P2X7 receptor antagonism in the treatment of cancers

Abstract

ATP-gated P2X7 receptors (P2X7) make a unique family of extracellular ATP-activated plasma membrane ion channels expressed in haematopoietic and epithelial cells. They have been extensively studied in immune cells where their activation leads to the rapid release of pro-inflammatory cytokines and the initiation of the inflammatory cascade. As such, P2X7 represent a pharmaceutical target for the treatment of inflammatory diseases. Recently, P2X7 expression has been found in diverse tumours and has been suggested as a potential cancer cell biomarker. On ATP stimulation, tumour cells can use P2X7 signalling in different scenarios: i) as a reaction to this death-related signal, they can downregulate P2X7 to avoid apoptosis or ii) as a cancer-promoting signal to survive and enhance invasion of new niches. The high levels of extracellular ATP found in tumours could represent a stressful stimulus for cancer cells by initiating P2X7-driven cell death. Therefore, the increased P2X7-dependent invasiveness of cancer cells could be an escape strategy to flee the noxious high level of ATP. The use of specific P2X7 antagonists could be a new alternative way to reduce the development of cancer metastases and improve the efficacy of conventional treatments.

Keywords::

• cancer
• cell growth
• extracellular ATP
• invasion
• metastases
• P2X7 receptor
• tumour

Acknowledgements

The authors thank the ‘Partenariat Hubert Curien – Alliance’ from the French Foreign and European Ministry and the French Embassy in the UK. The authors thank Pierre Besson (University of Tours) for reading the manuscript. Research work in S Roger's lab is supported by a grant from the Ligue Nationale Contre le Cancer – Région Grand-Ouest and a financial support from the ‘Association CANCEN’. Research work in P Pelegrín's lab is supported by the PN I + D+I 2008 – 2011, Instituto de Salud Carlos III-FEDER (grant number EMER07/049 and PS09/00120), Fundación Séneca (grant number 11922/PI/09) and Spanish Health Ministry (grant EC10/020).