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Evidence that Farnesoid X Receptor ligand through SF‐1 responsive element inhibits aromatase expression in Leydig tumor cells.
Author(s) -
Andò Sebastiano,
Malivindi Rocco,
Rizza Pietro,
Gu Guowei,
Panza Salvatore,
Catalano Stefania
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.438.12
Subject(s) - aromatase , farnesoid x receptor , retinoid x receptor , transactivation , biology , nuclear receptor , medicine , endocrinology , retinoid x receptor alpha , estrogen receptor , chemistry , microbiology and biotechnology , transcription factor , biochemistry , cancer , breast cancer , gene , genetics
The Farnesoid X Receptor (FXR) is a member of the nuclear receptor superfamily of ligand‐dependent transcription factors, that heterodimerizes with the Retinoid X Receptor (RXR). FXR, normally present in the liver and in the gastrointestinal tract, has been characterized as a bile acid receptor, but it is also expressed in nonenterohepatic tissues, including kidneys, adrenal gland, heart, vascular tissue, thymus, ovary, spleen, breast and testis. In this study, we investigated how transactivation of FXR by a specific ligand, chenodeoxycholic acid (CDCA), may modulate aromatase expression in R2C Leydig tumor cells. Upon prolonged exposure to CDCA we observed a strong decrease of aromatase expression, in terms of protein content, as revealed by immunocitochemistry and western‐blotting analysis, mRNA and aromatase enzymatic activity. Transient transfection experiment, using vector containing rat aromatase promoter PII, evidenced that CDCA reduced basal aromatase promoter activity. Specific mutagenesis studies, EMSA and ChIP assay, revealed that these inhibitory effects were due to FXR binding to SF‐1 responsive element present in the aromatase promoter region. Our findings address how FXR ligands may perspectively represent potential pharmacological tools to inhibit local estrogen production sustaining Leydig cell tumor growth and progression