Research Papers:

GPER-independent inhibition of adrenocortical cancer growth by G-1 involves ROS/Egr-1/BAX pathway

Ivan Casaburi, Paola Avena, Arianna De Luca, Rosa Sirianni, Vittoria Rago, Adele Chimento, Francesca Trotta, Carmela Campana, William E. Rainey and Vincenzo Pezzi _

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Oncotarget. 2017; 8:115609-115619. https://doi.org/10.18632/oncotarget.23314

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Ivan Casaburi1,*, Paola Avena1,*, Arianna De Luca1,*, Rosa Sirianni1, Vittoria Rago1, Adele Chimento1, Francesca Trotta1, Carmela Campana1, William E. Rainey2 and Vincenzo Pezzi1

1Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende, Cosenza, Italy

2Departments of Molecular & Integrative Physiology and Internal Medicine, University of Michigan, Medical School, Ann Arbor, MI, USA

*These authors have contributed equally to this work

Correspondence to:

Vincenzo Pezzi, email: [email protected]

Keywords: GPER agonist G-1; Egr-1; ROS; mitochondrial apoptotic pathway; adrenocortical cancer cell

Received: September 21, 2017     Accepted: December 04, 2017     Published: December 14, 2017


We previously demonstrated that treatment of the H295R adrenocortical cancer cell line with the non-steroidal, high-affinity GPER (G protein-coupled estrogen receptor 1) agonist G-1 reduced tumor growth in vitro and in vivo through a GPER independent action. Moreover, we observed that G-1 treatment induces cell-cycle arrest and apoptosis following a sustained ERK1/2 activation. However, the precise mechanisms causing these effects were not clarified. Starting from our preliminary published results, we performed a microarray study that clearly evidenced a strong and significative up-regulation of EGR-1 gene in H295R cells treated for 24h with micromolar concentration of G-1. The microarray findings were confirmed by RT-PCR and Western-blot analysis as well as by immunofluorescence that revealed a strong nuclear staining for EGR-1 after G-1 treatment. EGR-1 is a point of convergence of many intracellular signaling cascades that control tumor cell growth and proliferation as well as others that relate to cell death machinery. Here we found that the increased Egr-1 expression was a consequence of G-1-mediated ROS-dependent ERK activation that were promptly reversed by the presence of the antioxidant n-acetyl-cysteine. Finally, we observed that silencing EGR-1 gene expression reversed the main effects induced by G-1 in ACC cells, including upregulation of the negative regulator of cell cycle, p21Waf1/Cip1 and the positive regulator of mitochondrial apoptotic pathway, BAX, as well as the cell growth inhibition. The identified ROS/MAPK/Egr-1/BAX pathway as a potential off-target effect of the G-1 could be useful in implementing the pharmacological approach for ACC therapy.

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