Ricerc@Sapienza

Glioblastoma multiforme is the most frequent malignant brain tumor. A key feature of malignant gliomas is their cellular heterogeneity. In particular, the presence of an undifferentiated cell population defined Glioblastoma Stem cells (GSCs) has been reported. GSCs are considered the main cell population responsible for the beginning of neoplastic process and recurrence formation. Several studies report how muscarinic receptors (mAChRs) are involved in the regulation of cell cycle, chemotaxis of brain tumors. For years, our research group has been studying the antiproliferative effects of M2 mAChR activation in different tumors, such as glioblastoma, neuroblastoma and breast cancer [1¿5]. Our previous data have showed that the activation of M2 mAChR by orthosteric agonist Arecaidine Propargyl Ester (APE) caused a significant decrease of cell proliferation and survival in GSCs [2]. In our lab we have also characterized the N-8-Iper (N8), a dualsteric agonist able to activate M2 mAChR with higher affinity than APE. N8 is able to induce a pro-apoptotic and cytotoxic effect already at low doses [3]. These results suggest that N8 may be a promising therapeutic drug for the treatment of glioblastoma. M2 mAChR belongs to the class of G-protein-coupled receptors (GPCRs). After being activated, GPCR signaling is mediated by G-proteins and is followed by their rapid desensitization, i.e. the rapid return to the basal level of GPCR. This process is mainly orchestrated by GPCR kinases and ß-arrestins [6]. In recent years, a new role of ß-arrestins has emerged. These proteins, upon activation of a GPCR, are in turn activated by directing several signaling pathways of particular interest for the study of tumor progression, such as cell proliferation, cell survival and migration [7,8]. Based on this evidence, the aim of this project is to study the signaling pathways downstream of the M2 mAChR activated by APE or N8, focusing on the possible role of ß-arrestins in tumor migration.