Пептиды врожденного иммунитета как потенциальные противоопухолевые агенты: плюсы и минусы

Онкологические заболевания представляют серьезную социально-экономическую проблему. Основным подходом к терапии опухолей является их хирургическая резекция, часто дополняемая лучевой и химиотерапией. Эффективность такого комплексного лечения во многих случаях остается невысокой. В связи с этим возникает острая необходимость поиска новых соединений, обладающих селективной цитотоксической активностью в отношении опухолевых клеток и не повреждающих нормальные ткани организма. В обзоре рассматриваются механизмы противоопухолевого действия катионных антимикробных пептидов (АМП) семейства кателицидинов – α-спирального кателицидина человека (LL-37) и пептида с конформацией β-шпильки – протегрина-1 (PG-1) на клетки рака легкого, молочной, поджелудочной, предстательной желез, меланомы, плоскоклеточного рака кожи, полости рта, желудка, яичников, колоректального рака, лейкозов, лимфом, глиом и нейробластом. Обсуждается возможность противоопухолевого и противоположного – проонкогенного действия пептидов и взаимосвязь этих эффектов c иммуномодулирующей активностью АМП на опухоль-ассоциированные макрофаги, естественные киллерные клетки и T-лимфоциты. Приводятся возможные механизмы селективного действия LL-37 и PG-1 на опухолевые клетки, включающее взаимодействие LL-37 с G-белок-связанными рецепторами: N-формилпептида-2 (FPR2), CXC хемокина-2 (CXCR2), Mas-ассоциированным с геном X (MrgX2), пуринергическим (P2Y11), эпидермального (EGFR/ErbB1, ERBb2), инсулино-подобного (IGF1R) факторов роста, лиганд-управляемых ионных каналов (LGIC) и Toll-подобными (TLR) рецепторами, экспрессия которых значительно изменяется в разных типах опухолей по сравнению с нормой. Однако при этом особенно важно учитывать, что терапевтические эффекты LL-37 и его производных могут использоваться только для конкретных типов опухолей. Механизмы действия PG-1 на опухолевые клетки остаются еще плохо изученными, хотя имеющиеся данные свидетельствуют, что протегрин проявляет более однонаправленное действие – повреждает мембраны. Протегрин-1 и LL-37 могут синергически усиливать противоопухолевые эффекты химиопрепаратов и оказывают более выраженное действие на опухолевые, чем на нормальные клетки. Природные АМП представляются перспективными кандидатами на роль новых противоопухолевых средств, которые проявляют активность и в отношении злокачественных метастазирующих, рецидивирующих опухолей с множественной лекарственной устойчивостью. С другой стороны, такие пептиды, как LL-37, проявляют в некоторых случаях свойства, которые могут рас- сматриваться как проонкогенные, что указывает на необходимость дальнейшего детального изучения молекулярных механизмов их действия на опухолевые клетки.

1. Абатуров А.Е., Никулина А.А. Развитие иммунного ответа при стафилококковой пневмонии (часть 4) // Здоровье ребенка, 2017. № 12. С. 648-656.

2. Баландин С.В., Емельянова А.А., Калашникова М.Б., Кокряков В.Н., Шамова О.В., Овчинникова Т.В. Молекулярные механизмы противоопухолевого действия природных антимикробных пептидов // Биоорганическая химия, 2016. Т. 42, № 6. С. 633-648.

3. Жаркова М.С. Сочетанное действие белков и пептидов системы врожденного иммунитета и соединений различной химической природы в реализации их антибиотических свойств: автореф. … канд. биол. наук. СПб.: Институт экспериментальной медицины, 2016. 23 с.

4. Жаркова М.С., Артамонов А.Ю., Гринчук Т.М., Буцкина Е.А., Пазина Т.Ю., Орлов Д.С., Шамова О.В. Пептиды системы врожденного иммунитета модулируют цитотоксическое действие противоопухолевых антибиотиков // Российский иммунологический журнал, 2016. Т. 10, № 2. C. 548-550.

5. Шамова О.В., Орлов Д.С., Пазина Т.Ю., Ямщикова Е.В., Орлов С.Б., Жаркова М.С., Гринчук Т.М., Арцыбашева И.В., Юхнев В.А., Кокряков В.Н. Изучение молекулярно-клеточных основ цитотоксического действия антимикробных пептидов на опухолевые клетки // Фундаментальные исследования, 2012. № 5, Ч. 1. С. 207-212.

6. Шамова О.В., Сакута Г.А., Орлов Д.С., Зенин В.В., Штейн Г.И., Колодкин Н.И., Афонина И.Н., Кокряков В.Н. Действие атимикробных пептидов из нейтрофильных гранулоцитов на опухолевые и нормальные клетки в культуре // Цитология, 2007. Т. 49, № 12. С. 1000-1010.

7. Agerberth B., Charo J., Werr J., Olsson B., Idali F., Lindbom L., Kiessling R., Jörnvall H., Wigzell H., Gudmundsson G.H. The human antimicrobial and chemotactic peptides LL-37 and alpha-defensins are expressed by specific lymphocyte and monocyte populations. Blood, 2000, Vol. 96, no. 9, pp. 3086-3093.

8. Alzahrani S., Lina T.T., Gonzalez J., Pinchuk I.V., Beswick E.J., Reyes V.E. Effect of Helicobacter pylori on gastric epithelial cells. World J. Gastroenterol., 2014, Vol. 20, pp. 12767-12780.

9. An L.L., Yang Y.H., Ma X.T., Lin Y.M., Li G., Song Y.H., Wu K.F. LL-37 enhances adaptive antitumor immune response in a murine model when genetically fused with M-CSFR (J6-1) DNA vaccine. Leuk. Res., 2005, Vol. 29, no. 5, pp. 535-543.

10. Armogida S.A., Yannaras N.M., Melton A.L. Srivastava M.D. Identification and quantification of innate immune system mediators in human breast milk. Allergy Asthma Proc., 2004, Vol. 25, no. 5, pp. 297-304.

11. Arnoult D., Gaume B., Karbowski M., Sharpe J.C., Cecconi F., Youle R.J. Mitochondrial release of AIF and EndoG requires caspase activation downstream of Bax/Bak-mediated permeabilization. EMBO, 2003, Vol. 22, no. 17, pp. 4385-4399.

12. Bals R., Wang X., Zasloff M., Wilson J.M. The peptide antibiotic LL-37/hCAP-18 is expressed in epithelia of the human lung where it has broad antimicrobial activity at the airway surface. Proc. Natl Acad. Sci. USA., 1998, Vol. 95, no. 16, pp. 9541-9546.

13. Bartek J., Lukas J. Pathways governing G1/S transition and their response to DNA damage. FEBS Lett., 2001, Vol. 490, no. 3, pp. 117-122.

14. Bruns H., Büttner M., Fabri M., Mougiakakos D., Bittenbring J.T., Hoffmann M.H., Beier F., Pasemann S., Jitschin R., Hofmann A.D., Neumann F., Daniel C., Maurberger A., Kempkes B., Amann K., Mackensen A., Gerbitz A. Vitamin D-dependent induction of cathelicidin in human macrophages results in cytotoxicity against high-grade B cell lymphoma. Sci. Transl. Med., 2015, Vol. 7, no. 282, 282ra47. doi: 10.1126/scitranslmed.aaa3230.

15. Büchau A.S., Morizane S., Trowbridge J., Schauber J., Kotol P., Bui J.D., Gallo R.L. The host defense peptide cathelicidin is required for NK cell-mediated suppression of tumor growth. J. Immunol., 2010, Vol. 184, no. 1, pp. 369-378.

16. Campaner S., Doni M., Hydbring P., Verrecchia A., Bianchi L., Sardella D., Schleker T., Perna D., Tronnersjo S., Murga M., Fernandez Capetillo O., Barbacid M., Larsson L.G., Amati B. Cdk2 suppresses cellular senescence induced by the c-myc oncogene. Nat. Cell Biol., 2010, Vol. 12, no. 1, pp. 54-59.

17. Can G., Akpinar B., Baran Y., Zhivotovsky B., Olsson M. 5-Fluorouracil signaling through a calciumcalmodulin-dependent pathway is required for p53 activation and apoptosis in colon carcinoma cells. Oncogene, 2013, Vol. 32, no. 38, pp. 4529-4538.

18. Carmona F.J., Montemurro F., Kannan S., Rossi V., Verma C., Baselga J., Scaltriti M. AKT signaling in ERBB2-amplified breast cancer. Pharmacol. Ther., 2016, Vol. 158, pp. 63-70.

19. Chen P.M., Yen M.L., Liu K.J., Sytwu H.K., Yen B.L. Immunomodulatory properties of human adult and fetal multipotent mesenchymal stem cells. J. Biomed. Sci., 2011, Vol. 18, no. 1, 49. doi: 10.1186/1423-0127-18-49.

20. Chen X., Qi G., Qin M., Zou Y., Zhong K., Tang Y., Guo Y., Jiang X., Liang L., Zou X. DNA methylation directly downregulates human cathelicidin antimicrobial peptide gene (CAMP) promoter activity. Oncotarget, 2017, Vol. 8, no. 17, pp. 27943-27952.

21. Chen X., Zou X., Qi G., Tang Y., Guo Y., Si J., Liang L. Roles and mechanisms of human cathelicidin LL-37 in сancer. Cell. Physiol. Biochem., 2018, Vol. 47, no. 3, pp. 1060-1073.

22. Cheng M., Ho S., Yoo J.H., Tran D. H.-Y., Bakirtzi K., Su B., Tran D. H.-N., Kubota Y., Ichikawa R., Koon H.W. Cathelicidin suppresses colon cancer development by inhibition of cancer associated fibroblasts. Clin. Exp. Gastroenterol., 2014, Vol. 8, pp. 13-29.

23. Choi K.Y., Napper S., Mookherjee N. Human cathelicidin LL-37 and its derivative IG-19 regulate interleukin32-induced inflammation. Immunology, 2014, Vol. 143, no.1, pp. 68-80.

24. Chuang C.M., Monie A., Wu A., Mao C-P., Hung C-F. Treatment with LL-37 peptide enhances antitumor effects induced by CpG oligodeoxynucleotides against ovarian cancer. Hum. Gene Ther., 2009, Vol. 20, no. 4, pp. 303-313.

25. Coffelt S.B., Waterman R.S., Florez L., Höner zu Bentrup K., Zwezdaryk K.J., Tomchuck S.L., LaMarca H.L., Danka E.S., Morris C.A., Scandurro A.B. Ovarian cancers overexpress the antimicrobial protein hCAP-18 and its derivative LL-37 increases ovarian cancer cell proliferation and invasion. Int. J. Cancer, 2008, Vol. 122, no. 5, pp. 1030-1039.

26. Coffelt S.B., Marini F.C., Watson K., Zwezdaryk K.J., Dembinski J.L., LaMarca H.L., Tomchuck S.L., Honer zu Bentrup K., Danka E.S., Henkle S.L., Scandurro A.B. The pro-inflammatory peptide LL-37 promotes ovarian tumor progression through recruitment of multipotent mesenchymal stromal cells. Proc. Natl Acad. Sci. USA, 2009, Vol. 106, no. 10, pp. 3806-3811.

27. Colle J.-H., Périchon B., Garcia A. Antitumor and antibacterial properties of virally encoded cationic sequences. Biologics, 2019, Vol. 13, pp. 117-126.

28. Dennison S.R., Whittaker M., Harris F., Phoenix D.A. Anticancer alpha-helical peptides and structure/ function relationships underpinning their interactions with tumour cell membranes. Curr. Protein Pept. Sci., 2006, Vol. 7, no. 6, pp. 487-499.

29. Deslouches B., Di P.Y. Antimicrobial peptides with selective antitumor mechanisms: prospect for anticancer applications. Oncotarget, 2017, Vol. 8, no. 28, pp. 46635-46651.

30. di Virgilio F., Falzoni S., Giuliani A.L., Adinolfi E. P2 receptors in cancer progression and metastatic spreading. Curr. Opin. Pharmacol., 2016, Vol. 29, pp. 17-25.

31. Do N., Weindl G., Grohmann L., Salwiczek M., Koksch B., Korting H.C., Schäfer-Korting M. Cationic membrane-active peptides – anticancer and antifungal activity as well as penetration into human skin. Exp. Dermatol., 2014, Vol. 23, no. 5, pp. 326-331.

32. Dobrzyńska I., Szachowicz-Petelska B., Sulkowski S., Figaszewski Z. Changes in electric charge and phospholipids composition in human colorectal cancer cells. Mol. Cell. Biochem., 2005, Vol. 276, no. 1-2, pp. 113-119.

33. Drin G., Cottin S., Blanc E., Rees A.R., Temsamani J. Studies on the internalization mechanism of cationic cell-penetrating peptides. J. Biol. Chem., 2003, Vol. 278, no. 33, pp. 31192-31201.

34. Dube D.H., Bertozzi C.R. Glycans in cancer and inflammation – potential for therapeutics and diagnostics. Nat. Rev. Drug Discov., 2005, Vol. 4, no. 6, pp. 477-488.

35. Fan R., Tong A., Li X., Gao X., Mei L., Zhou L., Zhang X., You C., Guo G. Enhanced antitumor effects by docetaxel/LL37-loaded thermosensitive hydrogel nanoparticles in peritoneal carcinomatosis of colorectal cancer. Intern. J. Nanomedicine, 2015, Vol. 10, pp. 7291-7305.

36. Farabaugh S.M., Chan B.T., Cui X., Dearth R.K., Lee A.V. Lack of interaction between ErbB2 and insulin receptor substrate signaling in breast cancer. Cell Commun. Signal., 2016, Vol. 14, 25. doi: 10.1186/s12964-016-0148-8.

37. Ferrari D., Pizzirani C., Adinolfi E., Lemoli R.M., Curti A., Idzko M., Panther E., di Virgilio F. The P2X7 receptor: a key player in IL-1 processing and release. J. Immunol., 2006, Vol. 176, no. 7, pp. 3877-3883.

38. Findlay E.G., Currie A.J., Zhang A., Ovciarikova J., Young L., Stevens H., McHugh BJ., Canel M., Gray M., Milling S.W.F., Campbell J.D.M., Savill J., Serrels A., Davidson D.J. Exposure to the antimicrobial peptide LL-37 produces dendritic cells optimized for immunotherapy. Oncoimmunology, 2019, Vol. 8, no. 8, 1608106. doi: 10.1080/2162402X.2019.1608106.

39. Frohm M., Agerberth B., Ahangari G., Stâhle-Bäckdahl M., Lidén S., Wigzell H., Gudmundsson G.H. The expression of the gene coding for the antibacterial peptide LL-37 is induced in human keratinocytes during inflammatory disorders. J. Biol. Chem., 1997, no. 24, Vol. 272, pp. 15258-15263.

40. Gambade A., Zreika S., Guéguinou M., Chourpa I., Fromont G., Bouchet AM., Burlaud-Gaillard J., PotierCartereau M., Roger S., Aucagne V., Chevalier S., Vandier C., Goupille C., Weber G. Activation of TRPV2 and channels by the LL-37 enantiomers stimulates calcium entry and migration of cancer cells. Oncotarget, 2016, Vol. 7, no. 17, pp. 23785-23800.

41. Gao P., Zhao H., You J., Jing F., Hu Y. Association between interleukin-8 -251A/T polymorphism and risk of lung cancer: a meta-analysis. Cancer Invest., 2014, Vol. 32, pp. 518-525.

42. Girnita A., Zheng H., Grönberg A., Girnita L., Ståhle M. Identification of the cathelicidin peptide LL-37 as agonist for the type I insulin-like growth factor receptor. Oncogene, 2012, Vol. 31, pp. 352-365.

43. Gombart A.F., Borregaard N., Koeffler H.P. Human cathelicidin antimicrobial peptide (CAMP) gene is a direct target of the vitamin D receptor and is strongly up-regulated in myeloid cells by 1, 25-dihydroxyvitamin D3. FASEB J., 2005, Vol. 19, no. 9, pp. 1067-1077.

44. Gupta K., Kotian A., Subramanian H., Daniell H., Ali H. Activation of human mast cells by retrocyclin and protegrin highlight their immunomodulatory and antimicrobial properties. Oncotarget, 2015, Vol. 6, no. 30, pp. 28573-28587.

45. Hase K., Murakami M., Iimura M., Cole SP., Horibe Y., Ohtake T., Obonyo M., Gallo R.L., Eckmann L., Kagnoff M.F. Expression of LL-37 by human gastric epithelial cells as a potential host defense mechanism against Helicobacter pylori. Gastroenterology, 2003, Vol. 125, no. 6, pp. 1613-1625.

46. Heilborn J.D., Nilsson M.F., Jimenez C.I., Sandstedt B., Borregaard N., Tham E., Sørensen O.E., Weber G., Ståhle M. Antimicrobial protein hCAP18/LL-37 is highly expressed in breast cancer and is a putative growth factor for epithelial cells. Int. J. Cancer., 2005, Vol. 114, no. 5, pp. 713-719.

47. Hensel J.A., Chanda D., Kumar S., Sawant A., Grizzle W.E., Siegal G.P., Ponnazhagan S. LL-37 as a therapeutic target for late stage prostate cancer. Prostate, 2011, Vol. 71, no. 6, pp. 659-670.

48. Henzler-Wildman K.A., Lee D.K., Ramamoorthy A. Mechanism of lipid bilayer disruption by the human antimicrobial peptide, LL-37. Biochemistry, 2003, Vol. 42, no. 21, pp. 6545-6558.

49. Hoskin D.W., Ramamoorthy A. Studies on anticancer activities of antimicrobial peptides. Biochim. Biophys. Acta, 2008, Vol. 1778, no. 2, pp. 357-375.

50. International agency for research of cancer (Globocan ) [Electronic resource]: the World of Health Organization, 2018. Mode of access: http: www.globocan.iarc.fr. Data of access: 23.05.2020.

51. Iozzo R.V., Sanderson R.D. Proteoglycans in cancer biology, tumour microenvironment and angiogenesis. J. Cell Mol Med., 2011, Vol. 15, no. 5, pp. 1013-1031.

52. Ishitsuka Y., Pham D.S., Waring A.J., Lehrer R.I., Lee K.Y. Insertion selectivity of antimicrobial peptide protegrin-1 into lipid monolayers: effect of head group electrostatics and tail group packing. Biochim. Biophys. Acta, 2006, Vol. 1758, no. 9, pp. 1450-1460.

53. Jana J., Kar R.K., Ghosh A., Biswas A., Ghosh S., Bhunia A., Chatterjee S. Human cathelicidin peptide LL37 binds telomeric G-quadruplex. Mol. BioSyst., 2013, Vol. 9, pp. 1833-1836.

54. Ji P., Zhou Y., Yang Y., Wu J., Zhou H., Quan W., Sun J., Yao Y., Shang A., Gu C., Zeng B,, Firrman J., Xiao W., Bals R., Sun Z., Li D. Myeloid cell-derived LL-37 promotes lung cancer growth by activating Wnt/β-catenin signaling. Theranostics, 2019, Vol. 9, no. 8, pp. 2209-2223.

55. Jia J., Zheng Y., Wang W., Shao Y., Li Z., Wang Q., Wang Y., Yan H. Antimicrobial peptide LL-37 promotes YB-1 expression, and the viability, migration and invasion of malignant melanoma cells. Mol. Med. Rep., 2017, Vol. 15, no. 1, pp. 240-248.

56. Johansson J., Gudmundsson G.H., Rottenberg M.E., Berndt K.D., Agerberth B. Conformation-dependent antibacterial activity of the naturally occurring human peptide LL-37. J. Biol Chem., 1998, Vol. 273, no. 6, pp. 3718-3724.

57. Khandwala H.M., McCutcheon I.E., Flyvbjerg A., Friend K.E. The effects of insulin-like growth factors on tumorigenesis and neoplastic growth. Endocr. Rev., 2000, Vol. 21, no. 3, pp. 215-244.

58. Kim H.J., Hwang S.W., Kim N., Yoon H., Shin C.M., Park Y.S., Lee D.H., Park D.J., Kim H.H., Kim J.S, Jung H.C, Lee H.S. Helicobacter pylori and molecular markers as prognostic indicators for gastric cancer in Korea. J. Cancer Prev., 2014, Vol. 19, no. 1, pp. 56-67.

59. Kim J.E., Kim H.J., Choi J.M., Lee K.H., Kim T.Y., Cho B.K., Jung J.Y., Chung K.Y., Cho D., Park H.J. The antimicrobial peptide human cationic antimicrobial protein-18/cathelicidin LL-37 as a putative growth factor for malignant melanoma. Br. J. Dermatol., 2010, Vol. 163, no. 5, pp. 959-967.

60. Koczulla R., von Degenfeld G., Kupatt C., Krötz F., Zahler S., Gloe T., Issbrücker K., Unterberger P., Zaiou M., Lebherz C., Karl A., Raake P., Pfosser A., Boekstegers P., Welsch U., Hiemstra P.S., Vogelmeier C., Gallo R.L., Clauss M., Bals R. An angiogenic role for the human peptide antibiotic LL-37/hCAP-18. J. Clin. Invest., 2003, Vol. 111, no. 11, pp. 1665-1672.

61. Koensgen D., Bruennert D., Ungureanu S., Sofroni D., Braicu EI., Sehouli J., Sümnig A., Delogu S., Zygmunt M., Goyal P., Evert M., Olek S., Biebler KE., Mustea A. Polymorphism of the IL-8 gene and the risk of ovarian cancer. Cytokine, 2015, Vol. 71, no. 2, pp. 334-338.

62. Kokryakov V.N., Harwig S.S.L., Panyutich E.A., Shevchenko A.A., Aleshina G.M., Shamova O.V., Korneva H.A., Lehrer R.I. Protegrins: leukocyte antimicrobial peptides that combine features of corticostatic defensins and tachyplesins. FEBS Lett., 1993, Vol. 327, no. 2, pp. 231-236.

63. Krętowski R., Stypułkowska A., Cechowska-Pasko M. Efficient apoptosis and necrosis induction by proteasome inhibitor: bortezomib in the DLD-1 human colon cancer cell line. Mol. Cell. Biochem., 2015, Vol. 398, no. 1-2, pp. 165-173.

64. Kuroda K., Fukuda T., Krstic-Demonacos M., Demonacos C., Okumura K., Isogai H., Hayashi M., Saito K., Isogai E. miR-663a regulates growth of colon cancer cells, after administration of antimicrobial peptides, by targeting CXCR4-p21 pathway. BMC Cancer, 2017, Vol. 17, no. 1, 33. doi: 10.1186/s12885-016-3003-9.

65. Kuroda K., Fukuda T., Yoneyama H. Katayama M., Isogai H., Okumura K., Isogai E. Anti-proliferative effect of an analogue of the LL-37 peptide in the colon cancer derived cell line HCT116 p53+/+ and p53-/-. Oncol. Rep., 2012, Vol. 28, no. 3, pp. 829-834.

66. Kuroda K., Okumura K., Isogai H., Isogai E. The human cathelicidin antimicrobial peptide LL-37 and mimics are potential anticancer drugs. Front Oncol., 2015, Vol. 5, 144. doi: 10.3389/fonc.2015.00144.

67. Lande R., Gregorio J., Facchinetti V., Chatterjee B., Wang Y.H., Homey B., Cao W., Wang Y.H., Su B., Nestle F.O., Zal T., Mellman I., Schröder J.-M., Liu Y.-J., Gilliet M. Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide. Nature, 2007, Vol. 449, pp. 564-569.

68. Lau Y.E., Rozek A, Scott MG., Goosney D.L., Davidson D.J., Hancock R.EW. Interaction and cellular localization of the human host defense peptide LL-37 with lung epithelial cells. Infect. Immun., 2005, Vol. 73, no. 1, pp. 583-591.

69. Lee H.Y., Kim S.D., Shim J.W., Lee S.Y., Yun, J., Bae Y.S. LL-37 inhibits serum amyloid A-induced IL-8 production in human neutrophils. Exp. Mol. Med., 2009, Vol. 41, pp. 325-333.

70. Leifer C.A., Medvedev A.E. Molecular mechanisms of regulation of Toll-like receptor signaling. J. Leukoc. Biol., 2016, Vol. 100, no. 5, pp. 927-941.

71. Li D., Wang X., Wu J.L., Quan W.Q., Ma L., Yang F., Wu K.Y., Wan H.Y. Tumor-produced versican V1 enhances hCAP18/LL-37 expression in macrophages through activation of TLR2 and vitamin D3 signaling to promote ovarian cancer progression in vitro. PLoS One, 2013, Vol. 8, no. 2, e56616. doi: 10.1371/journal.pone.0056616.

72. Lohner K., Blondelle S.E. Molecular mechanisms of membrane perturbation by antimicrobial peptides and the use of biophysical studies in the design of novel peptide antibiotics. Comb. Chem. High Throughput Screen., 2005, Vol. 8, no. 3, pp. 241-256.

73. Mader J.S., Mookherjee N., Hancock R.E., Bleackley R.C. The human host defense peptide LL-37 induces apoptosis in a calpain- and apoptosis-inducing factor-dependent manner involving Bax activity. Mol. Cancer Res., 2009, Vol. 7, no. 5, pp. 689-702.

74. Maga G., Hubscher U. Proliferating cell nuclear antigen (PCNA): a dancer with many partners. J. Cell Sci., 2003, Vol. 116, Pt 15, pp. 3051-3060.

75. Mangoni M.E., Aumelas A., Charnet P., Roumestand C., Chiche L., Despaux E., Grassy G., Calas B., Chavanieu A. Change in membrane permeability induced by protegrin 1: implication of disulfide bridges for pore formation. FEBS Lett., 1996, Vol. 383, no. 1-2, pp. 93-98.

76. Menssen A., Epanchintsev A., Lodygin D., Rezaei N., Jung P., Verdoodt B., Diebold J., Hermeking H. c-MYC delays prometaphase by direct transactivation of MAD2 and Bub R1: identification of mechanisms underlying c-MYC-induced DNA damage and chromosomal instability. Cell Cycle, 2007, Vol. 6, no. 3, pp. 339-352.

77. Miller K.D., Nogueira L., Mariotto A.B., Rowland J.H., Yabroff K.R., Alfano C.M., Jemal A., Kramer L., Siegel R.L. Cancer treatment and survivorship statistics, 2019. CA Cancer J. Clin., 2019, Vol. 69, no. 5, pp. 363-385.

78. Montreekachon P., Chotjumlong P., Bolscher J.G. Nazmi K., Reutrakul V., Krisanaprakornkit S. Involvement of P2X(7) purinergic receptor and MEK1/2 in interleukin-8 up-regulation by LL-37 in human gingival fibroblasts. J. Periodontal Res., 2011, Vol. 46, no. 3, pp. 327-337.

79. Mookherjee N., Brown K.L., Bowdish D.M., Doria S., Falsafi R., Hokamp K., Roche F.M., Mu R., Doho G.H., Pistolic J., Powers J.P., Bryan J., Brinkman F.S., Hancock R.E. Modulation of the TLR-mediated inflammatory response by the endogenous human host defense peptide LL-37. J. Immunol., 2006, Vol. 176, no. 4, pp. 2455-2464.

80. Moon J.Y., Henzler-Wildman K.A., Ramamoorthy A. Expression and purification of a recombinant LL-37 from Escherichia coli. BBA-Biomembranes, 2006, Vol. 1758, no. 9, pp. 1351-1358.

81. Mostowska A., Sajdak S., Pawlik P., Lianeri M., Jagodzinski P.P. Vitamin D receptor gene BsmI and FokI polymorphisms in relation to ovarian cancer risk in the Polish population. Genet. Test. Mol. Biomarkers, 2013, Vol. 17, no. 3, pp. 183-187.

82. Neto G.T.C., de Lima T.M., Barbeiro H.V., Chammas R.M. Cathelicidin LL-37 Promotes or inhibits cancer cell stemness depending on the tumor origin. Oncomedicine, 2016, Vol. 1, pp. 14-17.

83. Nilsson M.F., Sandstedt B., Sørensen O., Weber G., Borregaard N., Ståhle-Bäckdahl M. The human cationic antimicrobial protein (hCAP18), a peptide antibiotic, is widely expressed in human squamous epithelia and colocalizes with interleukin-6. Infect. Immun., 1999, Vol. 67, no. 5, pp. 2561-2566.

84. Okumura K., Itoh A., Isogai E., Hirose K., Hosokawa Y., Abiko Y., Shibata T., Hirata M., Isogai H. C-terminal domain of human CAP18 antimicrobial peptide induces apoptosis in oral squamous cell carcinoma SAS-H1 cells. Cancer Lett., 2004, Vol. 212, no. 2, pp. 185-194.

85. Oren Z., Lerman J.C., Gudmundsson G.H., Agerberth B., Shai Y. Structure and organization of the human antimicrobial peptide LL-37 in phospholipid membranes: relevance to the molecular basis for its non-selective activity. Biochem J., 1999, Vol. 341, Pt 3, pp. 501-513.

86. Peng L.S., Zhuang Y., Li W.H. Zhou Y-Y., Wang T-T., Chen N., Cheng P., Li B-S., Guo H., Yang S-M., Chen W-S., Zou Q-M. Elevated interleukin-32 expression is associated with Helicobacter pylori-related gastritis. PLoS One, 2014, Vol. 9, no. 3, e88270. doi: 10.1371/journal.pone.0088270.

87. Piktel E., Niemirowicz K., Wnorowska U., Wątek M., Wollny T., Głuszek K., Góźdź S., Levental I., Bucki R. The role of cathelicidin LL-37 in cancer development. Arch. Immunol. Ther. Exp. (Warsz), 2016, Vol. 64, pp. 33-46.

88. Prevete N., Liotti F., Visciano C., Marone G., Melillo R.M., de Paulis A. The formyl peptide receptor 1 exerts a tumor suppressor function in human gastric cancer by inhibiting angiogenesis. Oncogene, 2015, Vol. 34, no. 29, pp. 3826-3838.

89. Pushpanathan M., Gunasekaran P., Rajendhran J. Antimicrobial peptides: versatile biological properties. Intern. J. Peptides, 2013, Vol. 2013, 675391. doi: 10.1155/2013/675391.

90. Qin X., Lu Y., Qin A., Chen Z., Peng Q., Deng Y., Xie L., Wang J., Li R., Zeng J., Li S., Zhao J. Vitamin D receptor BsmІ polymorphism and ovarian cancer risk: a meta-analysis. Int. J. Gynecol. Cancer, 2013, Vol. 23, no. 7, pp. 1178-1183.

91. Qiu Y., Li W.H., Zhang H.Q., Liu Y., Tian X.X., Fang W.G. P2X7 mediates ATP-driven invasiveness in prostate cancer cells. PLoS One, 2014, Vol. 9, no. 12, e114371. doi: 10.1371/journal.pone.0114371.

92. Ren S.X., Cheng A.S., To K.F., Tong J.H., Li M.S., Shen J., Wong C.C., Zhang L., Chan R.L., Wang X.J., Ng S.S., Chiu L.C., Marquez V.E., Gallo R.L., Chan F.K., Yu J., Sung J.J., Wu W.K., Cho C.H. Host immune defense peptide LL-37 activates caspase-independent apoptosis and suppresses colon cancer. Cancer Res., 2012, Vol. 72, no. 24, pp. 6512-6523.

93. Ren S.X., Shen J., Cheng A.S., Lu L., Chan R.L., Li Z.J., Wang X.J., Wong C.C., Zhang L., Ng S.S., Chan F.L., Chan F.K., Yu J., Sung J.J., Wu W.K., Cho C.H. FK-16 derived from the anticancer peptide LL-37 induces caspaseindependent apoptosis and autophagic cell death in colon cancer cells. PLoS One, 2013, Vol. 8, no. 5, e63641. doi: 10.1371/journal.pone.0063641.

94. Reya T., Morrison S.J., Clarke M.F., Weissman I.L. Stem cells, cancer, and cancer stem cells. Nature, 2001, Vol. 414, no. 6859, pp. 105-111.

95. Rothan H.A., Mohamed Z., Sasikumar P.G., Reddy K.A., Rahman N.A., Yusof. R. In Vitro Characterization of Novel Protegrin-1 Analogues Against Neoplastic Cells. Intern. J. Peptide Res. Ther, 2014, Vol. 20, no. 3, pp. 259-267.

96. Sainz B.Jr., Alcala S., Garcia E., Sanchez-Ripoll Y., Azevedo M.M., Cioffi M., Tatari M., Miranda Lorenzo I., Hidalgo M., Gomez-Lopez G., Cañamero M., Erkan M., Kleeff J., García-Silva S., Sancho P., Hermann PC., Heeschen C. Microenvironmental hCAP-18/LL-37 promotes pancreatic ductal adenocarcinoma by activating its cancer stem cell compartment. Gut, 2015, Vol. 64, no. 12, pp. 1921-1935.

97. Schweizer F. Cationic amphiphilic peptides with cancer-selective toxicity. Eur. J. Pharmacol., 2009, Vol. 625, no. 1-3, pp. 190-194.

98. Shaykhiev R., Beisswenger C., Kändler K., Senske J., Püchner A., Damm T., Behr J., Bals R. Human endogenous antibiotic LL-37 stimulates airway epithelial cell proliferation and wound closure. Am. J. Physiol. Lung Cell. Mol. Physiol., 2005, Vol. 289, pp. L842-L848.

99. Simons K., Ikonen E. How cells handle cholesterol. Science, 2000, Vol. 290, no. 5497, pp. 1721-1726.

100. Sørensen O., Arnljots K., Cowland J.B., Bainton D.F., Borregaard N. The human antibacterial cathelicidin, hCAP-18, is synthesized in myelocytes and metamyelocytes and localized to specific granules in neutrophils. Blood, 1997, Vol. 90, no. 7, pp. 2796-2803.

101. Sørensen O.E., Gram L., Johnsen A.H., Andersson E., Bangsbøll S., Tjabringa G.S., Hiemstra P.S., Malm J., Egesten A., Borregaard N. Processing of seminal plasma hCAP-18 to ALL-38 by gastricsin: a novel mechanism of generating antimicrobial peptides in vagina. J. Biol. Chem., 2003, Vol. 278, no. 31, pp. 28540-28546.

102. Sorrentino C., di Carlo E. Expression of IL-32 in human lung cancer is related to the histotype and metastatic phenotype. Am J. Respir. Crit. Care Med., 2009, Vol. 180, no. 8, pp. 769-779.

103. Soundrarajan N., Park S., Quy L.V.C., Cho H-S., Raghunathan G., Ahn B., Song H., Kim J-H., Park C. Protegrin-1 cytotoxicity towards mammalian cells positively correlates with the magnitude of conformational changes of the unfolded form upon cell interaction. Sci. Rep., 2019, Vol. 9, 11569. doi: 10.1038/s41598-019-47955-2.

104. Sugawara K., Shinohara H., Kadoya T., Kuramitz H. Sensing lymphoma cells based on a cell-penetrating/ apoptosis-inducing/electron-transfer peptide probe. Anal. Chim. Acta, 2016, Vol. 924, pp. 106-113.

105. Sun J. The Role of Vitamin D and Vitamin D receptors in colon cancer. Clin. Transl. Gastroenterol., 2017, Vol. 8, no. 6, e103. doi: 10.1038/ctg.2017.31.

106. Suzuki K., Murakami T., Hu Z., Tamura H., Kuwahara-Arai K., Iba T., Nagaoka I. Human host defense cathelicidin peptide ll-37 enhances the lipopolysaccharide uptake by liver sinusoidal endothelial cells without cell activation. J. Immunol., 2016, Vol. 196, no. 3, pp. 1338-1347.

107. Takazawa Y., Kiniwa Y., Ogawa E., Uchiyama A., Ashida A., Uhara H., Goto Y., Okuyama R. Toll-like receptor 4 signaling promotes the migration of human melanoma cells. Tohoku J. Exp. Med., 2014, Vol. 234, no. 1, pp. 57-65.

108. Tjabringa G.S., Ninaber D.K., Drijfhout J.W., Rabe K.F., Hiemstra P.S. Human cathelicidin LL-37 is a chemoattractant for eosinophils and neutrophils that acts via formyl-peptide receptors. Int. Arch. Allergy Immunol., 2006, Vol. 140, no. 2, pp. 103-112.

109. Tokumaru S., Sayama K., Shirakata Y., Komatsuzawa H., Ouhara K., Hanakawa Y., Yahata Y., Dai X., Tohyama M., Nagai H., Yang L., Higashiyama S., Yoshimura A., Sugai M., Hashimoto K. Induction of keratinocyte migration via transactivation of the epidermal growth factor receptor by the antimicrobial peptide LL-37. J. Immunol., 2005, Vol. 175, no. 7, pp. 4662-4668.

110. Vandamme D., Landuyt B., Luyten W., Schoofs L. A comprehensive summary of LL-37, the factotum human cathelicidin peptide. Cell. Immunol., 2012, Vol. 280, no. 1, pp. 22-35.

111. Vignoni M., de Alwis Weerasekera H., Simpson M.J. Phopase J., Mah T-F., Griffith M., Alarcon E.I., Scaiano J.C. LL37 peptide@silver nanoparticles: combining the best of the two worlds for skin infection control. Nanoscale, 2014, Vol. 6, no. 11, pp. 5725-5728.

112. von Haussen J., Koczulla R., Shaykhiev R., Herr C., Pinkenburg O., Reimer D., Wiewrodt R., Biesterfeld S., Aigner A., Czubayko F., Bals R. The host defence peptide LL-37/hCAP-18 is a growth factor for lung cancer cells. Lung Cancer, 2008, Vol. 59, no. 1, pp. 12-23.

113. Wang L., Dong C., Li X., Han W., Su X. Anticancer potential of bioactive peptides from animal sources. Oncol. Rep., 2017, Vol. 38, no. 2, pp. 637-651.

114. Wang W., Zheng Y., Jia J., Li C., Duan Q., Li R., Wang X., Shao Y., Chen C., Yan H. Antimicrobial peptide LL-37 promotes the viability and invasion of skin squamous cell carcinoma by upregulating YB-1. Exp. Ther. Med., 2017, Vol. 14, no. 1, pp. 499-506.

115. Wang W., Jia J., Li C., Duan Q., Yang J., Wang X., Li R., Chen C., Yan H., Zheng Y. Antimicrobial peptide LL-37 promotes the proliferation and invasion of skin squamous cell carcinoma by upregulating DNA-binding protein A. Oncol. Lett., 2016, Vol. 12, no. 3, pp. 1745-1752.

116. Weber G., Chamorro C.I., Granath F., Liljegren A., Zreika S., Saidak Z., Sandstedt B., Rotstein S., Mentaverri R., Sánchez F., Pivarcsi A., Ståhle M. Human antimicrobial protein hCAP18/LL-37 promotes a metastatic phenotype in breast cancer. Breast Cancer Res., 2009, Vol. 11, R6. doi: 10.1186/bcr2221.

117. Wu W.K., Cho C.H., Lee C.W., Wu K., Fan D., Yu J., Sung J.J. Proteasome inhibition: a new therapeutic strategy to cancer treatment. Cancer Lett., 2010, Vol. 293, no. 1, pp. 15-22.

118. Wu W.K., Sung J.J., To K.F., Yu L., Li H.T., Li Z.J., Chu K.M., Yu J., Cho C.H. The host defense peptide LL-37 activates the tumor-suppressing bone morphogenetic protein signaling via inhibition of proteasome in gastric cancer cells. J. Cell. Physiol., 2010, Vol. 223, pp. 178-186.

119. Yan H.X., Wu H.P., Zhang H.L., Ashton C., Tong C., Wu J., Qian Q.J., Wang H.Y., Ying Q.L. DNA damageinduced sustained p53 activation contributes to inflammation-associated hepatocarcinogenesis in rats. Oncogene, 2013, Vol. 32, no. 38, pp. 4565-4571.

120. Yang D., Chertov O., Oppenheim J.J. Participation of mammalian defensins and cathelicidins in antimicrobial immunity: receptors and activities of human defensins and cathelicidin (LL-37). J. Leukoc. Biol., 2001, Vol. 69, no. 5, pp. 691-697.

121. Yang De, Chen Q., Schmidt A.P., Anderson G.M., Wang J.M., Wooters J., Oppenheim J.J., Chertov O. LL-37, the neutrophil granule- and epithelial cell-derived cathelicidin, utilizes formyl peptide receptor-like 1 (FPRL1) as a receptor to chemoattract human peripheral blood neutrophils, monocytes, and T cells. J. Exp Med., 2000, Vol. 192, no. 7, pp. 1069-1074.

122. Zeng Q., Li S., Zhou Y., Ou W., Cai X., Zhang L., Huang W., Huang L., Wang Q. Interleukin-32 contributes to invasion and metastasis of primary lung adenocarcinoma via NF-kappaB induced matrix metalloproteinases 2 and 9 expression. Cytokine, 2014, Vol. 65, no. 1, pp. 24-32.

123. Zhao X., Wu H., Lu H., Li G., Huang Q. LAMP: a database linking antimicrobial peptides. PLoS One, 2013, Vol. 8, no. 6, e66557. doi: 10.1371/journal.pone.0066557.

124. Zharkova M.S., Orlov D.S., Golubeva O.Y., Chakchir O.B., Eliseev I.E., Grinchuk T.M., Shamova O.V. Application of antimicrobial peptides of the innate immune system in combination with conventional antibiotics-a novel way to combat antibiotic resistance? Front. Cell. Infect. Microbiol., 2019, Vol. 9, 128. doi: 10.3389/fcimb.2019.00128.

125. Zhu Y., Wang P.P., Zhai G., Bapat B., Savas S., Woodrow J.R., Sharma I., Li Y., Zhou X., Yang N., Campbell P.T., Dicks E., Parfrey P.S., Mclaughlin J.R. Vitamin D receptor and calcium-sensing receptor polymorphisms and colorectal cancer survival in the Newfoundland population. Br. J. Cancer, 2017, Vol. 117, no. 6, pp. 898-906.

126. Zwaal R.F., Comfurius P., Bevers E.M. Surface exposure of phosphatidylserine in pathological cells. Cell. Mol. Life Sci., 2005, Vol. 62, no. 9, pp. 971-988.