci of both cells in the peritoneal cavity (p < 0.005). Survival rate in mice inoculated with MKN28 or Colo320 cells was significantly recovered by CLA treatment (p 5 0.0025 and 0.0052, respectively). Protein production in MKN28 and Colo320 cells treated with CLA showed a decrease in epidermal growth factor receptor and transforming growth factor-a and an increase in Bax. These findings suggest that CLA inhibits metastasis of human gastric and colon cancer cells.
Journal of Leukocyte Biology, 2009
The infiltration of PMNs into tissues is a prominent feature in inflammation. The mechanism underlying PMN recruitment depends on the release of chemotactic mediators and CAM expression on endothelial cells. The nuclear receptor PPAR/␦ is widely expressed in many tissues, including the vascular endothelium; however, its role in acute inflammation remains unclear. Using intravital microscopy in the mouse cremasteric microcirculation, we have shown that activation of PPAR/␦ by its selective ligand GW501516 inhibits TNF-␣-induced leukocyte rolling flux, adhesion, and emigration in a dose-dependant manner. Moreover, GW501516 reduced the expression of adhesion molecules such as ICAM-1, VCAM-1, and E-selectin in the cremasteric postcapillary venules. Similarly, rolling and adhesion of hPMNs under physiological flow on TNF-␣activated HUVECs were also inhibited markedly by GW501516. These inhibitory responses of GW501516 on activated endothelium were accompanied by a reduction in TNF-␣-induced endothelial GRO-␣ release and VCAM-1, E-selectin, and ICAM-1 mRNA expression. Taken together, our results show that PPAR/␦ modulates acute inflammation in vivo and in vitro under flow by targeting the neutrophil-endothelial cell interaction.
British Journal of Nutrition, 2006
Conjugated linoleic acid (CLA) has protective properties in breast cancer. Here, we studied the mechanisms underlying the effects of CLA on MCF-7 breast cancer cell proliferation, especially in correlation with the involvement of the extracellular signal-regulated kinase 1/2 (ERK1/2) pathway and protein phosphatase 2A (PP2A). CLA inhibits MCF-7 cell growth in a concentration-and time-dependent manner, without triggering apoptosis. In assessing expression levels of proteins that play obligatory roles in the ERK cascade, we evidenced that CLA down-regulated Raf-1 and decreased levels of phospho-ERK1/2, as well as c-myc expression. Increase in PP2A expression rates were additionally observed after CLA treatment of MCF-7 cells. The above effects, as well as CLA-induced inhibition of cell growth, were reversed by okadaic acid, a specific inhibitor of PP2A. Thus, PP2A likely participates in deactivation of ERK1/2, and its up-regulation may represent a novel mechanism for CLA-induced inhibition of cell proliferation.