Farnesoid X receptor, through the binding with steroidogenic factor 1-responsive element, inhibits aromatase expression in tumor Leydig cells.
The farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily that regulates bile acid homeostasis. It is expressed in the liver and the gastrointestinal tract, but also in several non-enterohepatic tissues including testis. Recently, FXR was identified as a negative modulator of the androgen-estrogen-converting aromatase enzyme in human breast cancer cells. In the present study we detected the expression of FXR in Leydig normal and tumor cell lines and in rat testes tissue. We found, in rat Leydig tumor cells, R2C, that FXR activation by the primary bile acid chenodeoxycholic acid (CDCA) or a synthetic agonist GW4064, through a SHP-independent mechanism, down-regulates aromatase expression in terms of mRNA, protein levels, and its enzymatic activity. Transient transfection experiments, using vector containing rat aromatase promoter PII, evidenced that CDCA reduces basal aromatase promoter activity. Mutagenesis studies, electrophoretic mobility shift, and chromatin immunoprecipitation analysis reveal that FXR is able to compete with steroidogenic factor 1 in binding to a common sequence present in the aromatase promoter region interfering negatively with its activity. Finally, the FXR-mediated anti-proliferative effects exerted by CDCA on tumor Leydig cells are at least in part due to an inhibition of estrogen-dependent cell growth. In conclusion our findings identify for the first time the activators of FXR as negative modulators of the aromatase enzyme in Leydig tumor cell lines.
Catalano
Stefania
S
Department of Pharmaco-Biology, University of Calabria, 87030 Arcavacata di Rende (CS), Italy
Malivindi
Rocco
R
Giordano
Cinzia
C
Gu
Guowei
G
Panza
Salvatore
S
Bonofiglio
Daniela
D
Lanzino
Marilena
M
Sisci
Diego
D
Panno
Maria Luisa
ML
Andò
Sebastiano
S
D000818:Animals; D001141:Aromatase / Q000096:biosynthesis* / Q000235:genetics; D002400:Cathartics / Q000494:pharmacology; D002635:Chenodeoxycholic Acid / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology; D007984:Leydig Cell Tumor / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007985:Leydig Cells / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements; D054339:Steroidogenic Factor 1 / Q000235:genetics / Q000378:metabolism*; D000099150:Receptor, Farnesoid X-Activated
D001141:Aromatase; D002400:Cathartics; D002635:Chenodeoxycholic Acid; D007555:Isoxazoles; D009363:Neoplasm Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D054339:Steroidogenic Factor 1; D000099150:Receptor, Farnesoid X-Activated; C515057:NR5A1 protein, human; C099713:nuclear receptor subfamily 0, group B, member 2; C515058:steroidogenic factor 1, mouse; C515060:steroidogenic factor 1, rat; C412815:GW 4064