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Cell Surface ATP Synthase: A Potential Target for Anti-Angiogenic Therapy

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Book cover Extracellular ATP and Adenosine as Regulators of Endothelial Cell Function

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Abstract

Since the presence of F1F0 adenosine triphosphate (ATP) synthase was discovered on the surface of human cells, numerous studies have elucidated new functions for this molecule that classically functions as part of the electron transport chain in mitochondria. Like mitochondrial ATP synthase, the cell surface form of this molecule functions as an energy-producing proton pump, coupling the production of extracellular ATP with the transport of protons outside the cell. ATP synthase also acts as an endothelial cell surface receptor for angiostatin, which has led several groups to examine this molecule as a target for inhibiting angiogenesis. Given its involvement in proton transport and the pH-dependent activity of angiostatin and antibodies directed against it, ATP synthase likely functions in part to regulate pH for endothelial cells existing in an acidic microenvironment. In addition, it catalyzes the synthesis and hydrolysis of ATP in the extracellular milieu, potentially affecting purinergic signaling. ATP synthase also plays a role in endothelial cell signaling in response to flow-induced shear stress. Recently, ATP synthase on the surface of endothelial cells has been identified as the receptor for two additional proteins: coupling factor 6 and endothelial monocyte-activating polypeptide II. This chapter will focus on the role of endothelial cell surface ATP synthase in angiogenesis, shear stress response, and as a receptor.

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References

  1. Ando J, Ohtsuka A, Korenaga R, Kamiya A. (1991) Effect of extracellular ATP level on flow-induced Ca++ response in cultured vascular endothelial cells. Biochem Biophys Res Commun 179(3):1192–9.

    Article  CAS  PubMed  Google Scholar 

  2. Arakaki N, Nagao T, Niki R, Toyofuku A, Tanaka H, Kuramoto Y, Emoto Y, Shibata H, Magota K, Higuti T. (2003) Possible role of cell surface H+-ATP synthase in the extracellular ATP synthesis and proliferation of human umbilical vein endothelial cells. Mol Cancer Res 1(13):931–9.

    CAS  PubMed  Google Scholar 

  3. Awasthi N, Schwarz MA, Verma V, Cappiello C, Schwarz RE. (2009) Endothelial monocyte activating polypeptide II interferes with VEGF-induced proangiogenic signaling. Lab Invest 89(1):38–46.

    Article  CAS  PubMed  Google Scholar 

  4. Beerepoot LV, Witteveen EO, Groenewegen G, Fogler WE, Sim BK, Sidor C, Zonnenberg BA, Schramel F, Gebbink MF, Voest EE. (2003) Recombinant human angiostatin by twice-daily subcutaneous injection in advanced cancer: a pharmacokinetic and long-term safety study. Clin Cancer Res 9(11):4025–33.

    CAS  PubMed  Google Scholar 

  5. Berger AC, Alexander HR, Tang G, Wu PS, Hewitt SM, Turner E, Kruger E, Figg WD, Grove A, Kohn E, Stern D, Libutti SK. (2000) Endothelial monocyte activating polypeptide II induces endothelial cell apoptosis and may inhibit tumor angiogenesis. Microvasc Res 60(1):70–80.

    Article  CAS  PubMed  Google Scholar 

  6. Bodin P, Bailey D, Burnstock G. (1991) Increased flow-induced ATP release from isolated vascular endothelial cells but not smooth muscle cells. Br J Pharmacol 103(1):1203–5.

    CAS  PubMed  Google Scholar 

  7. Bodin P, Burnstock G. (2001) Evidence that release of adenosine triphosphate from endothelial cells during increased shear stress is vesicular. J Cardiovasc Pharmacol 38(6):900–8.

    Article  CAS  PubMed  Google Scholar 

  8. Boyer PD. (1997) The ATP synthase–a splendid molecular machine. Annu Rev Biochem 66:717–49.

    Article  CAS  PubMed  Google Scholar 

  9. Boyer PD. (2000) Catalytic site forms and controls in ATP synthase catalysis. Biochim Biophys Acta 1458(2–3):252–62.

    CAS  PubMed  Google Scholar 

  10. Capaldi RA, Aggeler R. (2002) Mechanism of the F(1)F(0)-type ATP synthase, a biological rotary motor. Trends Biochem Sci 27(3):154–60.

    Article  CAS  PubMed  Google Scholar 

  11. Chang SY, Ko HJ, Heo TH, Kang CY. (2005) Heparan sulfate regulates the antiangiogenic activity of endothelial monocyte-activating polypeptide-II at acidic pH. Mol Pharmacol 67(5):1534–43.

    Article  CAS  PubMed  Google Scholar 

  12. Chang SY, Park SG, Kim S, Kang CY. (2002) Interaction of the C-terminal domain of p43 and the alpha subunit of ATP synthase. Its functional implication in endothelial cell proliferation. J Biol Chem 277(10):8388–94.

    Article  CAS  PubMed  Google Scholar 

  13. Chi SL, Pizzo SV. (2006) Angiostatin is directly cytotoxic to tumor cells at low extracellular pH: a mechanism dependent on cell surface-associated ATP synthase. Cancer Res 66(2):875–82.

    Article  CAS  PubMed  Google Scholar 

  14. Chi SL, Pizzo SV. (2006) Cell surface F1Fo ATP synthase: a new paradigm? Ann Med 38(6):429–38.

    Article  CAS  PubMed  Google Scholar 

  15. Chi SL, Wahl ML, Mowery YM, Shan S, Mukhopadhyay S, Hilderbrand SC, Kenan DJ, Lipes BD, Johnson CE, Marusich MF, Capaldi RA, Dewhirst MW, Pizzo SV. (2007) Angiostatin-like activity of a monoclonal antibody to the catalytic subunit of F1F0 ATP synthase. Cancer Res 67(10):4716–24.

    Article  CAS  PubMed  Google Scholar 

  16. Das B, Mondragon MO, Sadeghian M, Hatcher VB, Norin AJ. (1994) A novel ligand in lymphocyte-mediated cytotoxicity: expression of the beta subunit of H+ transporting ATP synthase on the surface of tumor cell lines. J Exp Med 180(1):273–81.

    Article  CAS  PubMed  Google Scholar 

  17. Fessenden-Raden JM. (1972) Purification and properties of a new coupling factor required for oxidative phosphorylation in silicotungstate-treated submitochondrial particles. J Biol Chem 247(8):2351–7.

    CAS  PubMed  Google Scholar 

  18. Gerasimovskaya EV, Woodward HN, Tucker DA, Stenmark KR. (2008) Extracellular ATP is a pro-angiogenic factor for pulmonary artery vasa vasorum endothelial cells. Angiogenesis 11(2):169–82.

    Article  CAS  PubMed  Google Scholar 

  19. Hahn C, Schwartz MA. (2009) Mechanotransduction in vascular physiology and atherogenesis. Nat Rev Mol Cell Biol 10(1):53–62.

    Article  CAS  PubMed  Google Scholar 

  20. Hassessian H, Bodin P, Burnstock G. (1993) Blockade by glibenclamide of the flow-evoked endothelial release of ATP that contributes to vasodilatation in the pulmonary vascular bed of the rat. Br J Pharmacol 109(2):466–72.

    CAS  PubMed  Google Scholar 

  21. Kao J, Houck K, Fan Y, Haehnel I, Libutti SK, Kayton ML, Grikscheit T, Chabot J, Nowygrod R, Greenberg S, et al. (1994) Characterization of a novel tumor-derived cytokine. Endothelial-monocyte activating polypeptide II. J Biol Chem 269(40):25106–19.

    CAS  PubMed  Google Scholar 

  22. Komi Y, Ohno O, Suzuki Y, Shimamura M, Shimokado K, Umezawa K, Kojima S. (2007) Inhibition of tumor angiogenesis by targeting endothelial surface ATP synthase with sangivamycin. Jpn J Clin Oncol 37(11):867–73.

    Article  PubMed  Google Scholar 

  23. Loomis CR, Bell RM. (1988) Sangivamycin, a nucleoside analogue, is a potent inhibitor of protein kinase C. J Biol Chem 263(4):1682–92.

    CAS  PubMed  Google Scholar 

  24. Martinez LO, Jacquet S, Esteve JP, Rolland C, Cabezon E, Champagne E, Pineau T, Georgeaud V, Walker JE, Terce F, Collet X, Perret B, Barbaras R. (2003) Ectopic beta-chain of ATP synthase is an apolipoprotein A-I receptor in hepatic HDL endocytosis. Nature 421(6918):75–9.

    Article  CAS  PubMed  Google Scholar 

  25. Moser TL, Kenan DJ, Ashley TA, Roy JA, Goodman MD, Misra UK, Cheek DJ, Pizzo SV. (2001) Endothelial cell surface F1-F0 ATP synthase is active in ATP synthesis and is inhibited by angiostatin. Proc Natl Acad Sci USA 98(12):6656–61.

    Article  CAS  PubMed  Google Scholar 

  26. Moser TL, Stack MS, Asplin I, Enghild JJ, Hojrup P, Everitt L, Hubchak S, Schnaper HW, Pizzo SV. (1999) Angiostatin binds ATP synthase on the surface of human endothelial cells. Proc Natl Acad Sci USA 96(6):2811–6.

    Article  CAS  PubMed  Google Scholar 

  27. O'Reilly MS, Holmgren L, Chen C, Folkman J. (1996) Angiostatin induces and sustains dormancy of human primary tumors in mice. Nat Med 2(6):689–92.

    Article  PubMed  Google Scholar 

  28. O'Reilly MS, Holmgren L, Shing Y, Chen C, Rosenthal RA, Moses M, Lane WS, Cao Y, Sage EH, Folkman J. (1994) Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell 79(2):315–28.

    Article  PubMed  Google Scholar 

  29. Ohno O, Shima Y, Ikeda Y, Kondo SI, Kato K, Toi M, Umezawa K. (2001) Selective growth inhibition by sangivamycin of human umbilical vein endothelial cells. Int J Oncol 18(5): 1009–15.

    CAS  PubMed  Google Scholar 

  30. Osada H, Sonoda T, Tsunoda K, Isono K. (1989) A new biological role of sangivamycin; inhibition of protein kinases. J Antibiot (Tokyo) 42(1):102–6.

    CAS  Google Scholar 

  31. Osanai T, Kamada T, Fujiwara N, Katoh T, Takahashi K, Kimura M, Satoh K, Magota K, Kodama S, Tanaka T, Okumura K. (1998) A novel inhibitory effect on prostacyclin synthesis of coupling factor 6 extracted from the heart of spontaneously hypertensive rats. J Biol Chem 273(48):31778–83.

    Article  CAS  PubMed  Google Scholar 

  32. Osanai T, Magota K, Tanaka M, Shimada M, Murakami R, Sasaki S, Tomita H, Maeda N, Okumura K. (2005) Intracellular signaling for vasoconstrictor coupling factor 6: novel function of beta-subunit of ATP synthase as receptor. Hypertension 46(5):1140–6.

    Article  CAS  PubMed  Google Scholar 

  33. Osanai T, Tanaka M, Kamada T, Nakano T, Takahashi K, Okada S, Sirato K, Magota K, Kodama S, Okumura K. (2001) Mitochondrial coupling factor 6 as a potent endogenous vasoconstrictor. J Clin Invest 108(7):1023–30.

    CAS  PubMed  Google Scholar 

  34. Palczewski K, Kahn N, Hargrave PA. (1990) Nucleoside inhibitors of rhodopsin kinase. Biochemistry 29(26):6276–82.

    Article  CAS  PubMed  Google Scholar 

  35. Quevillon S, Agou F, Robinson JC, Mirande M. (1997) The p43 component of the mammalian multi-synthetase complex is likely to be the precursor of the endothelial monocyte-activating polypeptide II cytokine. J Biol Chem 272(51):32573–9.

    Article  CAS  PubMed  Google Scholar 

  36. Saffer JD, Glazer RI. (1981) Inhibition of histone H1 phosphorylation by sangivamycin and other pyrrolopyrimidine analogues. Mol Pharmacol 20(1):211–7.

    CAS  PubMed  Google Scholar 

  37. Schmidt C, Lepsverdize E, Chi SL, Das AM, Pizzo SV, Dityatev A, Schachner M. (2008) Amyloid precursor protein and amyloid beta-peptide bind to ATP synthase and regulate its activity at the surface of neural cells. Mol Psychiatry 13(10):953–69.

    Google Scholar 

  38. Schwarz MA, Zheng H, Liu J, Corbett S, Schwarz RE. (2005) Endothelial-monocyte activating polypeptide II alters fibronectin based endothelial cell adhesion and matrix assembly via alpha5 beta1 integrin. Exp Cell Res 311(2):229–39.

    Article  CAS  PubMed  Google Scholar 

  39. Schwarz RE, Schwarz MA. (2004) In vivo therapy of local tumor progression by targeting vascular endothelium with EMAP-II. J Surg Res 120(1):64–72.

    Article  CAS  PubMed  Google Scholar 

  40. Sprenger RR, Speijer D, Back JW, De Koster CG, Pannekoek H, Horrevoets AJ. (2004) Comparative proteomics of human endothelial cell caveolae and rafts using two-dimensional gel electrophoresis and mass spectrometry. Electrophoresis 25(1):156–72.

    Article  CAS  PubMed  Google Scholar 

  41. Veitonmaki N, Cao R, Wu LH, Moser TL, Li B, Pizzo SV, Zhivotovsky B, Cao Y. (2004) Endothelial cell surface ATP synthase-triggered caspase-apoptotic pathway is essential for k1-5-induced antiangiogenesis. Cancer Res 64(10):3679–86.

    Article  PubMed  Google Scholar 

  42. Wahl ML, Grant DS. (2000) Effects of microenvironmental extracellular pH and extracellular matrix proteins on angiostatin's activity and on intracellular pH. Gen Pharmacol 35(5):277–85.

    CAS  PubMed  Google Scholar 

  43. Wahl ML, Kenan DJ, Gonzalez-Gronow M, Pizzo SV. (2005) Angiostatin’s molecular mechanism: aspects of specificity and regulation elucidated. J Cell Biochem 96(2):242–61.

    Article  CAS  PubMed  Google Scholar 

  44. Wahl ML, Owen CS, Grant DS. (2002) Angiostatin induces intracellular acidosis and anoikis in endothelial cells at a tumor-like low pH. Endothelium 9(3):205–16.

    Article  CAS  PubMed  Google Scholar 

  45. Wang J, Han Y, Liang J, Cheng X, Yan L, Wang Y, Liu J, Luo G, Chen X, Zhao L, Zhou X, Wu K, Fan D. (2008) Effect of a novel inhibitory mAb against beta-subunit of F1F0 ATPase on HCC. Cancer Biol Ther 7(11):1829–35.

    Google Scholar 

  46. Wang T, Chen Z, Wang X, Shyy JY, Zhu Y. (2006) Cholesterol loading increases the translocation of ATP synthase beta chain into membrane caveolae in vascular endothelial cells. Biochim Biophys Acta 1761(10):1182–90.

    CAS  PubMed  Google Scholar 

  47. Watts SW. (2005) Vasoconstriction caused by the ATP synthase subunit-coupling factor 6: a new function for a historical enzyme. Hypertension 46(5):1100–2.

    Article  CAS  PubMed  Google Scholar 

  48. Yamamoto K, Korenaga R, Kamiya A, Qi Z, Sokabe M, Ando J. (2000) P2X(4) receptors mediate ATP-induced calcium influx in human vascular endothelial cells. Am J Physiol Heart Circ Physiol 279(1):H285–92.

    CAS  PubMed  Google Scholar 

  49. Yamamoto K, Shimizu N, Obi S, Kumagaya S, Taketani Y, Kamiya A, Ando J. (2007) Involvement of cell surface ATP synthase in flow-induced ATP release by vascular endothelial cells. Am J Physiol Heart Circ Physiol 293(3):H1646–53.

    Article  CAS  PubMed  Google Scholar 

  50. Yamamoto K, Sokabe T, Matsumoto T, Yoshimura K, Shibata M, Ohura N, Fukuda T, Sato T, Sekine K, Kato S, Isshiki M, Fujita T, Kobayashi M, Kawamura K, Masuda H, Kamiya A, Ando J. (2006) Impaired flow-dependent control of vascular tone and remodeling in P2X4-deficient mice. Nat Med 12(1):133–7.

    Article  CAS  PubMed  Google Scholar 

  51. Yamamoto K, Sokabe T, Ohura N, Nakatsuka H, Kamiya A, Ando J. (2003) Endogenously released ATP mediates shear stress-induced Ca2+ influx into pulmonary artery endothelial cells. Am J Physiol Heart Circ Physiol 285(2):H793–803.

    CAS  PubMed  Google Scholar 

  52. Yegutkin GG. (2008) Nucleotide- and nucleoside-converting ectoenzymes: Important modulators of purinergic signalling cascade. Biochim Biophys Acta 1783(5):673–694.

    Article  CAS  PubMed  Google Scholar 

  53. Yonally SK, Capaldi RA. (2006) The F(1)F(0) ATP synthase and mitochondrial respiratory chain complexes are present on the plasma membrane of an osteosarcoma cell line: An immunocytochemical study. Mitochondrion 6(6):305–314.

    Article  CAS  PubMed  Google Scholar 

  54. Zhang X, Gao F, Yu LL, Peng Y, Liu HH, Liu JY, Yin M, Ni J. (2008) Dual functions of a monoclonal antibody against cell surface F1F0 ATP synthase on both HUVEC and tumor cells. Acta Pharmacol Sin 29(8):942–50.

    Article  CAS  PubMed  Google Scholar 

  55. Zheng YZ, Berg KB, Foster LJ. (2009) Mitochondria do not contain lipid rafts and lipid rafts do not contain mitochondrial proteins. J Lipid Res 50(5):988–98.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Pathology, Duke University, DUMC, Box 3712, Durham, NC, 27710, USA

    Yvonne M. Mowery & Salvatore V. Pizzo

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  1. Yvonne M. Mowery
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  2. Salvatore V. Pizzo
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Correspondence to Yvonne M. Mowery .

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Editors and Affiliations

  1. Dept. Pediatrics, Pediatric Clinical Services, University of Colorado, Denver, East 19th Avenue 12700, Aurora, 80045, USA

    Evgenia Gerasimovskaya

  2. Beth Israel Deaconess Medical Center, Harvard Medical School, Brookline Ave. 99, Boston, 02215, USA

    Elzbieta Kaczmarek

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Mowery, Y.M., Pizzo, S.V. (2010). Cell Surface ATP Synthase: A Potential Target for Anti-Angiogenic Therapy. In: Gerasimovskaya, E., Kaczmarek, E. (eds) Extracellular ATP and Adenosine as Regulators of Endothelial Cell Function. Springer, Dordrecht. https://doi.org/10.1007/978-90-481-3435-9_9

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