P2X7/PI3K/AKT/HIF1a pathway: a novel network influencing neuroblastoma growth

Introduction. P2X7 receptor for extracellular ATP has been focus of interest over the last years as a receptor promoting cell proliferation, tumor growth, engraftment, tumor vascularization and aerobic glycolysis.1,2 In support of these findings, P2X7 expression was reported to be increased in several tumors, including breast and skin cancers, leukemia and neuroblastoma.3,4,5 Neuroblastoma is a common and aggressive extra cranial solid tumor in childhood and still causes death in 40% of the cases. Here we elucidate the role of P2X7 receptor in neuroblastoma. Materials and Methods. For in vitro and in vivo experiments we took advantage of two P2X7 expressing neuroblastoma cell lines: human ACN, that release VEGF in a P2X7 dependent fashion1, and murine Neuro-2a. We injected them in nude/nude and Albino J mice to obtain an allogeneic and a syngeneic model, respectively. Results. We show here that basal P2X7 receptor expression supported ACN and Neuro-2a tumor growth in vivo. P2X7 silencing and antagonism with AZ10606120 and A740003 caused cell growth arrest through the PI3K/Akt/HIF1α/GSK3β pathway modulation, both in vitro and in vivo. Pharmacological treatment of P2X7 also reduced mitochondrial potential in Neuro- 2a cells. Moreover, we found a correlation between P2X7 mRNA expression and a decreased overall survival of stage IV neuroblastoma patients. Conclusions. Altogether, these data show that P2X7 receptor plays an important role in neuroblastoma growth by modulating PI3K/Akt/HIF1α/GSK3β pathway. Thus, we suggest P2X7 receptor as a possible pharmacological target for neuroblastoma treatment. 1Adinolfi, E; Raffaghello, L; Giuliani, AL; et al (2012), Cancer Res. 72(12):2957-69. 2Amoroso, F; Falzoni, S; Adinolfi, E; Ferrari, D; Di Virgilio, F (2012), Cell Death Dis. 3:e370. 3Adinolfi, E; Amoroso, F and Giuliani, AL (2012), J Osteoporosis 2012:637863.