Oncotarget 15868 www.impactjournals.com/oncotarget www.impactjournals.com/oncotarget/ Oncotarget, Vol. 7, No. 13 SI113, a SGK1 inhibitor, potentiates the effects of radiotherapy, modulates the response to oxidative stress and induces cytotoxic autophagy in human glioblastoma multiforme cells Cristina Talarico 1 , Vincenzo Dattilo 1 , Lucia D’Antona 1 , Agnese Barone 2 , Nicola Amodio 2 , Stefania Belviso 2 , Francesca Musumeci 3 , Claudia Abbruzzese 5 , Cataldo Bianco 2 , Francesco Trapasso 2 , Silvia Schenone 3 , Stefano Alcaro 1 , Francesco Ortuso 1 , Tullio Florio 4 , Marco G. Paggi 5 , Nicola Perrotti 1 and Rosario Amato 1 1 Department of “Scienze della Salute”, University ”Magna Graecia” of Catanzaro, Catanzaro, Italy 2 Department of “Medicina Sperimentale e Clinica”, University ”Magna Graecia” of Catanzaro, Catanzaro, Italy 3 Department of Farmacia, University of Genova, Genova, Italy 4 Department of Medicina Interna e Specialità Mediche e Center of Excellence per la Ricerca Biomedica (CEBR), University of Genova, Genova, Italy 5 Experimental Oncology, Regina Elena National Cancer Institute, IRCCS, Rome, Italy Correspondence to: Rosario Amato, email: rosario.amato@unicz.it Correspondence to: Nicola Perrotti, email: perrotti@unicz.it Keywords: SGK1, SI113, radiotherapy, glioblastoma, oxidative stress Received: December 18, 2015 Accepted: February 08, 2016 Published: February 19, 2016 AbstrAct Glioblastoma multiforme (GBM) is the most aggressive CNS tumor and is characterized by a very high frequency of clinical relapse after therapy and thus by a dismal prognosis, which strongly compromises patients survival. We have recently identifed the small molecule SI113, as a potent and selective inhibitor of SGK1, a serine/threonine protein kinase, that modulates several oncogenic signaling cascades. The SI113-dependent SGK1 inhibition induces cell death, blocks proliferation and perturbs cell cycle progression by modulating SGK1-related substrates. SI113 is also able to strongly and consistently block, in vitro and in vivo, growth and survival of human hepatocellular-carcinomas, either used as a single agent or in combination with ionizing radiations. In the present paper we aim to study the effect of SI113 on human GBM cell lines with variable p53 expression. Cell viability, cell death, caspase activation and cell cycle progression were then analyzed by FACS and WB-based assays, after exposure to SI113, with or without oxidative stress and ionizing radiations. Moreover, autophagy and related reticulum stress response were evaluated. We show here, that i) SGK1 is over-expressed in highly malignant gliomas and that the treatment with SI113 leads to ii) signifcant increase in caspase-mediated apoptotic cell death in GBM cell lines but not in normal fbroblasts; iii)enhancement of the effects of ionizing radiations; iv) modulation of the response to oxidative reticulum stress; v) induction of cytotoxic autophagy. Evidence reported here underlines the therapeutic potential of SI113 in GBM, suggesting a new therapeutic strategy either alone or in combination with radiotherapy. IntroductIon Malignant gliomas are the most frequent adult primary brain tumors and among these, glioblastoma multiforme (GBM) represent approximately 70% of glial tumors. Despite important advances in surgical techniques, chemotherapy, as well as conventional and stereotaxic radiotherapy approaches, for these patients the