Purinergic Signalling

, Volume 5, Issue 2, pp 251–256 | Cite as

P2X7: a growth-promoting receptor—implications for cancer

  • Francesco Di Virgilio
  • Davide Ferrari
  • Elena Adinolfi
Original Article


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.


Extracellular 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.


  1. 1.
    Di Virgilio F, Bronte V, Collavo D, Zanovello P (1989) Responses of mouse lymphocytes to extracellular adenosine 5′-triphosphate (ATP). Lymphocytes with cytotoxic activity are resistant to the permeabilizing effects of ATP. J Immunol 143:1955–1960PubMedGoogle Scholar
  2. 2.
    Filippini A, Taffs RE, Agui T, Sitkovsky MV (1990) Ecto-ATPase activity in cytolytic T-lymphocytes. Protection from the cytolytic effects of extracellular ATP. J Biol Chem 265:334–340PubMedGoogle Scholar
  3. 3.
    Chiozzi P, Murgia M, Falzoni S, Ferrari D, Di Virgilio F (1996) Role of the purinergic P2Z receptor in spontaneous cell death in J774 macrophage cultures. Biochem Biophys Res Commun 218:176–181PubMedCrossRefGoogle Scholar
  4. 4.
    Baricordi OR, Ferrari D, Melchiorri L, Chiozzi P, Hanau S, Chiari E et al (1996) An ATP-activated channel is involved in mitogenic stimulation of human T lymphocytes. Blood 87:682–690PubMedGoogle Scholar
  5. 5.
    Baricordi OR, Melchiorri L, Adinolfi E, Falzoni S, Chiozzi P, Buell G et al (1999) Increased proliferation rate of lymphoid cells transfected with the P2X(7) ATP receptor. J Biol Chem 274:33206–33208PubMedCrossRefGoogle Scholar
  6. 6.
    Adinolfi E, Melchiorri L, Falzoni S, Chiozzi P, Morelli A, Tieghi A et al (2002) P2X7 receptor expression in evolutive and indolent forms of chronic B lymphocytic leukemia. Blood 99:706–708PubMedCrossRefGoogle Scholar
  7. 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
  8. 8.
    Bianco F, Ceruti S, Colombo A, Fumagalli M, Ferrari D, Pizzirani C et al (2006) A role for P2X7 in microglial proliferation. J Neurochem 99:745–758PubMedCrossRefGoogle Scholar
  9. 9.
    Raffaghello L, Chiozzi P, Falzoni S, Di Virgilio F, Pistoia V (2006) The P2X7 receptor sustains the growth of human neuroblastoma cells through a substance P-dependent mechanism. Cancer Res 66:907–914PubMedCrossRefGoogle Scholar
  10. 10.
    Di Virgilio F (1995) The P2Z purinoceptor: an intriguing role in immunity, inflammation and cell death. Immunol Today 16:524–528PubMedCrossRefGoogle Scholar
  11. 11.
    North RA (2002) Molecular physiology of P2X receptors. Physiol Rev 82:1013–1067PubMedGoogle Scholar
  12. 12.
    Coutinho-Silva R, Persechini PM (1997) P2Z purinoceptor-associated pores induced by extracellular ATP in macrophages and J774 cells. Am J Physiol 273:C1793–C1800PubMedGoogle Scholar
  13. 13.
    Pelegrin P, Surprenant A (2006) Pannexin-1 mediates large pore formation and interleukin-1beta release by the ATP-gated P2X7 receptor. EMBO J 25:5071–5082PubMedCrossRefGoogle Scholar
  14. 14.
    Pelegrin P, Surprenant A (2007) Pannexin-1 couples to maitotoxin- and nigericin-induced interleukin-1beta release through a dye uptake-independent pathway. J Biol Chem 282:2386–2394PubMedCrossRefGoogle Scholar
  15. 15.
    el-Moatassim C, Dornand J, Mani JC (1987) Extracellular ATP increases cytosolic free calcium in thymocytes and initiates the blastogenesis of the phorbol 12-myristate 13-acetate-treated medullary population. Biochim Biophys Acta 927:437–444PubMedCrossRefGoogle Scholar
  16. 16.
    DosReis GA, Nobrega AF, de Carvalho RP (1986) Purinergic modulation of T-lymphocyte activation: differential susceptibility of distinct activation steps and correlation with intracellular 3’,5’-cyclic adenosine monophosphate accumulation. Cell Immunol 101:213–231PubMedCrossRefGoogle Scholar
  17. 17.
    Lin J, Krishnaraj R, Kemp RG (1985) Exogenous ATP enhances calcium influx in intact thymocytes. J Immunol 135:3403–3410PubMedGoogle Scholar
  18. 18.
    Chused TM, Apasov S, Sitkovsky M Murine T (1996) Lymphocytes modulate activity of an ATP-activated P2Z-type purinoceptor during differentiation. J Immunol 157:1371–1380PubMedGoogle Scholar
  19. 19.
    Rhodes J (1996) Covalent chemical events in immune induction: fundamental and therapeutic aspects. Immunol Today 17:436–441PubMedCrossRefGoogle Scholar
  20. 20.
    Ferrari D, Los M, Bauer MK, Vandenabeele P, Wesselborg S, Schulze-Osthoff K (1999) P2Z purinoreceptor ligation induces activation of caspases with distinct roles in apoptotic and necrotic alterations of cell death. FEBS Lett 447:71–75PubMedCrossRefGoogle Scholar
  21. 21.
    Pfeiffer ZA, Aga M, Prabhu U, Watters JJ, Hall DJ, Bertics PJ (2004) The nucleotide receptor P2X7 mediates actin reorganization and membrane blebbing in RAW 264.7 macrophages via p38 MAP kinase and Rho. J Leukoc Biol 75:1173–1182PubMedCrossRefGoogle Scholar
  22. 22.
    Morelli A, Chiozzi P, Chiesa A, Ferrari D, Sanz JM, Falzoni S et al (2003) Extracellular ATP causes ROCK I-dependent bleb formation in P2X7-transfected HEK293 cells. Mol Biol Cell 14:2655–2664PubMedCrossRefGoogle Scholar
  23. 23.
    Giorgi C, Romagnoli A, Pinton P, Rizzuto R (2008) Ca2+ signaling, mitochondria and cell death. Curr Mol Med 8:119–130PubMedCrossRefGoogle Scholar
  24. 24.
    MacKenzie A, Adinolfi E, Grainge A, Surprenant A (2005) Pseudoapoptosis induced by brief activation of ATP-gated P2X7 receptors. J Biol Chem 280:33968–33976PubMedCrossRefGoogle Scholar
  25. 25.
    Jouaville LS, Pinton P, Bastianutto C, Rutter GA, Rizzuto R (1999) Regulation of mitochondrial ATP synthesis by calcium: evidence for a long-term metabolic priming. Proc Natl Acad Sci U S A 96:13807–13812PubMedCrossRefGoogle Scholar
  26. 26.
    Denton RM, McCormack JG (1980) On the role of the calcium transport cycle in heart and other mammalian mitochondria. FEBS Lett 119:1–8PubMedCrossRefGoogle Scholar
  27. 27.
    Warburg O (1956) On respiratory impairment in cancer cells. Science 124:269–270PubMedGoogle Scholar
  28. 28.
    Kim Jw, Dang CV (2006) Cancer’s molecular sweet tooth and the Warburg Effect. Cancer Res 66:8927–8930PubMedCrossRefGoogle Scholar
  29. 29.
    Schulz TJ, Thierbach R, Voigt A, Drewes G, Mietzner B, Steinberg P et al (2006) Induction of oxidative metabolism by mitochondrial frataxin inhibits cancer growth: Otto Warburg revisited. J Biol Chem 281:977–981PubMedCrossRefGoogle Scholar
  30. 30.
    Slater M, Danieletto S, Gidley-Baird A, Teh LC, Barden JA (2004) Early prostate cancer detected using expression of non-functional cytolytic P2X7 receptors. Histopathology 44:206–215PubMedCrossRefGoogle Scholar
  31. 31.
    Slater M, Danieletto S, Pooley M, Cheng TL, Gidley-Baird A, Barden JA (2004) Differentiation between cancerous and normal hyperplastic lobules in breast lesions. Breast Cancer Res Treat 83:1–10PubMedCrossRefGoogle Scholar
  32. 32.
    Greig AV, Linge C, Healy V, Lim P, Clayton E, Rustin MH et al (2003) Expression of purinergic receptors in non-melanoma skin cancers and their functional roles in A431 cells. J Invest Dermatol 121:315–327PubMedCrossRefGoogle Scholar
  33. 33.
    Solini A, Cuccato S, Ferrari D, Santini E, Gulinelli S, Callegari MG et al (2008) Increased P2X7 receptor expression and function in thyroid papillary cancer: a new potential marker of the disease? Endocrinology 149:389–396PubMedCrossRefGoogle Scholar
  34. 34.
    Damdimopoulos AE, Miranda-Vizuete A, Pelto-Huikko M, Gustafsson JA, Spyrou G (2002) Human mitochondrial thioredoxin. Involvement in mitochondrial membrane potential and cell death. J Biol Chem 277:33249–33257PubMedCrossRefGoogle Scholar
  35. 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
  36. 36.
    Heerdt BG, Houston MA, Augenlicht LH (2006) Growth properties of colonic tumor cells are a function of the intrinsic mitochondrial membrane potential. Cancer Res 66:1591–1596PubMedCrossRefGoogle Scholar
  37. 37.
    Pellegatti P, Raffaghello L, Bianchi G, Piccardi F, Pistoia V, Di Virgilio F (2008) Increased level of extracellular atp at tumor sites: in vivo imaging with plasma membrane luciferase. PLoS ONE 3:e2599PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2009

Authors and Affiliations

  • Francesco Di Virgilio
    • 1
  • Davide Ferrari
    • 1
  • Elena Adinolfi
    • 1
  1. 1.Department of Experimental and Diagnostic Medicine, Section of General Pathology, and Interdisciplinary Center for the Study of Inflammation (ICSI)University of FerraraFerraraItaly

Personalised recommendations