Sigma-1 and Sigma-2 receptor ligands induce apoptosis and autophagy but have opposite effect on cell proliferation in uveal melanoma

// Lucia Longhitano 1 , Carlo Castruccio Castracani 1 , Daniele Tibullo 1 , Roberto Avola 1 , Maria Viola 1 , Giuliano Russo 1 , Orazio Prezzavento 4 , Agostino Marrazzo 4 , Emanuele Amata 4 , Michele Reibaldi 2 , Antonio Longo 2 , Andrea Russo 2 , Nunziatina Laura Parrinello 3 and Giovanni Li Volti 1, 5 1 Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy 2 Department of Ophthalmology, University of Catania, Catania, Italy 3 Regional Reference Center for Rare Diseases, Clinical Division of Hematology and Transplantation, PO Ferrarotto Hospital, Azienda Ospedaliera-Universitaria Policlinico-Vittorio Emanuele, Via Citelli, Catania, Italy 4 Department of Drug Sciences, University of Catania, Catania, Italy 5 Euromediterranean Institute of Science and Technology, Palermo, Italy Correspondence to: Giovanni Li Volti, email: livolti@unict.it Keywords: uveal melanoma, sigma receptors, apoptosis, autophagy, (+)-pentazocine Received: June 16, 2017      Accepted: July 13, 2017      Published: July 25, 2017 ABSTRACT Uveal melanoma is the most common primary intraocular tumor in adults, with about 1200–1500 new cases occurring per year in the United States. Metastasis is a frequent occurrence in uveal melanoma, and outcomes are poor once distant spread occurs and no clinically significant chemotherapeutic protocol is so far available. The aim of the present study was to test the effect of various σ 1 and σ 2 receptor ligands as a possible pharmacological strategy for this rare tumor. Human uveal melanoma cells (92.1) were treated with various concentrations of different σ 2 ligands (haloperidol and haloperidol metabolite II) and σ 1 ligand ((+)-pentazocine) at various concentrations (1, 10 and 25 μM) and time points (0, 4 h, 8 h, 24 h and 48 h). Cell proliferation and migration were evaluated respectively by continuous cell monitoring by xCELLigence analysis, clonogenic assay and wound healing. Apoptosis and autophagy were also measured by cytofluorimetric and microscopy analysis. Our results showed that σ 2 receptor ligands significantly reduced cell proliferation whereas (+)-pentazocine exhibited opposite results. All tested ligands showed significant decrease in cell migration. Interestingly, both σ 1 and σ 2 receptor ligands showed significant increase of autophagy and apoptosis at all concentrations. Taken all together these results suggest that sigma receptors mediates opposite biological effects but they also share common pharmacological effect on apoptosis and autophagy in uveal melanoma. In conclusion, these data provide the first evidence that sigma receptors may represent a “druggable” target to develop new chemotherapic agent for uveal melanoma.