title: Glucocorticoid Receptor as a Potential Target to Decrease Aromatase Expression and Inhibit Leydig Tumor Growth.
abstract: Leydig cell tumors are the most frequent interstitial neoplasms of the testis with increased incidence in recent years. They are hormonally active and are considered one of the steroid-secreting tumors. Although usually benign, the malignant phenotype responds poorly to conventional chemotherapy or radiation, highlighting the need to identify new therapeutic targets for treatment. Here, we identified a novel glucocorticoid-mediated mechanism that controls cell growth in Leydig cell tumors. We found that a synthetic glucocorticoid receptor agonist, dexamethasone, reduces cell proliferation in rat Leydig tumor cells by decreasing the expression and the enzymatic activity of the estrogen-producing enzyme aromatase. This inhibitory effect relies on the ability of activated glucocorticoid receptor to regulate the aromatase gene transcriptional activity through the recruitment of nuclear receptor corepressor protein and silencing mediator of retinoid and thyroid hormone receptors to a newly identified putative glucocorticoid responsive element within the aromatase promoter II. Our in vivo studies reveal a reduction of tumor growth, after dexamethasone treatment, in animal xenografts. Tumors from dexamethasone-treated mice exhibit a decrease in the expression of the proliferation marker Ki-67 and the aromatase enzyme. Our data demonstrate that activated glucocorticoid receptor, decreasing aromatase expression, induces Leydig tumor regression both in vitro and in vivo, suggesting that glucocorticoid receptor might be a potential target for the therapy of Leydig cell tumors.
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende, Cosenza, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Panza
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende, Cosenza, Italy.
authors.forename: Rocco
authors.initials: R
authors.lastname: Malivindi
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende, Cosenza, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Chemi
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende, Cosenza, Italy.
authors.forename: Vittoria
authors.initials: V
authors.lastname: Rago
authors.affiliation: Health Center, University of Calabria, Arcavacata di Rende, Cosenza, Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Giordano
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende, Cosenza, Italy.
authors.forename: Ines
authors.initials: I
authors.lastname: Barone
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende, Cosenza, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Bonofiglio
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende, Cosenza, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Gelsomino
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende, Cosenza, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Giordano
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende, Cosenza, Italy; Health Center, University of Calabria, Arcavacata di Rende, Cosenza, Italy. Electronic address: sebastiano.ando@unical.it.
authors.forename: Sebastiano
authors.initials: S
authors.lastname: Andò
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende, Cosenza, Italy. Electronic address: stefania.catalano@unical.it.
authors.forename: Stefania
authors.initials: S
authors.lastname: Catalano
mesh_terms: D000818:Animals; D001141:Aromatase / Q000378:metabolism*; D047072:Aromatase Inhibitors / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology*; D064593:Heterografts; D007984:Leydig Cell Tumor / Q000188:drug therapy / Q000473:pathology*; D008297:Male; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors*; D013736:Testicular Neoplasms / Q000188:drug therapy / Q000473:pathology*
chemical_list: D047072:Aromatase Inhibitors; D011965:Receptors, Glucocorticoid; D003907:Dexamethasone; D001141:Aromatase