title: Resveratrol, through NF-Y/p53/Sin3/HDAC1 complex phosphorylation, inhibits estrogen receptor alpha gene expression via p38MAPK/CK2 signaling in human breast cancer cells.
abstract: Agents to counteract acquired resistance to hormonal therapy for breast cancer would substantially enhance the long-term benefits of hormonal therapy. In the present study, we demonstrate how resveratrol (Res) inhibits human breast cancer cell proliferation, including MCF-7 tamoxifen-resistant cells (IC(50) values for viability were in the 30-45 μM range). We show that Res, through p38(MAPK) phosphorylation, causes induction of p53, which recruits at the estrogen receptor α (ERα) proximal promoter, leading to an inhibition of ERα expression in terms of mRNA and protein content. These events appear specifically p53 dependent, since they are drastically abrogated with p53-targeting siRNA. Coimmunoprecipitation assay showed specific interaction between p53, the Sin3A corepressor, and histone deacetylase 1 (HDAC1), which was phosphorylated. The enhancement of the tripartite complex p53/Sin3A/HDAC1, together with NF-Y on Res treatment, was confirmed by chromatin immunoprecipitation analyses, with a concomitant release of Sp1 and RNA polymerase II, thereby inhibiting the cell transcriptional machinery. The persistence of such effects in MCF-7 tamoxifen-resistant cells at a higher extent than parental MCF-7 cells addresses how Res may be considered a useful pharmacological tool to be exploited in the adjuvant settings for treatment of breast cancer developing hormonal resistance.
authors: Centro Sanitario, Department of Pharmaco-Biology, University of Calabria, Arcavacata di Rende (CS) 87030, Italy.
authors: Francesca
authors: F
authors: De Amicis
authors: Francesca
authors: F
authors: Giordano
authors: Adele
authors: A
authors: Vivacqua
authors: Michele
authors: M
authors: Pellegrino
authors: Maria Luisa
authors: ML
authors: Panno
authors: Donatella
authors: D
authors: Tramontano
authors: Suzanne A W
authors: SA
authors: Fuqua
authors: Sebastiano
authors: S
authors: Andò
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D001943:Breast Neoplasms / Q000378:metabolism*; D023081:CCAAT-Binding Factor / Q000235:genetics / Q000378:metabolism*; D047390:Casein Kinase II / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056284:Histone Deacetylase 1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D000077185:Resveratrol; D056264:Sin3 Histone Deacetylase and Corepressor Complex / Q000235:genetics / Q000378:metabolism*; D013267:Stilbenes / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D023081:CCAAT-Binding Factor; D047628:Estrogen Receptor alpha; D013267:Stilbenes; D016159:Tumor Suppressor Protein p53; D047390:Casein Kinase II; D048051:p38 Mitogen-Activated Protein Kinases; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1; D056264:Sin3 Histone Deacetylase and Corepressor Complex; D000077185:Resveratrol