P2X(7): a growth-promoting receptor-implications for cancer

Abstract

The P2X(7) 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 P2X(7) 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 P2X(7)-like receptor; (2) P2X(7) transfection into several cell lines confers growth advantage; (3) HEK293 cells transfected with P2X(7) show enhanced mitochondrial metabolic activity and growth; (4) lipopolysaccharide (LPS)-dependent growth arrest of microglia is mediated via P2X(7) down-modulation; (5) several malignant tumours express high P2X(7) 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 P2X(7) receptor. The molecular basis of P2X(7)-mediated growth-promoting activity is poorly known, but mitochondria appear to play a central role. A deeper understanding of the role played by P2X(7) in cell proliferation might provide an insight into the mechanism of normal and malignant cell growth and suggest novel anti-tumour therapies.

Fig. 1

Schematic rendition of the differential effects of P2X₇-stimulated intracellular Ca²⁺ increases. ATP is continuously released into the extracellular environment via as yet poorly characterized pathways. This causes tonic stimulation of the P2X₇ receptor leading to moderately increased cytoplasmic Ca²⁺, which translates into an elevation of intramitochondrial Ca²⁺ from 0.1–0.2 μM (blue line) to about 1.5–2.0 μM (green line). Such a Ca²⁺ increase stimulates NADH synthesis and ATP production via oxidative phosphorylation. Increased cellular ATP content then facilitates cell survival and growth. However, in the presence of massive amounts of extracellular ATP, the P2X₇ receptor is overstimulated, this leads to uncontrolled Ca²⁺ influx and unchecked increase in the cytoplasm as well as the mitochondria (red line), with catastrophic consequences on the cell