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The P2X7 receptor is a key modulator of the PI3K/GSK3β/VEGF signaling network: evidence in experimental neuroblastoma

F Amoroso1, M Capece1, A Rotondo1

  • 1Department of Morphology, Surgery and Experimental Medicine, Section of Experimental Pathology, Oncology and Biology, University of Ferrara, Ferrara, Italy.

Oncogene
|January 27, 2015
PubMed

Insights

Targeting the P2X7 receptor offers a new therapeutic strategy for neuroblastoma (NB). Blocking P2X7 receptor reduces tumor growth, vascularization, and MYCN oncogene expression in preclinical models, suggesting its potential in treating aggressive pediatric cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Neuroblastoma (NB) is a highly aggressive pediatric cancer with limited treatment options for advanced stages.
  • The P2X7 receptor, activated by extracellular ATP, is implicated in NB cell proliferation and tumor progression.
  • Understanding P2X7 receptor's role in NB signaling pathways is crucial for developing novel therapies.

Purpose of the Study:

  • To investigate the role of the P2X7 receptor in regulating key signaling pathways in neuroblastoma.
  • To evaluate the therapeutic potential of P2X7 receptor antagonists in preclinical neuroblastoma models.

Main Methods:

  • Analysis of PI3K/Akt/GSK3β/MYCN and HIF1α/VEGF pathways following P2X7 receptor modulation (activation or silencing) in human NB cells.
  • Administration of P2X7 antagonists (AZ10606120 or A740003) in both human NB xenograft and syngeneic mouse models.
  • Assessment of tumor growth, vascularization, and expression of key oncogenes (MYCN) and signaling molecules.

Main Results:

  • P2X7 receptor stimulation enhanced PI3K/Akt and decreased GSK3β activity, while P2X7 blockade showed opposite effects, impacting cellular glycogen stores.
  • Down-modulation of P2X7 receptor reduced HIF1α levels and vascular endothelial growth factor (VEGF) secretion.
  • Systemic administration of P2X7 antagonists significantly reduced tumor growth in both xenograft and syngeneic models, decreasing Akt/HIF1α axis activity, VEGF, and vessel formation.
  • P2X7 antagonists markedly reduced MYCN expression in both models.
  • P2X7 overexpression correlated with poor prognosis in advanced-stage NB patients.

Conclusions:

  • The P2X7 receptor acts as an upstream regulator of critical signaling pathways (PI3K/Akt, HIF1α/VEGF, MYCN) involved in neuroblastoma growth, metabolism, and angiogenesis.
  • P2X7 receptor blockade demonstrates significant anti-tumor efficacy in preclinical neuroblastoma models.
  • Targeting the P2X7 receptor represents a promising therapeutic strategy for neuroblastoma treatment.

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