title: Selective GPER activation decreases proliferation and activates apoptosis in tumor Leydig cells.
abstract: We have previously shown that estrogens binding to estrogen receptor (ER) α increase proliferation of Leydig tumor cells. Estrogens can also bind to G protein-coupled ER (GPER) and activation of this receptor can either increase or decrease cell proliferation of several tumor types. The aim of this study was to investigate GPER expression in R2C rat tumor Leydig cells, evaluate effects of its activation on Leydig tumor cell proliferation and define the molecular mechanisms triggered in response to its activation. R2C cells express GPER and its activation, using the specific ligand G-1, is associated with decreased cell proliferation and initiation of apoptosis. Apoptosis after G-1 treatment was asserted by appearance of DNA condensation and fragmentation, decrease in Bcl-2 and increase in Bax expression, cytochrome c release, caspase and poly (ADP-ribose) polymerase-1 (PARP-1) activation. These effects were dependent on GPER activation because after silencing of the gene, using a specific small interfering RNA, cyt c release, PARP-1 activation and decrease in cell proliferation were abrogated. These events required a rapid, however, sustained extracellular regulated kinase 1/2 activation. G-1 was able to decrease the growth of R2C xenograft tumors in CD1 nude mice while increasing the number of apoptotic cells. In addition, in vivo administration of G-1 to male CD1 mice did not cause any alteration in testicular morphology, while cisplatin, the cytotoxic drug currently used for the therapy of Leydig tumors, severely damaged testicular structure, an event associated with infertility in cisplatin-treated patients. These observations indicate that GPER targeting for the therapy of Leydig cell tumor may represent a good alternative to cisplatin to preserve fertility in Leydig tumor patients.
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende, Cosenza, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Chimento
authors.forename: I
authors.initials: I
authors.lastname: Casaburi
authors.forename: M
authors.initials: M
authors.lastname: Bartucci
authors.forename: M
authors.initials: M
authors.lastname: Patrizii
authors.forename: R
authors.initials: R
authors.lastname: Dattilo
authors.forename: P
authors.initials: P
authors.lastname: Avena
authors.forename: S
authors.initials: S
authors.lastname: Andò
authors.forename: V
authors.initials: V
authors.lastname: Pezzi
authors.forename: R
authors.initials: R
authors.lastname: Sirianni
mesh_terms: D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D053144:Cell Nucleus Shape / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D003517:Cyclopentanes / Q000494:pharmacology; D004249:DNA Damage; D004958:Estradiol / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015870:Gene Expression; D007984:Leydig Cell Tumor / Q000188:drug therapy* / Q000473:pathology; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008819:Mice, Nude; D011804:Quinolines / Q000494:pharmacology; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D013736:Testicular Neoplasms / Q000188:drug therapy* / Q000473:pathology; D013737:Testis / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: C517943:1-(4-(6-bromobenzo(1,3)dioxol-5-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta(c)quinolin-8-yl)ethanone; D018931:Antineoplastic Agents, Hormonal; D003517:Cyclopentanes; C520305:Gper1 protein, rat; D011804:Quinolines; D043562:Receptors, G-Protein-Coupled; D004958:Estradiol; D048049:Extracellular Signal-Regulated MAP Kinases
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