P2X7: a growth-promoting receptor—implications for cancer
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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.
KeywordsExtracellular ATP-P2 receptors-cancer
This research was supported by grants from the Italian Association for Cancer Research, Telethon of Italy (n. GGP06070), the Italian Space Agency (ASI-OSMA), the Italian Ministry of University and Scientific Research (PRIN), the Commission of European Communities (7th Framework Program HEALTH-F2-2007-202231), the Regione Emilia-Romagna, and institutional funds from the University of Ferrara.
- 7.Adinolfi E, Callegari MG, Ferrari D, Bolognesi C, Minelli M, Wieckowski MR et al (2005) Basal activation of the P2X7 ATP receptor elevates mitochondrial calcium and potential, increases cellular ATP levels, and promotes serum-independent growth. Mol Biol Cell 16:3260–3272PubMedCrossRefGoogle Scholar
- 35.Heerdt BG, Houston MA, Wilson AJ, Augenlicht LH (2003) The intrinsic mitochondrial membrane potential (Deltapsim) is associated with steady-state mitochondrial activity and the extent to which colonic epithelial cells undergo butyrate-mediated growth arrest and apoptosis. Cancer Res 63:6311–6319PubMedGoogle Scholar