Role of P2X7 receptor and its splice variants in oncogenesis

Extracellular ATP (eATP) recently emerged as an important constituent of tumour microenvironment promoting cancer cell growth and progression and modulating the anti-tumoral immune response. Among eATP receptors, P2X7 is probably the best-recognized onco-promoting protein as it is involved in cancer cell proliferation, vascularization and metastatic dissemination (1,2). Here we investigated the activity of P2X7 receptor blocking drugs in reducing experimental melanoma and neuroblastoma growth in murine models, demonstrating the efficacy of two different P2X7 antagonist in reducing cancer growth in both models (3,4). Moreover, we identified the PI3K/Akt and HIF1α VEGF axes as the central pathways involved in P2X7–dependent cancer growth. P2X7 antagonism also caused a reduction of intracellular glycogen stores and of the levels of the oncogene N-MYC through activation of GSK3β (4). In human nine different P2X7 splice variants have been identified among which just two functional as ion channels: P2X7A and P2X7B, both exerting a growth promoting activity (5). Evidence will be presented for an increased expression of P2X7B compared to P2X7A in different malignancies including acute myeloid leukaemia and osteosarcoma. In osteosarcoma, P2X7B correlates with increased Ki67 staining and augmented cell proliferation (6). Moreover, if overexpressed in Te85 osteosarcoma cells both P2X7A and B increase cell growth through the NFATc1 pathway causing increased eATP release (6). Taken together our data support the hypothesis that P2X7 receptor splice variants A and B influence oncogenesis acting at different signalling pathways and are attractive therapeutic targets for the cure of cancer.