title: GPER agonist G-1 decreases adrenocortical carcinoma (ACC) cell growth in vitro and in vivo.
abstract: We have previously demonstrated that estrogen receptor (ER) alpha (ESR1) increases proliferation of adrenocortical carcinoma (ACC) through both an estrogen-dependent and -independent (induced by IGF-II/IGF1R pathways) manner. Then, the use of tamoxifen, a selective estrogen receptor modulator (SERM), appears effective in reducing ACC growth in vitro and in vivo. However, tamoxifen not only exerts antiestrogenic activity, but also acts as full agonist on the G protein-coupled estrogen receptor (GPER). Aim of this study was to investigate the effect of a non-steroidal GPER agonist G-1 in modulating ACC cell growth. We found that G-1 is able to exert a growth inhibitory effect on H295R cells both in vitro and, as xenograft model, in vivo. Treatment of H295R cells with G-1 induced cell cycle arrest, DNA damage and cell death by the activation of the intrinsic apoptotic mechanism. These events required sustained extracellular regulated kinase (ERK) 1/2 activation. Silencing of GPER by a specific shRNA partially reversed G-1-mediated cell growth inhibition without affecting ERK activation. These data suggest the existence of G-1 activated but GPER-independent effects that remain to be clarified. In conclusion, this study provides a rational to further study G-1 mechanism of action in order to include this drug as a treatment option to the limited therapy of ACC.
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende, Cosenza, Italy.
authors.forename: Adele
authors.initials: A
authors.lastname: Chimento
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende, Cosenza, Italy.
authors.forename: Rosa
authors.initials: R
authors.lastname: Sirianni
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende, Cosenza, Italy.
authors.forename: Ivan
authors.initials: I
authors.lastname: Casaburi
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende, Cosenza, Italy.
authors.forename: Fabiana
authors.initials: F
authors.lastname: Zolea
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende, Cosenza, Italy.
authors.forename: Pietro
authors.initials: P
authors.lastname: Rizza
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende, Cosenza, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Avena
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: Arianna
authors.initials: A
authors.lastname: De Luca
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende, Cosenza, Italy.
authors.forename: Carmela
authors.initials: C
authors.lastname: Campana
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende, Cosenza, Italy.
authors.forename: Emilia
authors.initials: E
authors.lastname: Martire
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende, Cosenza, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Domanico
authors.affiliation: Department of Medicine-DIMED, University of Padova, Padova, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Fallo
authors.affiliation: Department of Cell Biology and Neurosciences, National Institute of Health, Rome, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Carpinelli
authors.affiliation: Department of Clinical and Molecular Medicine, Sant'Andrea Hospital, Faculty of Medicine and Psychology, Rome, Italy.
authors.forename: Lidia
authors.initials: L
authors.lastname: Cerquetti
authors.affiliation: Research Center, San Pietro Hospital-Fatebenefratelli, Rome, Italy.
authors.forename: Donatella
authors.initials: D
authors.lastname: Amendola
authors.affiliation: Department of Clinical and Molecular Medicine, Sant'Andrea Hospital, Faculty of Medicine and Psychology, Rome, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Stigliano
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende, Cosenza, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Pezzi
mesh_terms: D000293:Adolescent; D000306:Adrenal Cortex Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018268:Adrenocortical Carcinoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000328:Adult; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003517:Cyclopentanes / Q000494:pharmacology*; D004249:DNA Damage; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation; D011804:Quinolines / Q000494:pharmacology*; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C517943:1-(4-(6-bromobenzo(1,3)dioxol-5-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta(c)quinolin-8-yl)ethanone; D003517:Cyclopentanes; C109584:GPER1 protein, human; D011804:Quinolines; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3
keywords: G-1; GPER; adrenocortical cancer; apoptosis