Inhibition of leydig tumor growth by farnesoid X receptor activation: The in vitro and in vivo basis for a novel therapeutic strategy. Issue 10 (7th November 2012)

• Record Type: Journal Article
• Authors: Catalano, Stefania; Panza, Salvatore; Malivindi, Rocco; Giordano, Cinzia; Barone, Ines; Bossi, Gianluca; Lanzino, Marilena; Sirianni, Rosa; Mauro, Loredana; Sisci, Diego; Bonofiglio, Daniela; Andò, Sebastiano
• Is Part Of: International journal of cancer. Volume 132:Issue 10(2013:May 15)
• Page Start: 2237
• Page End: 2247
• Publication Date: 2012-11-07
• Subjects: Cancer -- Periodicals; Cancer -- Prevention -- Periodicals; 616.994
• DOI: 10.1002/ijc.27915
• Languages: English
• ISSNs: 0020-7136

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <p>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 <italic>in vivo</italic> 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 <italic>in vitro</italic>. Moreover, in both <italic>in vivo</italic> and <italic>in vitro</italic> models, FXR ligands upregulated mRNA and protein levels of p53 and of its downstream effector p21<sup>WAF1/Cip1</sup>. 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 <italic>in vivo</italic>, suggesting that activation of FXR may represent a promising therapeutic strategy for LCTs.</p> </abstract>