Estrogen related receptor α (ERRα) a promising target for the therapy of adrenocortical carcinoma (ACC)
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Ivan Casaburi1,*, Paola Avena1,*, Arianna De Luca1,*, Adele Chimento1, Rosa Sirianni1, Rocco Malivindi1, Vittoria Rago1, Marco Fiorillo1, Francesco Domanico1, Carmela Campana1, Anna Rita Cappello1, Federica Sotgia2, Michael P. Lisanti2, Vincenzo Pezzi1
1Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Italy
2The Breakthrough Breast Cancer Research Unit and the Manchester Centre for Cellular Metabolism, Institute of Cancer Sciences, University of Manchester, UK
*These authors have contributed equally to this work
Vincenzo Pezzi, e-mail: [email protected]
Keywords: ERRα, adrenocortical cancer, mitochondria, ATP depletion
Received: May 21, 2015 Accepted: July 17, 2015 Published: July 29, 2015
The pathogenesis of the adrenocortical cancer (ACC) involves integration of molecular signals and the interplay of different downstream pathways (i.e. IGFII/IGF1R, β-catenin, Wnt, ESR1). This tumor is characterized by limited therapeutic options and unsuccessful treatments. A useful strategy to develop an effective therapy for ACC is to identify a common downstream target of these multiple pathways. A good candidate could be the transcription factor estrogen-related receptor alpha (ERRα) because of its ability to regulate energy metabolism, mitochondrial biogenesis and signalings related to cancer progression.
In this study we tested the effect of ERRα inverse agonist, XCT790, on the proliferation of H295R adrenocortical cancer cell line. Results from in vitro and in vivo experiments showed that XCT790 reduced H295R cell growth. The inhibitory effect was associated with impaired cell cycle progression which was not followed by any apoptotic event. Instead, incomplete autophagy and cell death by a necrotic processes, as a consequence of the cell energy failure, induced by pharmacological reduction of ERRα was evidenced.
Our results indicate that therapeutic strategies targeting key factors such as ERRα that control the activity and signaling of bioenergetics processes in high-energy demanding tumors could represent an innovative/alternative therapy for the treatment of ACC.
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