Neuroblastoma (NB) is an aggressive pediatric
tumor, responsible for 15% of
cancer-related deaths in childhood, lacking an effective treatment in its advanced stages. The
P2X7 receptor for extracellular
ATP was associated to NB cell proliferation and recently emerged as a promoter of
tumor engraftment, growth and vascularization. In an effort to identify new therapeutic options for
neuroblastoma, we studied the role of
P2X7 receptor in NB biology. We first analyzed the effect of P2X7 activation or down-modulation of the main biochemical ways involved in NB progression: the PI3K/Akt/GSK3β/MYCN and the HIF1α/
VEGF pathways. In
ACN human NB cells, P2X7 stimulation enhanced PI3K/Akt, while decreasing GSK3β activity. In the same model, P2X7 silencing or antagonist administration reduced the activity of PI3K/Akt and increased that of GSK3β, leading to a decrease in cellular
glycogen stores. Similarly, P2X7 downmodulation caused a reduction in HIF1α levels and
vascular endothelial growth factor (
VEGF) secretion. Systemic administration of two different P2X7 antagonists (
AZ10606120 or
A740003) in nude/nude mice reduced
ACN-derived
tumor growth. An even stronger effect of P2X7 blockade was obtained in a syngeneic immune-competent
neuroblastoma model: Neuro2A cells injected in AlbinoJ mice. Together with
tumor regression, treatment with P2X7 antagonists caused downmodulation of the Akt/HIF1α axis, leading to reduced
VEGF content and decreased vessel formation. Interestingly, in both experimental models, P2X7 antagonists strongly reduced the expression of the probably best-accepted oncogene in NB: MYCN. Finally, we associated P2X7 overexpression with poor prognosis in advanced-stage NB patients. Taken together, our data suggest that
P2X7 receptor is an upstream regulator of the main signaling pathways involved in NB growth, metabolic activity and angiogenesis, and a promising therapeutic target for
neuroblastoma treatment.