GPER agonist G-1 decreases adrenocortical carcinoma (ACC) cell growth in vitro and in vivo
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Adele Chimento1,*, Rosa Sirianni1,*, Ivan Casaburi1,*, Fabiana Zolea1, Pietro Rizza1, Paola Avena1, Rocco Malivindi1, Arianna De Luca1, Carmela Campana1, Emilia Martire1, Francesco Domanico1, Francesco Fallo2, Giulia Carpinelli3, Lidia Cerquetti4, Donatella Amendola5, Antonio Stigliano4, Vincenzo Pezzi1
1Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende, Cosenza, Italy
2Department of Medicine-DIMED, University of Padova, Padova, Italy
3Department of Cell Biology and Neurosciences, National Institute of Health, Rome, Italy
4Department of Clinical and Molecular Medicine, Sant’Andrea Hospital, Faculty of Medicine and Psychology, Rome, Italy
5Research Center, San Pietro Hospital-Fatebenefratelli, Rome, Italy
*These authors have contributed equally to this work
Vincenzo Pezzi, e-mail: [email protected]
Keywords: GPER, G-1, adrenocortical cancer, apoptosis
Received: January 30, 2015 Accepted: May 23, 2015 Published: June 05, 2015
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.
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