Advances in Molecular OncologyAdvances in Molecular OncologyУспехи молекулярной онкологии2313-805X2413-3787Publishing House ABV Press35310.17650/2313-805X-2021-8-2-29-39REVIEW ARTICLESОБЗОРНЫЕ СТАТЬИRole of nitric oxide and endothelial NO synthase in carcinogenesisРоль оксида азота и эндотелиальной NO-синтазы в канцерогенезеhttps://orcid.org/0000-0002-3204-3481DeryaginaV. P.ДерягинаВ. П.
Russian Federation

Valentina Petrovna Deryagina

24 Kashirskoe Shosse, Moscow 115478, Russia

Валентина Петровна Дерягина

Россия, 115478 Москва, Каширское шоссе, 24

derygina@inbox.ruhttps://orcid.org/0000-0002-4224-6303RizhovaN. I.РыжоваН. И.
Russian Federation

24 Kashirskoe Shosse, Moscow 115478, Russia

Россия, 115478 Москва, Каширское шоссе, 24

SavluchinskayaL. A.СавлучинскаяЛ. А.
Russian Federation

24 Kashirskoe Shosse, Moscow 115478, Russia

Россия, 115478 Москва, Каширское шоссе, 24

https://orcid.org/0000-0002-8599-6833KirsanovK. I.КирсановК. И.
Russian Federation

24 Kashirskoe Shosse, Moscow 115478, Russia

6 Miklukho-Maklaya St., Moscow 117198, Russia

Россия, 115478 Москва, Каширское шоссе, 24

Россия, 117198 Москва, ул. Миклухо-Маклая, 6

N.N. Blokhin Russian Cancer Research Center, Ministry of Health of RussiaФГБУ «Национальный медицинский исследовательский центр онкологии им. Н. Н. Блохина» Минздрава РоссииPeoples’ Friendship University of RussiaФГАОУ ВО «Российский университет дружбы народов»150520218229392807202128072021Copyright ©; 2021, Deryagina V.P., Rizhova N.I., Savluchinskaya L.A., Kirsanov K.I.Copyright ©; 2021, Дерягина В.П., Рыжова Н.И., Савлучинская Л.А., Кирсанов К.И.2021Deryagina V.P., Rizhova N.I., Savluchinskaya L.A., Kirsanov K.I.Дерягина В.П., Рыжова Н.И., Савлучинская Л.А., Кирсанов К.И.https://creativecommons.org/licenses/by/4.0https://umo.abvpress.ru/jour/article/view/353

Introduction. Nitric oxide (NO) produced by NO synthases (NOS) is involved in the regulation of vital physiological functions. At the same time, NO and NOS are involved in events associated with the tumor process: mutagenesis, proliferation, apoptosis, angiogenesis, etc., exerting a multidirectional effect on the tumor.

Objectives – analyze and summarize literature data concerning the role of NO and endothelial NOS (eNOS) in the initiation and progression of tumors, as well as in the inhibition of tumor growth.

Materials and methods. In preparing the review, publications of information bases of biomedical literature were used: SciVerse Scopus (538), PubMed (1327), Web of Science (905), Russian Science Citation Index (125).

Results. The molecular mechanisms of the action of NO and its derivatives on the initiation and progression of carcinogenesis have been explored. Numerous factors and conditions regulating the activity of eNOS in health and tumor growth have been analyzed. The molecular signaling pathways through which the pro-tumor effects of NO and eNOS, stimulating angiogenesis, lymphangiogenesis, are realized, including through the mobilization of stem cells, are considered.

Conclusion. Nitric oxide produced by activated eNOS promotes tumor progression by increasing the proliferation of tumor cells, enhancing the action of pro-angiogenic factors, stimulating angiogenesis, lymphangiogenesis, and metastasis. Selective inhibition of increased eNOS activity may be a promising therapeutic approach aimed at reducing metastasis and tumor growth.

Введение. Оксид азота (NO), продуцируемый NO-синтазами (NOS), участвует в регуляции гомеостаза целого ряда жизненно важных систем организма. В то же время NO и NOS вовлечены в связанные с канцерогенезом процессы, такие как мутагенез, регуляция пролиферации, апоптоза, ангиогенеза, и могут оказывать на опухоль разнонаправленное действие.

Цель исследования – проанализировать и обобщить данные литературы, касающиеся роли NO и эндотелиальной NOS (eNOS) в инициации и прогрессии опухолей, а также в ингибировании опухолевого роста.

Материалы и методы. При подготовке обзора были использованы публикации информационных баз биомедицинской литературы: SciVerse Scopus (538), PubMed (1327), Web of Science (905), Российский индекс научного цитирования (125).

Результаты. Изучены молекулярные механизмы действия NO и его производных на инициацию и прогрессию канцерогенеза. Проанализированы многочисленные факторы и условия, регулирующие активность eNOS в норме и при опухолевом росте. Рассмотрены кальций- и аргинин-зависимые пути регуляции активности фермента, а также возможности его регуляции антиканцерогенными полифенолами. Проведен анализ молекулярных сигнальных путей, посредством которых реализуются проопухолевые эффекты NO и eNOS, стимулирующие ангиогенез и лимфангиогенез.

Заключение. Оксид азота, продуцируемый гиперактивированной eNOS, способствует прогрессии опухолей, усиливает действие проангиогенных факторов, стимулирует ангиогенез, лимфангиогенез и метастазирование. Селективное ингибирование повышенной активности eNOS может стать перспективным терапевтическим подходом, направленным на торможение роста опухоли и ее метастазирования.

nitric oxideendothelial nitric oxide synthase carcinogenesisangiogenesislymphangiogenesistumorsоксид азотаэндотелиальная синтаза оксида азотаканцерогенезангиогенезлимфангиогенезопухолиThe research was supported by the Russian Science Foundation (grant No. 17-15-01526)Исследование выполнено при финансовой поддержке Российского научного фонда (грант № 17-15-01526)Wang L., Shi G.G., Yao J.C. et al. Expression of endothelial nitric oxide synthase correlates with the angiogenic phenotype of and predicts poor prognosis in human gastric cancer. Gastric Cancer 2005;8(1):18–28. DOI: 10.1007/s10120-004-0310-7.Choudhari S.K., Chaudhary M., Bagde S. et al. Nitric oxide and cancer: a review. World J Surg Oncol 2013;11:118. DOI: 10.1186/1477-7819-11-118.Somasundaram V., Basudhar D., Bharadwaj G. et al. Molecular mechanisms of nitric oxide in cancer progression, signal transduction, and metabolism. Antioxid Redox Signal 2019;30:1124–43. DOI: 10.1089/ars.2018.7527.Nakamura Y., Yasuoka H., Tsujimoto M. et al. Nitric oxide in breast cancer: induction of vascular endothelial growth factor-C and correlation with metastasis and poor prognosis. Clin Cancer Res 2006;12(4):1201–7. DOI: 10.1158/1078-0432.CCR-05-1269.Randriamboavonjy V., Fleming I. Endothelial nitric oxide synthase (eNOS) in platelets: how is it regulated and what is it doing there? Pharmacol Rep 2005;57 Suppl:59–65.Forstermann U., Sessa W.C. Nitric oxide synthases: regulation and function. Eur Heart J 2012;33(7):829–37, 837a–837d. DOI: 10.1093/eurheartj/ehr304.Rabender C.S., Alam A., Sundaresan G. et al. The role of nitric oxide synthase uncoupling in tumor progression. Mol Cancer Res 2015;13(6):1034–43. DOI: 10.1158/1541-7786MCR-15-0057-T.Ravichandran L.V., Johns R.A., Rengasamy A. Direct and reversible inhibition of endothelial nitric oxide synthase by nitric oxide. Am J Physiol 1995;268(6 Pt 2):H2216–23. DOI: 10.1152/ajpheart.1995.268.6.H2216.Furuta S. Basal S-nitrosylation is the guardian of tissue homeostasis. Trends Cancer 2017;3(11):744–8. DOI: 10.1016/j.trecan.2017.09.003.Deryagina V.P., Ryzhova N.I., Savluchinskaya L.A. et al. Features of expression of NO-synthases (iNOS and eNOS) depending on the growth rate of Ehrlich’s adenocarcinoma in mice. Vestnik RONC im. N.N. Blohina = Journal of N.N. Blokhin Russian Cancer Research Center RAMS 2018;29(1–2):40–4. (In Russ.).Дерягина В.П., Рыжова Н.И., Савлучинская Л.А. и др. Особенности экспрессии NO-синтаз (iNOS и eNOS) в зависимости от скорости роста аденокарциномы Эрлиха у мышей. Вестник РОНЦ им. Н.Н. Блохина 2018;29(1–2): 40–4.Vanin A.F. Dinitrosyl iron complexes with thiol-containing ligands: physical chemistry, biology, medicine. M.; Izhevsk: Institut kompyuternyh issledovanij, 2015. 220 p. (In Russ.).Ванин А.Ф. Динитрозильные комплексы железа с тиолсодержащими лигандами: физикохимия, биология, медицина. М.; Ижевск: Институт компьютерных исследований, 2015. 220 с.Benhar M., Forrester M.T., Stamler J.S. Protein denitrosylation: enzymatic mechanisms and cellular functions. Nat Rev Mol Cell Biol 2009;10(10):721–32. DOI: 10.1038/nrm2764.Wei W., Li B., Hanes M.A. et al. S-nitrosylation from GSNOR deficiency impairs DNA repair and promotes hepatocarcinogenesis. Sci Transl Med 2010;2:(19):19ra13. DOI: 10.1126/scitranslmed.3000328.Thomas D.D., Ridnour L.A., Isenberg J.S. et al. The chemical biology of nitric oxide: implications in cellular signaling. Free Radic Biol Med 2008;4(1):18–31. DOI: 10.1016/j.freeradbiomed.2008.03.020.Sahni S., Hickok J.R., Thomas D.D. Nitric oxide reduces oxidative stress in cancer cells by forming dinitrosyliron complexes. Nitric Oxide 2018;76:37–44. DOI: 10.1016/j.niox.2018.03.003.Thomas D.D. Breathing new life into nitric oxide signaling: A brief overview of the interplay between oxygen and nitric oxide. Redox Biol 2015;5:225–33. DOI: 10.1016/j.redox.2015.05.002.Iyer A.K., Azad N., Wang L., Rojanasakul Y. Role of S-nitrosylation in apoptosis resistance and carcinogenesis. Nitric Oxide 2008;19(2):146–51. DOI: 10.1016/J.niox.2008.04.019.Mintz J., Vedenko A., Rosete O. et al. Current Advances of Nitric Oxide in Cancer and Anticancer Therapeutics. Vaccines(Basel) 2021;9(2):94. DOI: 10.3390/vaccines9020094.Wink D.A., Vodovotz Y., Laval J. et al. The multifaceted roles of nitric oxide in cancer. Carcinogenesis 1998;19(5):711–21. DOI: 10.1093/carcin/19.5.711.Jones L.E. Jr, Ying L., Hofseth A.B. et al. Differential effects of reactive nitrogen species on DNA base excision repair initiated by the alkyladenine DNA glycosylase. Carcinogenesis 2009;30(12):2123–9. DOI: 10.1093/carcin/bgp256.Graziewicz M., Wink D.A., Laval F. Nitric oxide inhibits DNA ligase activity: potential mechanisms for NO-mediated DNA damage. Carcinogenesis 1996;17(11):2501–5. DOI: 10.1093/carcin/17.11.2501.Xiao L., Eneroth P.H., Qureshi G.A. Nitric oxide synthase pathway may mediate human natural killer cell cytotoxicity. Scand J Immunol 1995;42(5):505–11. DOI: 10.1111/j.1365-3083.1995.tb03687.x.Bastian N.R., Yim C.Y., Hibbs J.B., Samlowski W.E. Induction of iron-derived EPR signals in murine cancers by nitric oxide. Evidence for multiple intracellular targets. J Biol Chem 1994;269(7):5127–31.Hara M.R., Snyder S.H. Nitric oxide- GAPDH-Siah: a novel cell death cascade. Cell Mol Neurobiol 2006;26(4–6):527–38. DOI: 10.1007/s10571-006-9011-6.Li C.Q., Pang B., Kiziltepe T. et al. Threshold effects of nitric oxide-induced toxicity and cellular responses in wild-type and p53-null human lymphoblastoid cells. Chem Res Toxicol 2006;19(3):399–406. DOI: 10.1021/tx050283e.Marshall H.E., Foster M.W. S-nitrosylation of Ras in breast cancer. Breast Cancer Res 2012;14(6):113. DOI: 10.1186/bcr3331.Lim K.H., Ancrile B.B., Kashatus D.F., Counter C.M. Tumour maintenance is mediated by eNOS. Nature 2008;452(7187):646–9. DOI: 10.1038/nature06778.Garrido P., Shalaby A., Walsh E.M. et al. Impact of inducible nitric oxide synthase (iNOS) expression on triple negative breast cancer outcome and activation of EGFR and ERK signaling pathways. Oncotarget 2017;8(46):80568–88. DOI: 10.18632/oncotarget.19631.Lopez-Rivera E., Jayaraman P., Parikh F. et al. Inducible nitric oxide synthase drives mTOR pathway activation and proliferation of human melanoma by reversible nitrosylation of TSC2. Cancer Res 2014;74(4):1067–78. DOI: 10.1158/0008-5472.CAN-13-0588.Du Q., Zhang X., Liu Q. et al. Nitric oxide production upregulates Wnt/betacatenin signaling by inhibiting Dickkopf-1. Cancer Res 2013;73(21):6526–37. DOI: 10.1158/0008-5472.CAN-13-1620.Quintero M., Brennan P.A., Thomas G.J., Moncada S. Nitric oxide is a factor in the stabilization of hypoxia-inducible factor- 1alpha in cancer: role of free radical formation. Cancer Res 2006;66(2):770–4. DOI: 10.1158/0008-5472.CAN-05-0333.Dimmeler S., Fleming I., Fisslthaler B. et al. Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation. Nature 1999;399(6736): 601–5. DOI: 10.1038/21224.Ju H., Zou R., Venema V.J., Venema R.C. Direct interaction of endothelial nitricoxide synthase and caveolin-1 inhibits synthase activity. J Biol Chem 1997;272(30):18522–5. DOI: 10.1074/jbc.272.30.18522.Sakoda T., Hirata K., Kuroda R. et al. Myristoylation of endothelial cell nitric oxide synthase is important for extracellular release of nitric oxide. Mol Cell Biochem 1995;152(2):143–8. DOI: 10.1007/BF01076076.Rafikov R., Fonseca F.V., Kumar S. et al. eNOS activation and NO function: structural motifs responsible for the posttranslational control of endothelial nitric oxide synthase activity. J Endocrinol 2011;210(3):271–84. DOI: 10.1530/JOE-11-0083.Severina I.S. Nitric oxide. Potentiation of NO-dependent activation of soluble guanylate cyclase – (patho)physiological and pharmacotherapeutic significance. Biomedicinskaya himiya = Biomedical Chemistry 2007;53(4):385–99. (In Russ.).Северина И.С. Оксид азота. Потенцирование NO-зависимой активации растворимой гуанилатциклазы – (пато) физиологическое и фармакотерапевтическое значение. Биомедицинская химия 2007;53(4):385–99.Hemmens B., Mayer B. Enzymology of nitric oxide synthases. Methods Mol Biol 1998;100:1–32. DOI: 10.1385/1-59259-749-1:1.Erwin P.A., Lin A.J., Golan D.E., Michel T. Receptor-regulated dynamic S-nitrosylation of endothelial nitric-oxide synthase in vascular endothelial cells. J Biol Chem 2005;280(20):19888–94. DOI: 10.1074/Jbc.M413058200.Keshet R., Erez A. Arginine and the metabolic regulation of nitric oxide synthesis in cancer. Dis Model Mech 2018;11(8):dmm033332. DOI: 10.1242/dmm.033332.Huang H.L., Chen W.C., Hsu H.P. et al. Argininosuccinate lyase is a potential therapeutic target in breast cancer. Oncol Rep 2015;34(6):3131–9. DOI: 10.3892/or.2015.4280.Huang H.L., Chen W.C., Hsu H.P. et al. Silencing of argininosuccinate lyase inhibits colorectal cancer formation. Oncol Rep 2017;37(1):163–70. DOI: 10.3892/or.2016.5221.Rizi S.B., Caneba C., Nowicka A. et al. Nitric oxide mediates metabolic coupling of omentum-derived adipose stroma to ovarian and endometrial cancer cells. Cancer Res 2015;75(2):456–71. DOI: 10.1158/0008-5472.CAN-14-1337.Zhao X., Liu H.Q., Li J., Liu X.L. Endothelial progenitor cells promote tumor growth and progression by enhancing new vessel formation. Oncol Lett 2016;12(2):793–9. DOI: 10.3892/ol.2016.4733.Heissig B., Hattori K., Dias S. et al. Recruitment of stem and progenitor cells from the bone marrow niche requires MMP-9 mediated release of kit-ligand. Cell 2002;109(5):625–37. DOI: 10.1016/s0092-8674(O2)00754-7.Fukumura D., Gohongi T., Kadambi A. et al. Predominant role of endothelial nitric oxide synthase in vascular endothelial growth factor-induced angiogenesis and vascular permeability. Proc Natl Acad Sci U S A 2001;98(5): 2604–9. DOI: 10.1073/pnas.041359198.Fujita S., Masago K., Hatachi Y. et al. Genetic polymorphisms in the endothelial nitric oxide synthase gene correlate with overall survival in advanced non-small-cell lung cancer patients treated with platinum-based doublet chemotherapy. BMC Med Genet 2010;11:167. DOI: 10.1186/1471-23-50-11-167.Oliveira-Paula G.H., Lacchini R., Tanus-Santos J.E. Endothelial nitric oxide synthase: From biochemistry and gene structure to clinical implications of NOS3 polymorphisms. Gene 2016; 575(2 Pt 3):584–99. DOI: 10.1016/j.gene.2015.09.061.Xia N., Forstermann U., Li H. Resveratrol and endothelial nitric oxide. Molecules 2014;19(10):16102–21. DOI: 10.3390/molecules1910-16102.Duarte J., Francisco V., Perez-Vizcaino F. Modulation of nitric oxide by flavonoids. Food Funct 2014;5(8):1653–68. DOI: 10.1039/c4fo00144C.Fukumura D., Kashiwagi S., Jain R.K. The role of nitric oxide in tumour progression. Nat Rev Cancer 2006;6(7):521–34. DOI: 10.1038/nrc1910.Hanahan D., Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 1996;86(3):353–64. DOI: 10.1016/s0092-8674(00)80108-7.Ziche M., Morbidelli L. Molecular regulation of tumour angiogenesis by nitric oxide. Eur Cytokine Netw 2009;20(4):164–70. DOI: 10.1684/ecn.2009.0169.Oliveira C.J., Schindler F., Ventura A.M. et al. Nitric oxide and cGMP activate the Ras-MAP kinase pathway-stimulating protein tyrosine phosphorylation in rabbit aortic endothelial cells. Free Radic Biol Med 2003;35(4):381–96. DOI: 10.1016/s0891-5849(03)00311-3.Kawasaki K., Smith Jr R.S., Hsieh C.M. et al. Activation of the phosphatidylinositol 3-kinase/protein kinase Akt pathway mediates nitric oxide-induced endothelial cell migration and angiogenesis. Mol Cell Biol 2003;23(16):5726–37. DOI: 10.1128/mcb.23.16.5726-5737.2003.Donnini S., Monti M., Roncone R. et al. Peroxynitrite inactivates human-tissue inhibitor of metalloproteinase-4. FEBS Lett 2008;582(7):1135–40. DOI: 10.1016/j.febslet.2008.02.080.Dudzinski D.M., Michel T. Life history of eNOS: partners and pathways. Cardiovasc Res 2007;75(2):247–60. DOI: 10.1016/j.cardiores.2007.03.23.Babaei S., Teichert-Kuliszewska K., Monge J.C. et al. Role of nitric oxide in the angiogenic response in vitro to basic fibroblast growth factor. Circ Res 1998;82(9):1007–15. DOI: 10.1161/01.res.82.9.1007.Babaei S., Teichert-Kuliszewska K., Zhang Q. et al. Angiogenic actions of angiopoietin-1 require endotheliumderived nitric oxide. Am J Pathol 2003;162(6):1927–36.Tolle M., Klockl L., Wiedon A. et al. Regulation of endothelial nitric oxide synthase activation in endothelial cells by S1P1 and S1P3. Biochem Biophys Res Commun 2016;476(4):627–4. DOI: 10.1016/j.bbrc.2016.06.009.Urbich C., Reissner A., Chavakis E. et al. Dephosphorylation of endothelial nitric oxide synthase contributes to the antiangiogenic effects of endostatin. FASEB J 2002;16(7):706–8. DOI: 10.1096/fj.01-0637fje. 61. Isenberg J.S., Frazier W.A., Roberts D. Thrombospondin-1: a physiological regulator of nitric oxide signaling. Cell Mol Life Sci 2008;65(5):728–2. DOI: 10.1007/S00018-007-7488-x.Namkoong S., Lee S.J., Kim C.K. et al. Prostaglandin E2 stimulates angiogenesis by activating the nitric oxide/cGMP pathway in human umbilical vein endothelial cells. Exp Mol Med 2005;37(6):588–600. DOI: 10.1038/emm.2005.72.Brouet A., DeWever J., Martinive P. et al. Antitumor effects of in vivo caveolin gene delivery are associated with the inhibition of the proangiogenic and vasodilatory effects of nitric oxide. FASEB J 2005;19(6):602–4. DOI: 10.1096/fj.04-2682fje.Alsharabasy A.M., Glynn S.A., Pandit A. The role of extracellular matrix in tumour angiogenesis: the throne has NOx servants. Biochem Soc Trans 2020;48(6):2539–55. DOI: 10.1042/BST20200208.Kroll J., Waltenberger J. VEGF-A induces expression of eNOS and iNOS in endothelial cells via VEGF receptor- 2(KDR). Biochem Biophys Res Commun 1998;252(3):743–6. DOI: 10.1006/bbrc.1998.9719.Duda D.G., Fukumura D., Jain R.K. Role of eNOS in neovascularization: NO for endothelial progenitor cells. Trends Mol Med 2004;10(4):143–5. DOI: 10.1016/j.molmed.2004.02.001.Kashiwagi S., Izumi Y., Gohongi T. et al. NO mediates mural cell recruitment and vessel morphogenesis in murine melanomas and tissue-engineered blood vessels. J Clin Invest 2005;115(7):1816–27. DOI: 10.1172/JCl24015.Aicher A., Heeschen C., Mildner-Rihm C. et al. Essential role of endothelial nitric oxide synthase for mobilization of stem and progenitor cells. Nat Med 2003;9(11):1370–76. DOI: 10.1038/nm948.De la Puente P., Muz B., Azab F., Azab A.K. Cell trafficking of endothelial progenitor cells in tumor progression. Clin Cancer Res 2013;19(13):3360–8. DOI: 10.1158/1078-0432.CCR-13-0462.Lahdenranta J., Hagendoorn J., Padera T.P. et al. Endothelial nitric oxide synthase mediates lymphangiogenesis and lymphatic metastasis. Cancer Res 2009;69(7):2801–8. DOI: 10.1158/0008-5472.CAN-08-4051.Padera T.P., Meijer E.F., Munn L.L. The Lymphatic System in Disease Processes and Cancer Progression. Annu Rev Biomed Eng 2016;18:125–58. DOI: 10.1146/annurev-bioeng-112315-031200.Hoshida T., Isaka N., Hagendoorn J. et al. Imaging steps of lymphatic metastasis reveals that vascular endothelial growth factor-C increases metastasis by increasing delivery of cancer cells to lymph nodes: therapeutic implications. Cancer Res 2006;66(16):8065–75. DOI: 10.1158/0008-5472.CAN-06-1392.Coso S., Zeng Y., Opeskin K., Williams E.D. Vascular endothelial growth factor receptor-3 directly interacts with phosphatidylinositol 3-kinase to regulate lymphangiogenesis. PLoS One 2012;7(6): e39558. DOI: 10.1371/journal.pone.0039558.