RESUMEN
In breast carcinoma cells, high levels of hyaluronan (HA) and its CD44 receptor are frequently associated with alteration in estrogen signaling. We demonstrate that stable hyaluronate synthase 2 (HAS2) overexpression in estrogen receptor α (ERα) -positive MCF7 cells oppositely altered estrogen dependence of cell growth and its sensitivity towards antiestrogens. Albeit without effect on ERα expression and estradiol binding properties, HAS2 overexpression increased ERα Ser118 phosphorylation as well as transcriptional activity of estrogen in an ERE-luciferase reporter gene assay. However, HAS2 overexpression induced partial silencing of E2 driven-genes without affecting the magnitude of regulation by estradiol. This effect was associated with half-reduction in the activity of nuclear histone deacetylases (HDACs) through a post-translational mechanism likely consecutive to the enhanced expression of the histone acetyl-transferase EP300. In conclusion, increase in HA/CD44 interactions may contribute, through an HDAC inhibitor-like and ER-independent mechanism, to the silencing of estrogen-driven genes in breast carcinoma.
Asunto(s)
Neoplasias de la Mama/genética , Receptor alfa de Estrógeno/metabolismo , Estrógenos/farmacología , Glucuronosiltransferasa/metabolismo , Inhibidores de Histona Desacetilasas/farmacología , Acetilación/efectos de los fármacos , Neoplasias de la Mama/patología , Proteína p300 Asociada a E1A/metabolismo , Receptor alfa de Estrógeno/genética , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Genes Reporteros , Humanos , Receptores de Hialuranos/metabolismo , Hialuronano Sintasas , Ácido Hialurónico/metabolismo , Ácidos Hidroxámicos/farmacología , Células MCF-7 , Metilación/efectos de los fármacos , Fosforilación/efectos de los fármacos , Fosfoserina/metabolismo , Unión Proteica/efectos de los fármacos , Fracciones Subcelulares/metabolismoRESUMEN
Recently, a new generation of highly promising inhibitors bearing ß-keto-enol functionality has emerged. Reported herein is the ï¬rst synthesis and use of novel designed drugs based on the ß-keto-enol group embedded with heterocyclic moieties such as pyrazole, pyridine, and furan, prepared in a one-step procedure by mixed Claisen condensation. All the newly synthesized compounds were characterized by FT-IR, ¹H-NMR, (13)C-NMR, ESI/LC-MS, elemental analysis, and evaluated for their in vitro antiproliferative activity against breast cancer (MDA-MB241) human cell lines and fungal strains (Fusarium oxysporum f.sp albedinis FAO). Three of the synthesized compounds showed potent activity against fungal strains with IC50 values in the range of 0.055-0.092 µM. The results revealed that these compounds showed better IC50 values while compared with positive controls.