Nucleolin antagonist triggers autophagic cell death in human glioblastoma primary cells and decreased <i>in vivo</i> tumor growth in orthotopic brain tumor model

Abstract

// Elisabetta Benedetti 1, * , Andrea Antonosante 1, * , Michele d&rsquo;Angelo 1 , Loredana Cristiano 1 , Renato Galzio 1 , Damien Destouches 2, 3 , Tiziana Marilena Florio 1 , Anne Chlo&eacute; Dhez 1 , Carlo Astarita 6 , Benedetta Cinque 1 , Alessia Fidoamore 1 , Floriana Rosati 4 , Maria Grazia Cifone 1 , Rodolfo Ippoliti 1 , Antonio Giordano 5, 6 , Jos&eacute; Courty 2, 3 , Annamaria Cimini 1, 6, 7 1 Department of Life, Health and Environmental Sciences, University of L&rsquo;Aquila, L&rsquo;Aquila, Italy 2 Department of Cell Biology, Universit&eacute; Paris-Est, UPEC, Cr&eacute;teil, France 3 Laboratoire de Recherche sur la Croissance Cellulaire, la R&eacute;paration et la R&eacute;g&eacute;n&eacute;ration Tissulaires (CRRET) CNRS, Cr&eacute;teil, France 4 Department of Life Sciences, University of Siena, Siena, Italy 5 Department of Medicine, Surgery and Neuroscience, University of Siena, Siena, Italy 6 Sbarro Institute for Cancer Research and Molecular Medicine and Center for Biotechnology, Temple University, Philadelphia, Pennsylvania, USA 7 National Institute for Nuclear Physics (INFN), Gran Sasso National Laboratory (LNGS), Assergi, Italy * These authors have contributed equally to this work Correspondence to: Annamaria Cimini, e-mail: annamaria.cimini@univaq.it Jos&eacute; Courty, e-mail: courty@u-pec-fr Keywords: glioblastoma, autophagy, targeted therapy Received: July 15, 2015&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Accepted: October 09, 2015&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Published: October 19, 2015 ABSTRACT Nucleolin (NCL) is highly expressed in several types of cancer and represents an interesting therapeutic target. It is expressed at the plasma membrane of tumor cells, a property which is being used as a marker for several human cancer including glioblastoma. In this study we investigated targeting NCL as a new therapeutic strategy for the treatment of this pathology. To explore this possibility, we studied the effect of an antagonist of NCL, the multivalent pseudopeptide N6L using primary culture of human glioblastoma cells. In this system, N6L inhibits cell growth with different sensitivity depending to NCL localization. Cell cycle analysis indicated that N6L-induced growth reduction was due to a block of the G1/S transition with down-regulation of the expression of cyclin D1 and B2. By monitoring autophagy markers such as p62 and LC3II, we demonstrate that autophagy is enhanced after N6L treatment. In addition, N6L-treatment of mice bearing tumor decreased in vivo tumor growth in orthotopic brain tumor model and increase mice survival. The results obtained indicated an anti-proliferative and pro-autophagic effect of N6L and point towards its possible use as adjuvant agent to the standard therapeutic protocols presently utilized for glioblastoma.