TY - JOUR
T1 - Inhibition of leydig tumor growth by farnesoid X receptor activation
T2 - The in vitro and in vivo basis for a novel therapeutic strategy
AU - Catalano, Stefania
AU - Panza, Salvatore
AU - Malivindi, Rocco
AU - Giordano, Cinzia
AU - Barone, Ines
AU - Bossi, Gianluca
AU - Lanzino, Marilena
AU - Sirianni, Rosa
AU - Mauro, Loredana
AU - Sisci, Diego
AU - Bonofiglio, Daniela
AU - Andò, Sebastiano
PY - 2013/5/15
Y1 - 2013/5/15
N2 - 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 p21WAF1/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. What's new? Leydig cell tumors are the most common tumors of the gonadal stroma, and currently there are no effective ways to treat such tumors should they be malignant. Farnesoid X receptors (FXR) are expressed in Leydig tumor cells, and here the authors show that FXR activation through synthetic ligands reduces tumor growth. The mechanism involves both inhibition of cell proliferation and induction of apoptosis, with an underlying increase of p53 gene expression. This study provides the first direct evidence for in vivo effects of FXR activation on Leydig carcinogenesis, suggesting that FXR ligands could potentially be used in a clinical approach.
AB - 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 p21WAF1/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. What's new? Leydig cell tumors are the most common tumors of the gonadal stroma, and currently there are no effective ways to treat such tumors should they be malignant. Farnesoid X receptors (FXR) are expressed in Leydig tumor cells, and here the authors show that FXR activation through synthetic ligands reduces tumor growth. The mechanism involves both inhibition of cell proliferation and induction of apoptosis, with an underlying increase of p53 gene expression. This study provides the first direct evidence for in vivo effects of FXR activation on Leydig carcinogenesis, suggesting that FXR ligands could potentially be used in a clinical approach.
KW - Farnesoid X receptor
KW - Leydig tumors
KW - NF-kB
KW - apoptosis
KW - p53
UR - http://www.scopus.com/inward/record.url?scp=84874944427&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84874944427&partnerID=8YFLogxK
U2 - 10.1002/ijc.27915
DO - 10.1002/ijc.27915
M3 - Article
C2 - 23124354
AN - SCOPUS:84874944427
SN - 0020-7136
VL - 132
SP - 2237
EP - 2247
JO - International Journal of Cancer
JF - International Journal of Cancer
IS - 10
ER -