P2X7: a growth-promoting receptor—implications for cancer

Abstract

The P2X₇ receptor is widely referred to as the paradigmatic cytotoxic nucleotide receptor, and is often taken as an epitome of cytotoxic receptors as a whole. However, cytotoxicity is the result of sustained pharmacological stimulation, which is likely to occur in vivo only under severe pathological conditions. Over the years, we have gathered robust experimental proof that led us to adopt an entirely different view, pointing to P2X₇ as a survival/growth-promoting rather than death-inducing receptor. Evidence in favour of this role is manifold: (1) extracellular ATP and benzoyl ATP support cell proliferation in peripheral T lymphocytes via a P2X₇-like receptor; (2) P2X₇ transfection into several cell lines confers growth advantage; (3) HEK293 cells transfected with P2X₇ show enhanced mitochondrial metabolic activity and growth; (4) lipopolysaccharide (LPS)-dependent growth arrest of microglia is mediated via P2X₇ down-modulation; (5) several malignant tumours express high P2X₇ levels and (6) the ATP concentration in tumour interstitium is several-fold higher than in healthy tissues, to a level in principle sufficient to activate the P2X₇ receptor. The molecular basis of P2X₇-mediated growth-promoting activity is poorly known, but mitochondria appear to play a central role. A deeper understanding of the role played by P2X₇ in cell proliferation might provide an insight into the mechanism of normal and malignant cell growth and suggest novel anti-tumour therapies.