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Hydrolysis of ATP, ADP, and AMP is increased in blood plasma of prostate cancer patients

  • Carla Fernanda Furtado Gardani
  • Angélica Regina Cappellari
  • Julia Brandt de Souza
  • Bruna Tertuliano da Silva
  • Paula Engroff
  • Cesar Eduardo Jacintho Moritz
  • Juliete Nathali Scholl
  • Ana Maria Oliveira Battastini
  • Fabrício Figueiró
  • Fernanda Bueno MorroneEmail author
Original Article

Abstract

Prostate cancer is among the major malignancies that affect men around the world. Adenine nucleotides are important signaling molecules that mediate innumerous biological functions in pathophysiological conditions, including cancer. These molecules are degraded by several ectoenzymes named ectonucleotidases that produce adenosine in the extracellular medium. Some of these ecto-enzymes can be found in soluble in the blood stream. Thus, the present study aimed to evaluate the hydrolysis of adenine nucleotides (ATP, ADP, and AMP) in the plasma blood of patients with prostate cancer. Peripheral blood samples were collected, and questionnaires were filled based on the clinical data of the medical records. The nucleotide hydrolysis was performed by Malachite Green method using ATP, ADP, and AMP as substrates. Plasma from prostate cancer patients presented an elevated hydrolysis of all nucleotides evaluated when compared to healthy individuals. NTPDase inhibitor (ARL67156) and the alkaline phosphatase inhibitor (levamisole) did not alter ATP hydrolysis. However, AMP hydrolysis was reduced by the CD73 inhibitor, APCP, and by levamisole, suggesting the action of a soluble form of CD73 and alkaline phosphatase. On microvesicles, it was observed that there was a low expression and activity of CD39 and almost absent of CD73. The correlation of ATP, ADP, and AMP hydrolysis with clinic pathological data demonstrated that patients who received radiotherapy showed a higher AMP hydrolysis than those who did not, and patients with lower clinical stage (CS-IIA) presented an elevated ATP hydrolysis when compared to those with more advanced clinical stages (CS-IIB and CS-III). Patients of all clinical stages presented an elevated AMPase activity. Therefore, we can suggest that the nucleotide hydrolysis might be attributed to soluble ecto-enzymes present in the plasma, which, in a coordinate manner, produce adenosine in the blood stream, favoring prostate cancer progression.

Keywords

Prostate cancer ATP ADP AMP Hydrolysis Plasma blood 

Notes

Acknowledgements

This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nivel Superior, Brasil (CAPES-001) scholarships, CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico) scholarships, FAPERGS (PPSUS-17/2551-0001455-3), FAPERGS/PRONEX (16/2551-0000473-0), FAPERGS/PqG 17/2551-000970-3PUCRS (Pontifícia Universidade Católica do Rio Grande do Sul), LACOG (Latin American Cooperative Oncology Group), FINEP (Financiadora de Estudos e Projetos) research grant “Implantação, Modernização e Qualificação de Estrutura de Pesquisa da PUCRS” (PUCRSINFRA) # 01.11.0014-00, INCT-MCTI/CNPq/CAPES/FAPERGS (project number 465671/2014-4), CNPq/PQ (project number 302879/2017-0), FAPERGS PQG (project number 17/2551-0000 970-3), and FAPERGS/PRONEX (project number 16/2551-0000473-0).

Compliance with ethical standards

Conflicts of interest notification

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The study was approved by the Ethical Committee of the Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre (CAAE: 62424416.0.0000.5336) and by the Ethical Council of the Hospital São Vicente de Paulo-CACON, Cruz Alta, RS (2017-001).

Informed consent

Informed consent was obtained from all individual participants included in the study.

References

  1. 1.
    De Moor JS, Mariotto AB, Parry C, Alfano CM, Padgett L, Kent EE, Forsythe L, Scoppa S, Hachey M, Rowland JH (2013) Cancer survivors in the United States: prevalence across the survivorship trajectory and implications for care. Cancer Epidemiol Biomarkers Prev 22(4):561–570.  https://doi.org/10.1158/1055-9965 CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Siegel RL, Miller KD, Jemal A (2018) Cancer statistics, 2018. CA Cancer J Clin 68(1):7–30.  https://doi.org/10.3322/caac.21442 CrossRefPubMedGoogle Scholar
  3. 3.
    World cancer biennial report 2016–2017 – IARC.Google Scholar
  4. 4.
    DeSantis CE, Lin CC, Mariotto AB, Siegel RL, Stein KD, Kramer JL, Alteri R, Robbins AS, Jemal A (2014) Cancer treatment and survivorship statistics, 2014. CA Cancer J Clin 64(4):252–271.  https://doi.org/10.3322/caac.21235 CrossRefPubMedGoogle Scholar
  5. 5.
    INCA—Instituto Nacional de Câncer (Brasil) – Estimativa 2018—Incidência do Câncer no BrasilGoogle Scholar
  6. 6.
    Chao HH, Mayer T, Concato J, Rose MG, Uchio E, Kelly WK (2010) Prostate cancer, comorbidity, and participation in randomized controlled trials of therapy. J Investig Med 58(3):566–568.  https://doi.org/10.2310/JIM.0b013e3181cf9002 CrossRefPubMedGoogle Scholar
  7. 7.
    Catalona WJ, Smith DS, Ratliff TL, Dodds KM, Coplen DE, Yuann JJ, Petros JA, Andriole GL (1991) Measurement of prostate-specific antigen in serum as a screening test for prostate cancer. N Engl J Med 324(17):1156–1161 [Erratum in N Engl J Med 1991; Oct 31; 325 (18): 1324.].  https://doi.org/10.1056/NEJM199104253241702 CrossRefPubMedGoogle Scholar
  8. 8.
    Stamey TA, Yang N, Hay AR, McNeal JE, Freiha FS, Redwine E (1987) Prostate-specific antigen as a serum marker for adenocarcinoma of the prostate. N Engl J Med 317(15):909–916.  https://doi.org/10.1056/NEJM198710083171501 CrossRefPubMedGoogle Scholar
  9. 9.
    Gleason DF, Mellinger GT (1974) Prediction of prognosis for prostatic adenocarcinoma by combined histological grading and clinical staging. J Urol 111(1):58–64CrossRefGoogle Scholar
  10. 10.
    Daniyal M, Siddiqui ZA, Akram M, Asif HM, Sultana S, Khan A (2014) Epidemiology, etiology, diagnosis and treatment of prostate cancer. Asian Pac J Cancer Prev 15(22):9575–9578 ReviewCrossRefGoogle Scholar
  11. 11.
    AJCC cancer staging manual Eighth Edition—AJJC 8th.Google Scholar
  12. 12.
    Howlader N, Mariotto AB, Woloshin S, Schwartz LM (2014) Providing clinicians and patients with actual prognosis: cancer in the context of competing causes of death. J Natl Cancer Inst Monogr (49):255–264.  https://doi.org/10.1093/jncimonographs/lgu022
  13. 13.
    Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F (2015) Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 136(5):E359–E386.  https://doi.org/10.1002/ijc.29210 CrossRefPubMedGoogle Scholar
  14. 14.
    Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674.  https://doi.org/10.1016/j.cell.2011.02.013 CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Cekic C, Linden J (2016) Purinergic regulation of the immune system. Nat Rev Immunol. Mar 16(3):177–192.  https://doi.org/10.1038/nri.2016.4 CrossRefPubMedGoogle Scholar
  16. 16.
    Beavis PA, Stagg J, Darcy PK, Smyth MJ (2012) CD73: a potent suppressor of antitumor immune responses. Trends Immunol 33(5):231–237.  https://doi.org/10.1016/j.it.2012.02.009 CrossRefPubMedGoogle Scholar
  17. 17.
    Burnstock G, DiVirgilio F (2013) Purinergic signaling and cancer. Purinergic Signal 9(4):491–324.  https://doi.org/10.1007/s11302-013-9372-5 CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Schetinger MR, Morsch VM, Bonan CD, Wyse AT (2007) NTPDase and 5′-nucleotidase activities in physiological and disease conditions: new perspectives for human health. Biofactors 31(2):77–98CrossRefGoogle Scholar
  19. 19.
    Clayton AI, Al-Taei S, Webber J, Mason MD, Tabi Z (2011) Cancer exosomes express CD39 and CD73, which suppress T cells through adenosine production. J Immunol. 187(2):676–683.  https://doi.org/10.4049/jimmunol.1003884 CrossRefPubMedGoogle Scholar
  20. 20.
    Jiang ZG, Wu Y, Csizmadia E, Feldbrügge L, Enjyoji K, Tigges J, Toxavidis V, Stephan H, Müller CE, McKnight CJ, Moss A, Robson SC (2014) Characterization of circulating microparticle-associated CD39 family ecto-nucleotidases in human plasma. Purinergic Signal 10:611–618.  https://doi.org/10.1007/s11302-014-9423-6 CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Lal H, Kumar L, Kohli GS, Sharma A, Goel H (1989) Serum enzymes in head and neck cancer. IV: 5-nucleotidase. J Laryngol Otol. 103(2):200–202CrossRefGoogle Scholar
  22. 22.
    Engroff P, Sgnaolin V, Azambuja AA, Viola F, Battastini AMO, Morrone F (2016) Increased 5′ nucleotidase activity in the blood sérum of brain tumor patients. Vittalle—Revista de Ciências da Saúde 28:103–110Google Scholar
  23. 23.
    Araújo MC, Rocha JBT, Morsch A, Zanin R, Bauchspiess R, Morsch VM, Schetinger MRC (2005) Enzymes that hydrolyze adenine nucleotides in platelets from breast cancer patients. Biochim Biophys Acta 1740:421–426.  https://doi.org/10.1016/j.bbadis.2004.11.001 CrossRefGoogle Scholar
  24. 24.
    Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254.  https://doi.org/10.1016/0003-2697(76)90527-3 CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Moritz CEJ, Teixeira BC, Rockenbach L, Oliveira AR, Casali EA, Battastini AMO (2017) Altered extracellular ATP, ADP, and AMP hydrolysis in blood serum of sedentary individuals after an acute, aerobic, moderate exercise session. Mol Cell Biochem. 426(1–2):55–63.  https://doi.org/10.1007/s11010-016-2880-1 CrossRefPubMedGoogle Scholar
  26. 26.
    Suárez H, Gámez-Valero A, Reyes R, López-Martín S, Rodrígues MJ, Carrascosa JL, Cabañas C, Borràs FE, Yáñez-Mó M (2017) A bead-assisted flow cytometry method for the semi-quantitative analysis of extracellular vesicles. Sci Rep 7:11271.  https://doi.org/10.1038/s41594-017-11249-2 CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Battisti V, Maders LDK, Bagatini MD, Battisti IE, Belle LP, Santos KF, Maldonado PA, Thome GR, Schetinger MRC, Morsch VM (2013) Ectonucleotide pyrophosphatase/phosphodiesterase (E-NPP) and adenosine deaminase (ADA) activities in prostate cancer patients: influence of Gleason score, treatment and bone metastasis. Biomed Pharmacother 67:203–208CrossRefGoogle Scholar
  28. 28.
    Allard B, Longhi MS, Robson SC, Stagg J (2017) The ectonucleotidases CD39 and CD73: novel checkpoint inhibitor targets. Immunol Rev 276:121–144.  https://doi.org/10.1111/imr.12528 CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Yegutkin GG (2014) Enzymes involved in metabolism of extracellular nucleotides and nucleosides: functional implications and measurement of activities. Crit Rev Biochem Mol Biol. 49(6):473–497.  https://doi.org/10.3109/10409238.2014.953627 CrossRefPubMedGoogle Scholar
  30. 30.
    Antonioli L, Blandizzi C, Pacher P, Haskó G (2013) Immunity, inflammation and cancer: a leading role for adenosine. Nat Rev Cancer 13(12):842–857.  https://doi.org/10.1038/nrc3613 CrossRefPubMedGoogle Scholar
  31. 31.
    Bastid J, Cottalorda-Regairaz A, Alberici G, Bonnefoy, Eliaou J-F, Bensussan A (2013) ENTPD1/CD39 is a promising therapeutic target in oncology. Oncogene 32:1743–1751.  https://doi.org/10.1038/onc.2012.269 CrossRefPubMedGoogle Scholar
  32. 32.
    Bavaresco L, Bernardi A, Braganhol E, Cappellari AR, Rockenbach L, Farias PF, Wink MR, Delgado-Cañedo A, Battastini AM (2008) The role of ecto-5′-nucleotidase/CD73 in glioma cell line proliferation. Mol Cell Biochem 319(1–2):61–68.  https://doi.org/10.1007/s11010-008-9877-3 CrossRefPubMedGoogle Scholar
  33. 33.
    Salimu J, Webber J, Gurney M, Al-Tae S, Clayton A, Tabi Z (2017) Dominant immunosuppression of dendritic cell function by prostate-cancer-derived exosomes. J Extracell Vesicles 6(1):1368823.  https://doi.org/10.1080/20013078.2017.1368823 CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Rackley RR, Lewis TJ, Preston EM, Delmoro CM, Bradley EL, Resnick MI, Pretlow TP, Pretlow TG (1989) 5′-Nucleotidase activity in prostatic carcinoma and benign prostatic hyplerplasia. Cancer Res 49:3702–3707PubMedGoogle Scholar
  35. 35.
    Morello S, Capone M, Sorrentino C, Giannarelli D, Madonna G, Mallardo D, Grimaldi AM, Pinto A, Ascierto PE (2017) Soluble CD73 as biomarker in patients with metastatic melanoma patients treated with nivolumab. J Transl Med 15:244.  https://doi.org/10.1186/s12967-017-1348-8 CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Li D, Ly H, Hao X, Hu B, Song Y (2018) Prognostic value of serum alkaline phosphatase in the survival of prostate cancer: evidence from a meta-analysis. Cancer Manag Res 10:3125–3139.  https://doi.org/10.2147/CMAR,S174237. CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Chan KM, Delfert D, Junger KD (1986) A direct colorimetric assay for Ca2?-stimulated ATPase activity. Anal Biochem 157:375–380.  https://doi.org/10.1016/0003-2697(86)90640-8 CrossRefPubMedGoogle Scholar

Copyright information

© Springer Nature B.V. 2019

Authors and Affiliations

  • Carla Fernanda Furtado Gardani
    • 1
  • Angélica Regina Cappellari
    • 2
  • Julia Brandt de Souza
    • 3
  • Bruna Tertuliano da Silva
    • 4
  • Paula Engroff
    • 5
  • Cesar Eduardo Jacintho Moritz
    • 6
  • Juliete Nathali Scholl
    • 7
  • Ana Maria Oliveira Battastini
    • 7
    • 8
  • Fabrício Figueiró
    • 7
    • 8
  • Fernanda Bueno Morrone
    • 1
    • 2
    • 9
    • 10
    Email author
  1. 1.Escola de Medicina, Programa de Pós-Graduação em Medicina e Ciências da SaúdePontifícia Universidade Católica do Rio Grande do SulPorto AlegreBrazil
  2. 2.Escola de Ciências, Programa de Pós-Graduação em Biologia Celular e MolecularPontifícia Universidade Católica do Rio Grande do SulPorto AlegreBrazil
  3. 3.Escola de Ciências, Graduação em Ciências BiológicasPontifícia Universidade Católica do Rio Grande do SulPorto AlegreBrazil
  4. 4.Escola de MedicinaPontifícia Universidade Católica do Rio Grande do SulPorto AlegreBrazil
  5. 5.Instituto de Geriatria e GerontologiaPontifícia Universidade Católica do Rio Grande do SulPorto AlegreBrazil
  6. 6.Programa de Pós-Graduação em Ciências do Movimento Humano, Escola de Educação Física, Fisioterapia e DançaUniversidade Federal do Rio Grande do SulPorto AlegreBrazil
  7. 7.Programa de Pós-Graduação em Ciências Biológicas—Bioquímica, Instituto de Ciências Básicas da SaúdeUniversidade Federal do Rio Grande do SulPorto AlegreBrazil
  8. 8.Departamento de Bioquímica, Instituto de Ciências Básicas da SaúdeUniversidade Federal do Rio Grande do SulPorto AlegreBrazil
  9. 9.Escola de Ciências da SaúdePontifícia Universidade Católica do Rio Grande do SulPorto AlegreBrazil
  10. 10.Laboratório de Farmacologia Aplicada/Escola de Ciências da SaúdePontificia Universidade Catolica do Rio Grande do SulPorto AlegreBrazil

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