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Inhibition of leydig tumor growth by farnesoid X receptor activation: The in vitro and in vivo basis for a novel therapeutic strategy
Author(s) -
Catalano Stefania,
Panza Salvatore,
Malivindi Rocco,
Giordano Cinzia,
Barone Ines,
Bossi Gianluca,
Lanzino Marilena,
Sirianni Rosa,
Mauro Loredana,
Sisci Diego,
Bonofiglio Daniela,
Andò Sebastiano
Publication year - 2012
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.27915
Subject(s) - farnesoid x receptor , biology , in vivo , aromatase , downregulation and upregulation , cell growth , cancer research , chromatin immunoprecipitation , medicine , endocrinology , microbiology and biotechnology , nuclear receptor , transcription factor , gene expression , biochemistry , promoter , cancer , genetics , breast cancer , gene
Leydig cell tumors (LCTs) are the most common tumors of the gonadal stroma and represent about 3% of all testicular neoplasms. In most cases, LCTs are benign; however, if the tumor is malignant, no effective treatments are currently available. We have recently reported that farnesoid X receptor (FXR) is expressed in R2C Leydig tumor cells, and it reduces the estrogen‐dependent cell proliferation by negatively regulating aromatase expression. Here, we demonstrated that treatment with GW4064, a specific FXR agonist, markedly reduced Leydig tumor growth in vivo by inhibiting proliferation and inducing apoptosis. Indeed, the tumors from GW4064‐treated mice exhibited a decrease in the expression of the proliferation marker Ki‐67 and aromatase along with an increase in the apoptotic nuclei. FXR activation induced an enhanced poly(ADP‐ribose) polymerase cleavage, a marked DNA fragmentation and a strong increase in TUNEL‐positive R2C cells also in vitro . Moreover, in both in vivo and in vitro models, FXR ligands upregulated mRNA and protein levels of p53 and of its downstream effector p21 WAF1/Cip1 . Functional experiments showed that FXR ligands upregulated p53 promoter activity and this occurred through an increased binding of FXR/nuclear factor‐kB (NF‐kB) complex to the NF‐kB site located within p53 promoter region as revealed by electrophoretic mobility shift assay and chromatin immunoprecipitation analysis. Taken together, results from our study show, for the first time, that treatment with FXR ligands induces Leydig tumor regression in vivo , suggesting that activation of FXR may represent a promising therapeutic strategy for LCTs.