ISSN 2410-7751 (Print)
ISSN 2410-776X (Online)
Biotechnologia Acta V. 14, No 1, 2021
Р. 25-37, Bibliography 78, English
Universal Decimal Classification: 577.112:577.322:576.342:615.36
https://doi.org/10.15407/biotech14.01.025
Gulevskyy O. K., Akhatova Yu. S.
Institute for Problems of Cryobiology and Cryomedicine of the National Academy of Sciences of Ukraine, Kharkiv
This paper was aimed to review the literature data from native and foreign sources accumulated for 40-years period of research of the features of the molecular structure, functions, production and application of human alpha-fetoprotein (AFP), which is known as one of the most studied and increasingly demanded proteins. Results of fundamental studies performed with the use of modern methods, including various types of electrophoresis, chromatography, electron microscopy and immunoassay, in order to characterize the principal physicochemical capacities and localization of free and bound forms of AFP, as well as polypeptide structure, heterogeneity and topography of AFP receptors are highlighted here. The data on the mechanisms of AFP synthesis, its conformational features, binding sites and intracellular metabolism are also presented. The concepts of physiological functions and mechanisms of AFP transport in an organism are presented. Data on AFP isolation from the natural primary products and its production by means of recombinant and synthetic methods are shown. This review also summarizes information on the current possibilities of clinical application of AFP and the prospects for its usage in anticancer therapy for targeted delivery of chemotherapy drugs, with emphasis on the description of the recent progress in this field.
Key words: alpha-fetoprotein, sources of alpha-fetoprotein production, application of alpha-fetoprotein, targeted delivery of chemotherapy drugs.
© Palladin Institute of Biochemistry of National Academy of Sciences of Ukraine, 2021
References
1. Moldogazieva N. T., Terentiev A. A., Shait K. V. Relationship between the structure and functions of alpha-fetoprotein: its conformational changes and biological activity. Biomed. chem. 2005, 51 (2), 127–151. (In Russian).
2. Chereshnev V. A., Rodionov S. Yu., Cherkasov V. A., Malyutina N. N., Orlov O. A. Alfa-fetoprotein. Yekaterinburg: Uralskoe otdelenie RAN. 2004, 376 р. (In Russian).
3. Treshalina H. M., Smirnova G. B., Tsurkan S. A., Tcherkassova J. R., Lesnaya N.A. The role of alphafetoprotein receptor in the delivery of targeted preparations in oncology. Russian J. Oncol. 2017, 22 (1), 4–14. https://doi.org/10.18821/1028-9984-2017-22-1-4-14
4. Nikolaeva L. B., Ushakova G. A. The first pregnancy and first birth: a guide for doctors. Moskva: GEOTAR-Media. 2013, 264 p. (In Russian).
5. FryerA. A., Jones P., Strange R., Hume R., Bell J. E. Plasma protein levels in normal human fetuses: 13 to 41 weeks’ gestation. Br. J. Obstet. Gynaecol. 1993, 100 (9), 850–855. https://doi.org/10.1111/j.1471-0528.1993.tb14313.x
6. Hsu J. J., Hseih T. T., Chiu T. H., Liou J. D., Soong Y. K. Alpha-fetoprotein levels of paired samples between the amniotic fluid and maternal serum from 16 to 18 weeks’ gestation in Chinese women. J. Formos. Med. Assoc. 1994, 93 (5), 374–378.
7. Mizejewski G. J. Alpha-fetoprotein structure and function: relevance to isoforms, epitopes, and conformational variants. Exp. Biol. Med. 2001, V. 226, P. 377–408. https://doi.org/10.1177/153537020122600503
8. Naval J., Villacampa M. J., Goguel A. F., Uriel J. Cell-type specific receptors for alpha-fetoprotein in a mouse T-lymphoma cell line. Proc. Natl. Acad. Sci. USA. 1985, V. 82, P. 3301–3305. https://doi.org/10.1073/pnas.82.10.3301
9. Suzuki T., Sasano H., Aoki H., Nagura H., Sasano N., Sano T., Saito M., Watanuki T., Kato H., Aizawa S. Immunohistochemical comparison between anaplastic seminoma and typical seminoma. Acta Pathol. Jpn. 1993, 43 (12), 751–757. https://doi.org/10.1111/j.1440-1827.1993.tb02562.x
10. Moldogazieva N. T., Terentiev A. A. Alphafetoprotein and growth factors. Structurefunction relationships and analogies. Usp. Biol. Chim. 2006, No 46, P. 99–148. (In Russian).
11. Bogdanov A. Yu., Bogdanova T. M., Ilin A. I. Endocytic pathway of alpha-fetoprotein in mice bone marrow hematopoietic stem cells: molecular characterization and role in biological activity modification. Cytology and Genetics. 2014, 48 (1), 25–40. (In Russian). https://doi.org/10.3103/S0095452714010034
12. Shmagel K. V., Chereshnev V. A. Alphafetoprotein: structure, function and role in embryogenesis. Akusherstvo i ginekologiya. 2002, No 5, P. 6–8. (In Russian).
13. Clark G. F., Dell A., Morris H. R., Patankar M., Oehninger S., Sepp l M. Viewing AIDS from a glycobiological perspective: potential linkages to the human fetoembryonic defence system hypothesis. Mol. Hum. Reprod. 1997, 3 (1), 5–13. https://doi.org/10.1093/molehr/3.1.5
14. Filella X., Molina R., Alcover J., Coca F., Zarco M. A., Ballesta A. M. Influence of AFP, CEA and PSA on the in vitro production of cytokines. Tumour Biol. 2001, 22 (2), 67–71. https://doi.org/10.1159/000050598
15. Czokalo M., Wishnewski L. Culture conditions modify the effects exerted by human fetal AFP on some lymphocyte functions in vitro. Exp. Pathol. 1981, 20 (4), 233–238. https://doi.org/10.1016/S0232-1513(81)80028-X
16. Keel B. A., Eddy K. B., Cho S., May J. V. Human alpha-fetoprotein purified from amniotic proliferation in vitro. Mol. Reprod. Dev. 1991, 30 (2), 112–118. https://doi.org/10.1002/mrd.1080300207
17. Leal J. A., May J. V., Keel B. A. Human alphafetoprotein enhances epidermal growth factor proliferative activity upon porcine granulosa cells in monolayer culture. Endocrinol. 1990, 126 (1), 669–671. https://doi.org/10.1210/endo-126-1-669
18. Li M., Li H., Li C., Wang S., Jiang W., Liu Z., Zhou S., Liu X., McNutt M. A., Li G. Alphafetoprotein: a new member of intracellular signal molecules in regulation of the PI3K/ AKT signaling in human hepatoma cell lines. Int. J. Cancer. 2011, 128 (3), 524–532. https://doi.org/10.1002/ijc.25373
19. Zheng L., Gong W., Liang P., Huang X., You N., Han K. Q., Li Y. M., Li J. Effects of AFPactivated PI3K/Akt signaling pathway on cell proliferation of liver cancer. Tumour Biol. 2014, 35 (5), 4095–4099. https://doi.org/10.1007/s13277-013-1535-z
20. Tomashevsky A. I., Yuversky V. N. A new scheme for the isolation and purification of human alpha-fetoprotein. Bioorg. chem. 1999, 25 (6), 412–417. (In Russian).
21. Lin B., Peng G., Feng H., Li W., Dong X., Chen Y., Lu Y., Wang Q., Xie X., Zhu M., Li M. Purification and characterization of abioactive alpha-fetoprotein produced by HEK-293 cells. Protein Expr. Purif. 2017, V. 136, P. 1–6. https://doi.org/10.1016/j.pep.2017.05.008
22. Terentev A. A., Kazimirsky A. N., Lychkova A. E., Salmasi J. M. Lymphocyte apoptosis enhancement by the synthetic peptide of human alpha-fetoprotein (afp 14-20) in experimental ulcer. Exper. Clin. Gastroenterol. 2014, 110 (10), 50–52. (In Russian).
23. Fuller B. J., Lane N., Benson E. E. Life in the frozen state. London: CRC Press. 2004, 672 p. https://doi.org/10.1201/9780203647073
24. Shabunin S. V., Vostrilova G. A., Shabanov I. E. Screening of biologically active substances depending on the technological parameters of cryogenic fractionation of the placenta. Problems of cryobiology. 2005, 15 (3), 306– 309. (In Ukrainian).
25. Osetskiy A. I., Grischenko V. I., Snurnikov A. S., Shabanov I. Ye., Babijchuk G. A. Cryosublimation fractionating of biological material. Problems of cryobiology. 2006, 16 (2), 230–240. (In Ukrainian).
26. Mizejewski G. J. Therapeutic use of human alpha-fetoprotein in clinical patients: Is a cancer risk involved? Int. J. Cancer. 2011, V. 128, P. 239–249. https://doi.org/10.1002/ijc.25292
27. Dudich E. MM–093, a recombinant human alpha-fetoprotein for the potential treatment of rheumatoid arthritis and other autoimmune diseases. Curr. Opin. Mol. Ther. 2007, No 9, P. 603–10.
28. Mizejewski G. Mapping of structure-function peptide sites on the human alpha-fetoprotein amino acid sequence. Atlas Genet. Cytogenet. Oncol. Haematol. 2010, 14 (2), 169–216. https://doi.org/10.4267/2042/44695
29. Uversky V. N., Narizhneva N. V., Ivano va T. V., Tomashevski A. Y. Rigidity of human alphafetoprotein tertiary structure is under ligand control. Biochem. 1997, V. 36, P. 13638–13645. https://doi.org/10.1021/bi970332p
30. Dudich I. V., Semenkova L. N., Tatulov E., Korpela T., Dudich E. Improved delivery of poorly water soluble drugs with alphafetoprotein stabilized with metal ions. International Bureau PCT. WO2015075296 A1. 05. 28. 2015.
31. Pak V. N. The use ofalpha-fetoproteinfor the treatment of autoimmune diseases and cancer. Ther Deliv. 2018, 9 (1), 37–46. https://doi.org/10.4155/tde-2017-0073
32. Li M., Liu X., Zhou S., Li P., Li G. Effects of alpha fetoprotein on escape of Bel 7402 cells from attack of lymphocytes. BMC Cancer. 2005, No 5, P. 96. https://doi.org/10.1186/1471-2407-5-96
33. Li M., Zhou S., Liu X., Li P. Alpha-fetoprotein shield hepatocellular carcinoma cells from apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand. Cancer Lett. 2007, V. 249, P. 227–234. https://doi.org/10.1016/j.canlet.2006.09.004
34. Li M., Li H., Li C., Guo L., Zhou S. Cytoplasmic alpha-fetoprotein functions as a co-repressor in RA-RAR signaling to promote the growth of human hepatoma Bel 7402 cells. Cancer Lett. 2009, V. 285, P. 190–199. https://doi.org/10.1016/j.canlet.2009.05.014
35. Zhang W., Liu J., Wu Y., Xiao F., Wang Y., Wang R., Yang H., Wang G., Yang J., Deng H., Li J., Wen Y., Wei Y. Immunotherapy of hepatocellular carcinoma with a vaccine based on xenogeneic homologous alpha fetoprotein in mice. Biochem. Biophys. Res. Commun. 2008, 376 (1), 10–14. https://doi.org/10.1016/j. bbrc.2008.08.061
36. Semenkova L. N., Dudich E. I., Dudich I. V. Induction of apoptosis in human hepatoma cells by alpha-fetoprotein. Tumour Biol. 1997, V. 18, P. 261–273. https://doi.org/10.1159/000218039
37. Li M., Li H., Li C., Zhou S., Guo L., Jiang W. Alpha fetoprotein is a novel protein-binding partner for caspase-3 and blocks the apoptotic signaling pathway in human hepatoma cells. Int. J. Cancer. 2009, V. 124, P. 2845–2854. https://doi.org/10.1002/ijc.24272
38. Laderoute M. P., Pilarski L. M. The inhibition of apoptosis by alpha-fetoprotein (AFP) and the role of AFP receptors in anti-cellular senescence. Anticancer Res. 1994, No 14, P. 2429–2438.
39. Wang X., Wand Xu B. Stimulation of tumorcell growth by alpha-fetoprotein. Int. J. Cancer. 1998, V. 75, P. 596–599. https://doi.org/10.1002/(SICI)1097-0215(19980209)75:4<596::AID-IJC17>3.0.CO;2-7
40. Wang X. W., Xie H. Alpha-fetoprotein enhances the proliferation of human hepatoma cells in vitro. Life Sci. 1999, V. 64, P. 17–23. https://doi.org/10.1016/S0024-3205(98)00529-3
41. Pak V. N. a-fetoprotein-binding toxins and teratogens against cancer. Ther Deliv. 2019, No 1, P. 1–3. https://doi.org/10.4155/tde2018-0068
42. Hirano K., Watanabe Y., Adachi T., Ito Y., Sugiura M. Drug binding properties of human alpha-fetoprotein. Biochem. J. 1985, V. 231, P. 189–191. https://doi.org/10.1042/bj2310189
43. Belyaev N. N., Abdolla N., Perfilyeva Y. V., Ostapchuk Y. O., Krasnoshtanov V. K., Kali A., Tleulieva R. Daunorubicin conjugated with AFP selectively eliminates MDSCs and inhibits experimental tumor growth. Cancer Immunol. Immunother. 2018, 67 (1), 101–111.https://doi.org/10.1007/s00262-017-2067-y
44. Gabrilovich D. I. Myeloid-derived suppressor cells. Cancer Immunol. Res. 2017, 5 (1), 3–8. https://doi.org/10.1158/2326-6066.CIR-16-0297
45. Dudich E. MM-093, a recombinant human alpha-fetoprotein for the potential treatment of rheumatoid arthritis and other autoimmune diseases. Curr. Opin. Mol. Ther. 2007, 9 (6), 603–610.
46. Aussel C., Fehlmann M. Alpha-fetoprotein stimulates leukotriene synthesis in P388D1 macrophages. Cell. Immunol. 1986, V. 101, P. 415–424. https://doi.org/10.1016/0008-8749(86)90154-1
47. Nakanishi M., Rosenberg D. W. Multifaceted roles of PGE2in inflammation and cancer. Semin. Immunopathol. 2013, 35 (2), 123– 137. https://doi.org/10.1007/s00281-012- 0342-8
48. Mizejewski G. J. Alpha-fetoprotein (AFP) and inflammation: Is AFP an acute and/or chronic phase reactant? J. Hematol. Thrombo. Dis. 2015, 3 (1), 191–199. https://doi. org/10.4172/2329-8790.1000191
49. Murgita R. A. Recombinant human alphafetoprotein as an immunosuppressive agent. Pat. USA. US7423024. 09. 09. 2008.
50. Kusner L. L., Sengupta M., Aguilo-Seara G., Sherman I. Preclinical pilot study of alphafetoprotein on moderation of MG weakness. Abstracts of the 13th International Conference on Myasthenia Gravis and Related Disorders. NY: The New York Academy of Sciences. 2017.
51. Mizejewski G. J. Biological role of alphafetoprotein in cancer: prospects for anticancer therapy. Expert. Rev. Anticancer Ther. 2002, 2 (6), 709–735. https://doi.org/10.1586/14737140.2.6.709
52. Chereshnev V. A., Rodionov S. Iu., Vasil’ev N. V., Orlov O. A., Cherkasov V. A. Alpha-fetoprotein immunotherapy as a stage of combined treatment of cancer patients. Vopr. Onkol. 2005, 51 (1), 86–92.
53. Posypanova G., Severin S. Alpha-fetoprotein and recombinant alpha-fetoprotein fragments as drug delivery tools. In: Alpha-fetoprotein: functions and clinical applications. Lakhi N., Moretti M. (Eds). Nova Science Publishes, NY, USA. 2016, Р. 277–300. https://doi.org/10.4155/tde.14.59
54. Pak V. N. The use of alpha-fetoprotein for the delivery of cytotoxic payloads to cancer cells. Ther. Deliv. 2014, 5 (8), 885–892. https:// doi.org/10.4155/tde.14.59
55. Sharapova O. A. Recombinant fragments of human alpha-fetoprotein for creating targeted drug delivery (Ph. D. dissertation). Available from the Scientific Electronic Library of theses and abstracts. 2012.
56. Bereznikova A. B., Posypanova G. A., Makarov V. A., Antipova O. V., Severin E. S. AFP octapeptide is a promising peptide vector for targeted delivery of cytostatics to tumor cells. Vopr. biol. med. farm. chemistry. 2012, No 5, P. 15–21. (In Russian).
57. Sharapova O. A., Pozdnyakova N. V., Seve rin S. E., Laurinavichyute D. K., Yurkova M. S., Andronova S. M., Fedorov A. N., Severin E. S., Posypanova G. A. I s o l a t i o n a n d characterization of the recombinant human a-fetoprotein fragment corresponding to the c-terminal structural domain. Bioorganic chem. 2010, 36 (6), 696–703. (In Russian). https://doi.org/10.1134/S106816201006004X
58. Garc a-Fruit s E., Ar s A., Villaverde A. Localization of Functional Polypeptides in Bacterial Inclusion Bodies. Appl. Environ. Microbiol. 2007, 73 (1), 289–294. https://doi.org/10.1128/AEM.01952-06
59. Gil-Garcia М., Navarro S., Ventura S. Coiledcoil inspired functional inclusion bodies. Microb. Cell Fact. 2020, 19 (1), 117. https://doi.org/10.1186/s12934-020-01375-4
60. J ger V. D., Lamm R., K sters K., l c G., Oldiges M., Jaeger K. E., B chs J., Krauss U. Catalytically-active inclusion bodies for biotechnology-general concepts, optimization, and application. Appl. Microbiol. Biotechnol. 2020, 104 (17), 7313–7329. https://doi.org/10.1007/s00253-020-10760-3
61. Colligan S. H., Tzetzo S. L., Abrams S. I. Myeloid-driven mechanisms as barriers to antitumor CD8+T cell activity. Mol. Immunol. 2020, V. 118, P. 165–173.https://doi.org/10.1016/j.molimm.2019.12.012
62. Weiss J. M., Subleski J. J., Back T., Chen X., Watkins S. K., Yagita H., Sayers T. J., Murphy W. J., Wiltrout R. H. Regulatory T cells and myeloid-derived suppressor cells in the tumor microenvironment undergo Fas-dependent cell death during IL-2/aCD40 therapy. J. Immunol. 2014, 192 (12), 5821–5829. https://doi.org/10.4049/jimmunol.1400404
63. Atretkhany K. N., Drutskaya S. Myeloidderived suppressor cells and proinflammatory cytokines as targets for cancer therapy. Biochemistry (Mosc). 2016, 81 (11), 1274–1283. https://doi.org/10.1134/S0006297916110055
64. Belyaev N. N. Myeloid-derived suppressor cells (MDSC) as a main tumor induced negative regulators of cancer immunity and possible ways for their elimination. KazNU Bulletin Biol. Series. 2014, 1 (60), 79–83.
65. Alizadeh D., Trad M., Hanke N. T., Larmonier C. B., Janikashvili N., Bonnotte B., Katsanis E., Larmonier N. Doxorubicin eliminates myeloid-derived suppressor cells and enhances the efficacy of adoptive T-cell transfer in breast cancer. Cancer Res. 2014, 74 (1), 104–118. https://doi.org/10.1158/0008-5472.CAN-13-1545
66. Vincent J., Mignot G., Chalmin F., Ladoire, S., Bruchard M., Chevriaux A., Martin F., Apetoh L., R b C., Ghiringhelli F. 5-Fluorouracil selectively kills tumorassociated myeloid-derived suppressor cells resulting in enhanced T celldependent antitumor immunity. Cancer Res. 2010, 70 (8), 3052–3061. https://doi.org/10.1158/0008-5472.CAN-09-3690
67. Sevko A., Michels T., Vrohlings M., Umansky L., Beckhove P., Kato M., Shurin G.V., Shurin M. R., Umansky V. Antitumor effect of paclitaxel is mediated by inhibition of myeloid-derived suppressor cells and chronic inflammation in the spontaneous melanoma model. J. Immunol. 2013, 190 (5), 2464–2671. https://doi.org/10.4049/jimmunol.1202781
68. Bracci L., Schiavoni G., Sistigu A., Belardelli F. Immune-based mechanisms of cytotoxic chemotherapy: implications for the design of novel and rationale-based combined treatments against cancer. Cell Death Differ. 2014, 21 (1), 15–25. https://doi.org/10.1038/cdd.2013.67
69. Wang Z., Liu Y., Zhang Y., Shang Y., Gao Q. MDSC-decreasing chemotherapy increases the efficacy of cytokine-induced killer cell immunotherapy in metastatic renal cell carcinoma and pancreatic cancer. Oncotarge. 2016, 7 (4), 4760–4769. https://doi.org/10.18632/oncotarget.6734
70. Pak V. N. Magic bullet and immunotherapy against metastasis. J. Cancer Prev. Curr. Res. 2016, 6 (3), 00206. https://doi.org/10.15406/jcpcr.2016.06.00206
71. Qin H., Lerman B., Sakamaki I., Wei G., Cha S. C., Rao S. S., Qian J., Hailemichael Y., Nurieva R., Dwyer K. C., Roth J., Yi Q., Overwijk W. W., Kwak L. W. Generation of a new therapeutic peptide that depletes myeloid-derived suppressor cells in tumorbearing mice. Nat. Med. 2014, 20 (6), 676– 681. https://doi.org/10.1038/nm.3560
72. Arshad N. M., In L. L., Soh T. L., Azmi M. N., Ibrahim H., Awang K., Dudich E., Tatulov E., Nagoor N. H. Recombinant human alphafetoprotein synergistically potentiates the anti-cancer effects of 1’-S-1’-acetoxychavicol acetate when used as a complex against human tumours harbouring AFP-receptors. Oncotarget. 2015, 6 (18), 16151–16167. https://doi.org/10.18632/oncotarget.3951
73. Dominguez G. A., Condamine T., Mony S., Hashimoto A., Wang F., Liu Q., Forero A., Bendell J., Witt R., Hockstein N., Kumar P., Gabrilovich D. I. Selective targeting of myeloid-derived suppressor cells in cancer patients using DS-8273a, an agonistic TRAIL-R2 antibody. Clin. Cancer Res. 2016, 23 (12), 2942–2950. https://doi.org/10.1158/1078-0432.CCR-16-1784
74. Wilkerson A., Kim J., Huang A. Y., Zhang M. Nanoparticle systems modulating myeloidderived suppressor cells for cancer immunotherapy. Curr. Top. Med. Chem. 2017, 17 (16), 1843–1857. https://doi.org/1 0.2174/1568026617666161122121412
75. Wang H. F., Ning F., Liu Z. C., Wu L., Li Z. Q., Qi Y. F., Zhang G., Wang H. S., Cai S. H., Du J. Histone deacetylase inhibitors deplete myeloidderived suppressor cells induced by 4T1 mammary tumorsin vivoand in vitro. Cancer Immunol. Immunother. 2017, 66 (3), 355–366. https://doi.org/10.1007/s00262-016-1935-1
76. Pak V. N. Selective targeting of myeloidderived suppressor cells in cancer patients through AFP-binding receptors. Future Sci. OA. 2018, 5 (1), FSO321. https://doi.org/10.4155/fsoa-2018-0029
77. Belyaev N. N., Abdolla N., Perfilyeva Y. V., Ostapchuk Y. O., Krasnoshtanov V. K., Kali A., Tleulieva R. Daunorubicin conjugated withalpha-fetoproteinselectively eliminates myeloid-derived suppressor cells (MDSCs) and inhibits experimental tumor growth. Cancer Immunol. Immunother. 2018, 67 (1), 101–111. https://doi.org/10.1007/s00262-017-2067-y
78. Mollaev M., Gorokhovets N., Nikolskaya E., Faustova M., Zabolotsky A., ZhuninaO., Sokol M., Zamulaeva I., Severin E., Yabbarov N. Type of pH sensitive linker reveals different time-dependent intracellular localization, in vitro and in vivo efficiency inalpha-fetoproteinreceptor targeted doxorubicin conjugate. Int. J. Pharm. 2019, V. 559, P. 138–146. https://doi.org/10.1016/j.ijpharm.2018.12.073