Renin-angiotensin system: role in the development and progression of prostate cancer

Being the most common malignancy in men, prostate cancer (PCa) is a significant social and medical problem. The development of new approaches to the diagnosis, prognosis, and treatment of PCa is one of the most important tasks of current urological oncology.

The renin-angiotensin cascade plays a crucial role in the regulation of most physiological and pathophysiological conditions in the human organism, including vascular tone, blood pressure, development and progression of atherosclerosis, and key metabolic processes. The classical regulation axis of the renin-angiotensin system (RAS) is well known and includes angiotensin converting enzyme (ACE)/angiotensin II/ angiotensin II receptors. Recently, new RAS elements have been found and described, such as ACE2 (homologue of ACE), angiotensin isoforms 1—7, alamandin, etc. This resulted in the discovery of many new alternative axes of RAS regulation, including ACE2/angiotensin-(1—7)/ MAS receptor, prorenin/(pro)renin receptor/MAP kinase, and angiotensin A/almandin/receptor D (MrgD). The prostate gland has a local RAS; all main components of RAS are expressed in prostate tissues.

This review analyzes molecular mechanisms underlying carcinogenic effects of RAS, as well as classical and alternative pathways of RAS regulation in PCa. We have described the results of studies evaluating individual RAS parameters in PCa, which confirm the existence of a complex network between various elements of local RAS and molecular and cellular mechanisms of prostate carcinogenesis. RAS has been proved to play an important role in PCa development and progression.

We have also covered new therapeutic targets for PCa treatment, presumable mechanisms of action, and prospects of using RAS inhibitors for PCa.

1. Axel E.M., Matveev V.B. Statistics of malignant tumors of urinary and male urogenital organs in Russia and the countries of the former USSR. Onkourologiya = Cancer Urology 2019;15(2):15-24. (In Russ.). DOI: 10.17650/1726-9776-2019-15-2-15-24.

2. Kaprin A.D., Alekseev B.Ya., Kalpinskiy A.S. Urologiya = Urology 2019;4(Suppl.):19-24. (In Russ.). DOI: 10.18565/urology.2019.4(Suppl.).19-24.

3. Eliseeva Yu.E. Angiotensin-converting enzyme, its physiological role. Voprosy meditsinskoy khimii = Questions of Medical Chemistry 2001;1:43-54. (In Russ.).

4. Lavoie J.L., Sigmund C.D., Minireview: overview of the renin-angiotensin system - an endocrine and paracrine system. Endocrinology 2003;144(6):2179-83. DOI: 10.1210/en.2003-0150.

5. Paul M., Mehr A., Kreutz R. Physiology of local renin-angiotensin systems. Physiol Rev 2006;86:747-803. DOI: 10.1152/physrev.00036.2005.

6. Shestakova M.V. The role of the tissue renin-angiotensin-aldosterone system in the development of metabolic syndrome, diabetes mellitus and its vascular complications. Sakharnyy diabet = Diabetes 2010;3:14-9. (In Russ.).

7. Ager E.I., Neo J., Christophi C. The renin-angiotensin system and malignancy. Carcinogenesis 2008;29: 1675-84. DOI: 10.1093/carcin/bgn171.

8. Santos R.A.S., Oudit G.Y., Verano-Braga T. et al. The renin-angiotensin system: going beyond the classical paradigms. Am J Physiol Heart Circ Physiol 2019;316(5):H958-70. DOI: 10.1152/ajpheart.00723.2018.

9. Kugaevskaya E.V. Angiotensin converting enzyme. Domain structure and properties. Biomeditsinskaya khimiya = Biomedical Chemistry 2005;51(6):567-80. (In Russ.).

10. Kugaevskaya E.V., Timoshenko O.S., Solovyeva N.I. Angiotensin converting enzyme: the antigenic properties of the domain, role in alzheimer’s disease and tumor progression. Biomeditsinskaya khimiya = Biomedical Chemistry 2015;61(3):301-11. (In Russ.). DOI: 10.18097/PBMC20156103301.

11. Rieger K.J., Saez-Servent N., Papet M.P. et al. Involvement of human plasma angiotensin I-converting enzyme in the degradation of the haemoregulatory peptide N-acetyl-seryl-aspartyl-lysylproline. Biochem J 1993;296:373-8. DOI: 10.1042/bj2960373.

12. Dinh D.T., Frauman A.G., Somers G.R. et al. Evidence for activation of the reninangiotensin system in the human prostate: increased angiotensin II and reduced AT(1) receptor expression in benign prostatic hyperplasia. J Pathol 2002;196(2):213-9. DOI: 10.1002/path.1021.

13. Isaac R.E., Williams T.A., Sajid M. et al. Cleavage of arginyl-arginine and lysylarginine from the C-terminus of prohormone peptides by human germinal angiotensin Iconverting enzyme (ACE) and the C-domain of human somatic ACE. Biochem J 1997;328:587-91. DOI: 10.1042/bj3280587.

14. Ehlers M.R., Fox E.A., Strydom D.J., Riordan J.F. Molecular cloning of human testicular angiotensin-converting enzyme: the testis isozyme is identical to the C-terminal half of endothelial angiotensin-converting enzyme. Proc Natl Acad Sci USA 1989;86:7741-5. DOI: 10.1073/pnas.86.20.7741.

15. Sugimura K., Tian X.L., Hoffmann S. et al. Alternative splicing of the mRNA coding for the human endothelial angiotensin-converting enzyme: a new mechanism for solubilization. Biochem Biophys Res Commun 1998;47:466-72. DOI: 10.1006/bbrc.1998.8813.

16. Kryukova O.V., Tikhomirova V.E., Golukhova E.Z. et al. Tissue specificity of human angiotensin I-converting enzyme. PLoS One 2015;10(11):e0143455. DOI: 10.1371/journal.pone.0143455.

17. Deshayes F., Nahmias C. Angiotensin II receptors: a new role in cancer? Trends Endocrinol Metabol 2005;16(7):293-9. DOI: 10.1016/j.tem.2005.07.009.

18. Suzuki Y., Ruiz-Ortega M., Lorenzo O. et al. Inflammation and angiotensin II. Int J Biochem Cell Biol 2003;35(6):881-900. DOI: 10.1016/s1357-2725(02)00271-6.

19. Rodrigues-Ferreira S., Abdelkarim M., Dillenburg-Pilla P. et al. Angiotensin II facilitates breast cancer cell migration and metastasis. PLoS One 2012;7(4):e35667. DOI: 10.1371/journal.pone.0035667.

20. Kaschin E., Unger T. Angiotensin AT1/ AT2 receptors: regulation, signalling and function. Blood 2003;12(2):70-88. DOI: 10.1080/08037050310001057.

21. AbdAlla S., Lother H., Abdel-tawab A.M., Quitterer U. The angiotensin II AT2 receptor is an AT1 receptor antagonist. J Biol Chem 2001;276(43):39721-6. DOI: 10.1074/jbc.M105253200.

22. Singh K.D., Karnik S. Angiotensin receptors: structure, function, signaling and clinical applications. J Cell Signal 2016;1(2):111. DOI: 10.4172/jcs.1000111.

23. Carey R.M. Newly discovered components and actions of the renin-angiotensin system. Hypertension 2013;62(5):818-22. DOI: 10.1161/HYPERTENSIONAHA.113.01111.

24. Puddefoot J.R., Udeozo U.K., Barker S., Vinson G.P. The role of angiotensin II in the regulation of breast cancer cell adhesion and invasion. Endocr Relat Cancer 2006;13: 895-903. DOI: 10.1677/erc.1.01136.

25. Munro M.J., Wickremesekera A., Davis P. et al. Renin-angiotensin system and cancer: a review. Integr Cancer Sci Ther 2017;4(2):1-6. DOI: 10.15761/ICST.1000231.

26. Kogan M.I., Akhokhov Z.M., Chernogubova E.A. et al. The role of the renin-angiotensin system in the appearance and progression of renal cell carcinoma: a literature review. Onkourologiya = Cancer Urology 2019;15(3):143-9. (In Russ.). DOI: 10.17650/1726-9776-2019-15-3-143-149.

27. George A.J., Thomas W.G., Hannan R.D. The renin-angiotensin system and cancer: old dog, new tricks. Nat Rev Cancer 2010;10:745-59. DOI: 10.1038/nrc2945.

28. Carbajo-Lozoya J., Lutz S., Feng Y. et al. Angiotensin II modulates VEGF-driven angiogenesis by opposing effects of type 1 and type 2 receptor stimulation in the microvascular endothelium. Cell Signal 2012;24(6):1261-9. DOI: 10.1016/j.cellsig.2012.02.005.

29. Wegman-Ostrosky T., Soto-Reyes E., Vidal-Millan S., Sanchez-Coron J. The renin-angiotensin system meets the hallmarks of cancer. J Renin Angiotensin Aldosterone Syst 2015;6(2):227-33. DOI: 10.1177/1470320313496858.

30. Delforce S.J., Lumbers E.R., de Meaultsart C.C. et al. Expression of reninangiotensin system (RAS) components in endometrial cancer. Endocrine Connect 2017;6:9-19. DOI: 10.1530/EC-16-0082.

31. Wolgien M.D.C.G.M., Correa S.A.A., Breuel P.A.F. et al. Renin angiotensin system components and cancer: reports of association. JBM 2016;4:65-75. DOI: 10.4236/jbm.2016.45007.

32. Hashemzehia M., Beheshtibc F., Hassaniand S.M. et al. Therapeutic potential of renin angiotensin system inhibitors in cancer cells metastasis. Pathol Res Pract 2020;216(7):153010. DOI: 10.1016/j.prp.2020.153010.

33. Danilov S.M., Kadrev A.V., Kurilova O.V. et al. Tissue ACE phenotyping in prostate cancer. Oncotarget 2019;10(59):6349-61. DOI: 10.18632/oncotarget.27276.

34. Danilov S.M. Conformational fingerprinting using monoclonal antibodies (on the example of Angiotensin I-Converting EnzymeACE). Molekulyarnaya biologiya = Molecular Biology 2017;51(6):1046-61. (In Russ.). DOI: 10.7868/S0026898417060155.

35. Kamalov A.A., Samokhodskaya L.M., Karpov V.K. et al. Biomarkers of prostate cancer and potential for using ace produced in prostate gland for diagnosis of prostate cancer and benign prostatic hyperplasia. Urologiya = Urology 2019;2:73-81. (In Russ.). DOI: 10.18565/urology.2019.2.73-81.

36. Kogan M.I., Chernogubova E.A., Chibichyan M.B., Matishov D.G. The activity of proteolytic enzymes and their inhibitors in the secretion of the prostate in its benign hyperplasia and cancer. Onkourologiya = Cancer Urology 2011;7(2):46-51. (In Russ.). DOI: 10.17650/1726-9776-2011-7-2-46-51.

37. Kogan M.I., Chibichyan M.B., Chernogubova E.A. Method for establishing indications for prostate biopsy. Patent for invention No. 2406446. 20.12.2010 BIUM. 35. (In Russ.).

38. Wang Z.Y., Li H.Y., Jiang Z.P., Zhou T.B. Relationship between angiotensinconverting enzyme insertion/deletion gene polymorphism and prostate cancer susceptibility. J Can Res Ther 2018;14(S2):375-80. DOI: 10.4103/09731482.171366.

39. Chowa L., Rezmanna L., Catt K.J. et al. Role of the renin-angiotensin system in prostate cancer. Mol Cell Endocrinol 2009;302(2):219-29. DOI: 10.1016/j.mce.2008.08.032.

40. Guimaraes P.B., Alvarenga E.C., Siqueira P.D. et al. Angiotensin II binding to angiotensin I-converting enzyme triggers calcium signaling. Hypertension 2011;57(5):965-72. DOI: 10.1161/HYPERTENSIONAHA.110.167171.

41. Uemura H., Kubota Y. Application of angiotensin II receptor blocker in prostate cancer. Nippon Rinsho 2009;67(4):807-11.

42. Hunyady L., Catt K.J. Pleiotropic AT1 receptor signaling pathways mediating physiological and pathogenic actions of angiotensin II. Mol Endocrinol 2006;20:953-70. DOI: 10.1210/me.2004-0536.

43. Imai N., Hashimoto T., Kihara M. et al. Roles for host and tumor angiotensin II type 1 receptor in tumor growth and tumor-associated angiogenesis. Lab Invest 2007;87:189-98. DOI: 10.1038/labinvest.3700504.

44. Bauvois B. Transmembrane proteases in cell growth and invasion: new contributors to angiogenesis? Oncogene 2004;23(2):317-29. DOI: 10.1038/sj.onc.1207124.

45. Uemura H., Ishiguro H., Ishiguro Y. et al. Angiotensin II induces oxidative stress in prostate cancer. Mol Cancer Res 2008;6(2):250-8. DOI: 10.1158/1541-7786.MCR-07-0289.

46. Colman R.W. Regulation of angiogenesis by the kallikrein-kinin system. Curr Pharm Des 2006;12(21):2599-607. DOI: 10.2174/138161206777698710.

47. Fujita M., Hayashi I., Yamashina S. et al. Blockade of angiotensin AT1 receptor signaling reduces tumor growth, angiogenesis, and metastasis. Biochem Biophys Res Commun 2002;294:441-7. DOI: 10.1016/S0006-291X(02)00496-5.

48. Kogan M., Chibichyan M., Ilyash A. et al. Angiotensin-converting enzyme and kallikrein as a new concept in the study of prostate cancer. Urology 2012;80 (Suppl 3A):S81-2.

49. Chibichyan M.B., Kogan M.I., Chernogubova E.A. et al. Role of angiotensin II receptor type 2 in predicting biochemical recurrence in the treatment of prostate cancer. Urologiya = Urology 2016;6:89-94. (In Russ.).

50. Kogan M.I., Chernogubova E.A., Chibichyan M.B. et al. The role of kallikrein-kinin and angiotensin systems in the pathogenesis of prostate cancer. Urologiya = Urology 2015;(3):50-4. (In Russ.).

51. Gorbunova E.N., Davydova D.A., Krupin V.N. Chronic inflammation and fibrosis as risk factors of the prostatic intraepithelial neoplasia (PIN) and prostate cancer. Sovremennye tekhnologii v meditsine = Modern Technologies in Medicine 2011;(1): 79-83. (In Russ.).

52. Mao Y., Xu X., Wang X. et al. Is angiotensin-converting enzyme inhibitors/ angiotensin receptor blockers therapy protective against prostate cancer? Oncotarget 2016;7:6765-73. DOI: 10.18632/oncotarget.6837.

53. Kosaka T., Miyajima A., Shirotake S. et al. Phosphorylated Akt up-regulates angiotensin II type-1 receptor expression in castration resistant prostate cancer. Prostate 2011;71(14):1510-7. DOI: 10.1002/pros.21367.

54. Dolomatov S., Zukow W., Novikov N. et al. Expression of the renin-angiotensin system components in oncologic diseases Acta Clin Croat 2019;58(2):354-64. DOI: 10.20471/acc.2019.58.02.21.

55. Kogan M.I., Chernogubova E.A., Chibichyan M.B., Matishov D.G. Angiotensin converting enzyme -a new prognostic marker of recurrence in the treatment of prostate cancer. Onkourologiya = Cancer Urology 2016;12(4):87-93. (In Russ.). DOI: 10.17650/1726-9776-2016-12-4-87-93.

56. Alashkham A., Paterson C., Windsor P. et al. The incidence and risk of biochemical recurrence following radical radiotherapy for prostate cancer in men on angiotensinconverting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs). Clin Genitour Cancer 2016;14(5):398-405. DOI: 10.1016/j.clgc.2016.03.009.

57. Ishikane S., Takahashi-Yanaga F. The role of angiotensin II in cancer metastasis: potential of renin-angiotensin system blockade as a treatment for cancer metastasis. Biochem Pharmacol 2018;151:96-103. DOI: 10.1016/j.bcp.2018.03.008.

58. Leao R., Domingos C., Figueiredo A. et al. Cancer Stem cells in prostate cancer: implications for targeted therapy. Urol Int 2017;99(2):125-36. DOI: 10.1159/000455160.

59. Tikellis C., Thomas M.C. AngiotensinConverting Enzyme 2 (ACE2) is a key modulator of the renin angiotensin system in health and disease. Int J Pept 2012;2012:256294. DOI: 10.1155/2012/256294.

60. Singh Y., Gupta G., Sharma R. et al. Embarking effect of ACE2-angiotensin 1-7/Mas receptor axis in benign prostate hyperplasia. Crit Rev Eukaryot Gene Expr 2018;28(2):115-24. DOI: 10.1615/CritRevEukaryotGeneExpr.2018021364.

61. Donoghue M., Hsieh F., Baronas E. et al. A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9. Circ Res 2000;87(5):E1-9. DOI: 10.1161/01.res.87.5.e1.

62. Keidar S., Kaplan M., Gamliel-Lazarovich A. ACE2 of the heart: from angiotensin I to angiotensin (1-7). Cardiovasc Res 2007;73(3):463-9. DOI: 10.1016/j.cardiores.2006.09.006.

63. Letko M., Munster V. Functional assessment of cell entry and receptor usage for lineage B в-coronaviruses, including 2019-nCoV. Nat Microbiol 2020;5(4):562-9. DOI: 10.1038/s41564-020-0688-y.

64. Oudit G.Y., Herzenberg A.M., Kassiri Z. et al. Loss of angiotensin-converting enzyme-2 leads to the late development of angiotensin II-dependent glomerulosclerosis. Am J Patho 2006;(168):1808-20. DOI: 10.2353/ajpath.2006.051091.

65. Wu Z.S., Zhang Z.Q., Wu S. Focus on the crosstalk between COVID-19 and urogenital systems. J Urol 2020;204:7-8. DOI: 10.1097/JU.0000000000001068.

66. Bahmad H.F., Abou-Kheir W. Crosstalk between COVID-19 and prostate cancer. Prostate Cancer Prostatic Dis 2020;23(4):561-3. DOI: 10.1038/ s41391-020-0262-y. Available at: https://www.nature.com/articles/s41391-020-0262-y.pdf.

67. Cambados N., Walther T., Nahmod K. et al. Angiotensin-(1-7) counteracts the transforming effects triggered by angiotensin II in breast cancer cells. Oncotarget 2017;8(51):88475-87. DOI: 10.18632/oncotarget.19290.

68. Gonzaga A.L.A.C.P., Palmeira V.A., Ribeiro T.F.S. et al. ACE2/ Angiotensin-(1-7)/Mas receptor axis in human cancer: potential role for pediatric tumors. Curr Drug Targets 2020;21(9):892-901. DOI: 10.2174/1389450121666200210124217.

69. Dominska K., Okla P., Kowalska K. et al. Angiotensin 1-7 modulates molecular and cellular processes central to the pathogenesis of prostate cancer. Sci Rep 2018;8(1):15772. DOI: 10.1038/s41598-018-34049-8.

70. Dominska K., Kowalska K., Habrowska-Gorczynska D.E. et al. The opposite effects of angiotensin 1-9 and angiotensin 3-7 in prostate epithelial cells. Biochem Biophys Res Commun 2019;519(4):868-73. DOI: 10.1016/j.bbrc.2019.09.079.

71. Hrenak J., Paulis L., Simko F. Angiotensin A/Alamandine/MrgD Axis: another clue to understanding cardiovascular pathophysiology. Int J Mol Sci 2016;17(7):1098. DOI: 10.3390/ijms17071098.

72. Jankowski V., Vanholder R., van der Giet M. et al. Mass-spectrometric identification of a novel angiotensin peptide in human plasma. Arterioscler Thromb Vasc Biol 2007;27:297-302. DOI: 10.1161/01.ATV.0000253889.09765.5f.

73. Schleifenbaum J. Alamandine and its receptor MrgD pair up to join the protective arm of the renin-angiotensin system. Front Med 2019;6:107. DOI: 10.3389/fmed.2019.00107.

74. Lautner R.Q., Villela D.C., Fraga-Silva R.A. et al. Discovery and characterization of alamandine A novel component of the reninangiotensin system. Circ Res 2013;112(8):1104-11. DOI: 10.1161/CIRCRESAHA.113.301077.