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Activation of peroxisome proliferator-activated receptor-?/? (PPAR-?/?) inhibits human breast cancer cell line tumorigenicity.

ABSTRACT: The effect of activation and overexpression of the nuclear receptor PPAR-?/? in human MDA-MB-231 (estrogen receptor-negative; ER(-)) and MCF7 (estrogen-receptor-positive; ER(+)) breast cancer cell lines was examined. Target gene induction by ligand activation of PPAR-?/? was increased by overexpression of PPAR-?/? compared with controls. Overexpression of PPAR-?/? caused a decrease in cell proliferation in MCF7 and MDA-MB-231 cells compared with controls, whereas ligand activation of PPAR-?/? further inhibited proliferation of MCF7 but not MDA-MB-231 cells. Overexpression and/or ligand activation of PPAR-?/? in MDA-MB-231 or MCF7 cells had no effect on experimental apoptosis. Decreased clonogenicity was observed in both MDA-MB-231 and MCF7 overexpressing PPAR-?/? in response to ligand activation of PPAR-?/? as compared with controls. Ectopic xenografts developed from MDA-MB-231 and MCF7 cells overexpressing PPAR-?/? were significantly smaller, and ligand activation of PPAR-?/? caused an even greater reduction in tumor volume as compared with controls. Interestingly, the decrease in MDA-MB-231 tumor size after overexpressing PPAR-?/? and ligand activation of PPAR-?/? correlated with increased necrosis. These data show that ligand activation and/or overexpression of PPAR-?/? in two human breast cancer cell lines inhibits relative breast cancer tumorigenicity and provide further support for the development of ligands for PPAR-?/? to specifically inhibit breast carcinogenesis. These new cell-based models will be invaluable tools for delineating the role of PPAR-?/? in breast cancer and evaluating the effects of PPAR-?/? agonists.

SUBMITTER: Yao PL

PROVIDER: S-EPMC3981956 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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Activation of peroxisome proliferator-activated receptor-β/δ (PPAR-β/δ) inhibits human breast cancer cell line tumorigenicity.

Yao Pei-Li PL Morales Jose L JL Zhu Bokai B Kang Boo-Hyon BH Gonzalez Frank J FJ Peters Jeffrey M JM

Molecular cancer therapeutics 20140124 4

The effect of activation and overexpression of the nuclear receptor PPAR-β/δ in human MDA-MB-231 (estrogen receptor-negative; ER(-)) and MCF7 (estrogen-receptor-positive; ER(+)) breast cancer cell lines was examined. Target gene induction by ligand activation of PPAR-β/δ was increased by overexpression of PPAR-β/δ compared with controls. Overexpression of PPAR-β/δ caused a decrease in cell proliferation in MCF7 and MDA-MB-231 cells compared with controls, whereas ligand activation of PPAR-β/δ fu ...[more]

PMID: 24464939

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Project description:Although MK886 was originally identified as an inhibitor of 5-lipoxygenase activating protein (FLAP), recent data demonstrate that this activity does not underlie its ability to induce apoptosis [Datta, Biswal and Kehrer (1999) Biochem. J. 340, 371--375]. Since FLAP is a fatty-acid binding protein, it is conceivable that MK886 may affect other such proteins. A family of nuclear receptors that are activated by fatty acids and their metabolites, the peroxisome-proliferator-activated receptors (PPARs), have been implicated in apoptosis and may represent a target for MK886. The ability of MK886 to inhibit PPAR-alpha, -beta and -gamma activity was assessed using reporter assay systems (peroxisome-proliferator response element--luciferase). Using a transient transfection system in monkey kidney fibroblast CV-1 cells, mouse keratinocyte 308 cells and human lung adenocarcinoma A549 cells, 10--20 microM MK886 inhibited Wy14,643 activation of PPAR alpha by approximately 80%. Similar inhibition of PPAR alpha by MK886 was observed with a stable transfection reporter system in CV-1 cells. Only minimal inhibitory effects were seen on PPAR beta and PPAR gamma. MK886 inhibited PPAR alpha by a non-competitive mechanism as shown by its effects on the binding of arachidonic acid to PPAR alpha protein, and a dose-response study using a transient transfection reporter assay in COS-1 cells. An assay assessing PPAR ligand-receptor interactions showed that MK886 prevents the conformational change necessary for active-complex formation. The expression of keratin-1, a protein encoded by a PPAR alpha-responsive gene, was reduced by MK886 in a culture of mouse primary keratinocytes, suggesting that PPAR inhibition has functional consequences in normal cells. Although Jurkat cells express all PPAR isoforms, various PPAR alpha and PPAR gamma agonists were unable to prevent MK886-induced apoptosis. This is consistent with MK886 functioning as a non-competitive inhibitor of PPAR alpha, but may also indicate that PPAR alpha is not directly involved in MK886-induced apoptosis. Although numerous PPAR activators have been identified, the results show that MK886 can inhibit PPAR alpha, making it the first compound identified to have such an effect.

Dataset Information

Activation of peroxisome proliferator-activated receptor-?/? (PPAR-?/?) inhibits human breast cancer cell line tumorigenicity.

Publications

Activation of peroxisome proliferator-activated receptor-β/δ (PPAR-β/δ) inhibits human breast cancer cell line tumorigenicity.

Similar Datasets

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