ISSN 2410-7751 (Print)
ISSN 2410-776X (Online)
Biotechnologia Acta Т. 16, No. 5 , 2023
P. 5-16, Bibliography 47, Engl.
UDC:: 577.112.5: 57.088
DOI: https://doi.org/10.15407/biotech16.06.005
Full text: (PDF, in English)
BIOMEDICAL APPLICATION OF K5 PLASMINOGEN FRAGMENT
L.G. Kapustianenko, A.O. Tykhomyrov
Palladin Institute of Biochemistry of the National Academy of Sciences of Ukraine, Kyiv
Aim. Plasminogen kringle 5 is an endogenous angiogenic inhibitor. The review was purposed to highlight the potential biomedical application of Kringle 5 in the regulation of angiogenesis and tumor growth.
Methods. Angiogenesis is a complex process that involves endothelial cell proliferation, migration, basement membrane degradation, and neovessel organization. Since the uncontrolled growth of new blood vessels causes the progression of many common diseases, first of all, oncological diseases, autoimmune disorders, and neovascular damage of the eye, the use of angiostatins can be a promising pharmacotherapeutic approach to the prevention and adjuvant therapy of these pathological conditions. The advantages of angiostatin application are their non-toxicity even at high doses, non-immunogenicity, and lack of tolerance of target cells to their action. Angiostatins comprise a group of kringle-containing proteolytically-derived fragments of plasminogen/plasmin, which act as potent inhibitory mediators of endothelial proliferation and migration. Among all known angiostatin species, isolated K5 plasminogen fragment was shown to display the most potent inhibitory activity against proliferation of endothelial cells via triggering multiple signaling pathways, which lead to cell death and resulting angiogenesis suppression.
Results. Current literature data suggest that in addition to the expressed and highly specific cytotoxicity in relation to endotheliocytes and some types of tumor cells, the kringle domain 5 of human plasminogen has other advantages as an antiangiogenic and antitumor regulator, including its specific inhibitory activity, which affects only activated, proliferating endothelial cells, and therefore is non-toxic to different types of normal cells. As an endogenous protein, which is formed in the human organism, K5 does not provoke an immune response. K5, as a small polypeptide molecule with a stable structure, can be obtained as a recombinant protein in E. coli cells and can also be used in pharmacokinetic systems of targeted delivery and sustained release.
Conclusions. The prospect of successful use of K5 as a therapeutic agent to manage pathological processes associated with dysregulation of angiogenesis makes it necessary to develop and improve methods of its production and to test its plausible pleiotropic biological activities further.
Key words: angiostatins, plasminogen fragment kringle 5, angiogenesis, endothelial cells, neovascular diseases, tumor growth, retinopathy.
Refrebces
1. Folkman J. Angiogenesis: an organizing principle for drug discovery? Nat. Rev. Drug Discov. 2007, 6(4), 273‒286. https://doi.org/10.1038/nrd2115
2. Dvorak H.F. Angiogenesis: update. J. Thromb. Haemost. 2005, vol. 3, 1835‒1842. https://doi.org/10.1111/j.1538-7836.2005.01361.x.
3. van der Vorm L., Remijn J., de Laat B., Huskens D. Effects of Plasmin on von Willebrand Factor and Platelets: A Narrative Review. TH Open Georg Thieme Verlag KG Stuttgart, New York. 2018, 2, e218–e228. https://doi.org/10.1055/s-0038-1660505
4. O'Reilly M.S., Holmgren L., Shing Y., Chen C., Rosenthal R.A., Moses M., Lane W.S., Cao Y., Sage E.H., Folkman J. Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell. 1994, 79(2), 315‒328. https://doi.org/10.1016/0092-8674(94)90200-3.
5. Wahl M.L., Kenan D.J., Gonzalez-Gronow M., Pizzo S.V. Angiostatin's molecular mechanism: aspects of specificity and regulation elucidated. J. Cell Biochem. 2005, 96(2), 242‒261. https://doi.org/10.1002/jcb.20480.
6. Hiramoto K., Yamate Y. Tranexamic acid reduces endometrial cancer effects through the production of angiostatin. J. Cancer. 2022, 13(5), 1603‒1610. https://doi.org/10.7150/jca.68169.
7. Drixler T.A., Borel Rinkes I.H., Ritchie E.D. Treffers F.W., van Vroonhoven T.J., Gebbink M.F., Voest E.E. Angiostatin inhibits pathological but not physiological retinal angiogenesis. Invest. Ophthalmol. Vis. Sci. 2001, 42(13), 3325‒3330. PMID: 11726640
8. Rezzola S., Loda A., Corsini M., Semeraro F., Annese T., Presta M., Ribatti D. Angiogenesis-inflammation cross talk in diabetic retinopathy: novel insights from the chick embryo chorioallantoic membrane/human vitreous platform. Front. Immunol. 2020, 11, 581288. https://doi.org/10.3389/fimmu.2020.581288
9. Sack R.A., Beaton A.R., Sathe S. Diurnal variations in angiostatin in human tear fluid: a possible role in prevention of corneal neovascularization. Curr. Eye Res. 1999, 18(3), 186‒193. https://doi.org/10.1076/ceyr.18.3.186.5367
10. Chavakis T., Athanasopoulos A., Rhee J.S., Orlova V., Schmidt-Wöll T., Bierhaus A., May A.E., Celik I., Nawroth P.P., Preissner K.T. Angiostatin is a novel anti-inflammatory factor by inhibiting leukocyte recruitment. Blood. 2005, 105(3), 1036‒1043. https://doi.org/10.1182/blood-2004-01-0166
11. Perri S.R., Martineau D., François M., Lejeune L., Bisson L., Durocher Y., Galipeau J. Plasminogen kringle 5 blocks tumor progression by antiangiogenic and proinflammatory pathways. Mol. Cancer. Ther. 2007, 6(2), 441‒449. https://doi.org/10.1158/1535-7163.MCT-06-0434.
12. Lee T.Y., Muschal S., Pravda E.A., Folkman J., Abdollahi A., Javaherian K. Angiostatin regulates the expression of antiangiogenic and proapoptotic pathways via targeted inhibition of mitochondrial proteins. Blood. 2009, 114(9), 1987‒1998. https://doi.org/10.1182/blood-2008-12-197236.
13. Cao R., Wu H.L., Veitonmäki N., Linden P., Farnebo J., Shi G.Y., Cao Y. Suppression of angiogenesis and tumor growth by the inhibitor K1-5 generated by plasmin-mediated proteolysis. Proc. Natl. Acad. Sci. USA. 1999, 96(10), 5728‒5733. https://doi.org/10.1073/pnas.96.10.5728.
14. Cao Y., Chen A., An S.S., Ji R.W., Davidson D., Llinás M. Kringle 5 of plasminogen is a novel inhibitor of endothelial cell growth. J. Biol. Chem. 1997, 272(36), 22924‒22928. https://doi.org/10.1074/jbc.272.36.22924.
15. Spranger J., Bühnen J., Jansen V., Krieg M., Meyer-Schwickerath R., Blum W.F., Schatz H., Pfeiffer A.F. Systemic levels contribute significantly to increased intraocular IGF-I, IGF-II and IGF-BP3 [correction of IFG-BP3] in proliferative diabetic retinopathy. Horm. Metab. Res. 2000, 32(5), 196‒200. https://doi.org/10.1055/s-2007-978621.
16. Guzyk M.M., Tykhomyrov A.A., Nedzvetsky V.S., Prischepa I.V., Grinenko T.V., Yanitska L.V., Kuchmerovska T.M. Poly(ADP-Ribose) polymerase-1 (PARP-1) inhibitors reduce reactive gliosis and improve angiostatin levels in retina of diabetic rats. Neurochem. Res. 2016, 41(10), 2526‒2537. https://doi.org/10.1007/s11064-016-1964-3.
17. Lai С.С., Wu W.C., Chen S.L. X Xiao, Tsai T.C., Huan S.J., Chen T.L., Tsai R.J., Tsao Y.P. Suppression of choroidal neovascularization by adeno-associated virus vector expressing angiostatin. Vis. Sci. 2001, 42(10), 2401‒2407. PMID:11527956
18. Pearce J.W., Janardhan K.S., Caldwell S., Singh B. Angiostatin and integrin alphavbeta3 in the feline, bovine, canine, equine, porcine and murine retina and cornea. Vet. Ophthalmol. 2007, 10(5), 313‒319. https://doi.org/10.1111/j.1463-5224.2007.00560.x.
- Shyong M.P., Lee F.L., Kuo P.C., Wu A.C., Cheng H.C., Chen S.L., Tung T.H., Tsao Y.P. Reduction of experimental diabetic vascular leakage by delivery of angiostatin with a recombinant adeno-associated virus vector. Mol. Vis. 2007, 13, 133‒141. PMCID: PMC2533034
- Sima J., Zhang S.X., Shao C., Fant J., Ma J.X. The effect of angiostatin on vascular leakage and VEGF expression in rat retina. FEBS Lett. 2004, 564(1‒2), 19‒23. https://doi.org/10.1016/S0014-5793(04)00297-2
- Zhang S.X., Sima J., Shao C., Fant J., Chen Y., Rohrer B., Gao G., Ma J.X. Plasminogen kringle 5 reduces vascular leakage in the retina in rat models of oxygen-induced retinopathy and diabetes. Diabetologia. 2004, 47(1), 124‒131. https://doi.org/10.1007/s00125-003-1276-4.
- Lu K., Zhang S.X., Wang J.X., Shao C., Mott R., Ma J.X. Down-regulation of plasminogen kringle 5 receptor in Müller cells under hypoxia and in the diabetic retina. Invest. Ophthalmol. Vis. Sci. 2004, 45, 664.
- Gao G., Li Y., Gee S., Dudley A., Fant J., Crosson C., Ma J.X. Down-regulation of vascular endothelial growth factor and up-regulation of pigment epithelium-derived factor: a possible mechanism for the anti-angiogenic activity of plasminogen kringle 5. J. Biol. Chem. 2002, 277(11), 9492‒9497. https://doi.org/10.1074/jbc.M108004200
- Ma J., Li C., Shao C., Gao G., Yang X. Decreased K5 receptor expression in the retina, a potential pathogenic mechanism for diabetic retinopathy. Mol. Vis. 2012, 18, 330‒336. PMCID: PMC3283210
25. Tykhomyrov A. A., Yusova E. I., Diordieva S. I., Corsa V.V., Grinenko T.V. Production and characteristics of antibodies against K1-3 fragment of human plasminogen. Biotechnologia Acta. 2013, 6(1), 86‒96. (In Ukrainian). https://doi.org/10.15407/biotech6.01.086.
26. Gonzalez-Gronow M., Kalfa T., Johnson C.E., Gawdi G., Pizzo S. V. The voltage-dependent anion channel is a receptor for plasminogen kringle 5 on human endothelial cells. J. Biol. Chem. 2003, 278(29), 27312‒27318. https://doi.org/10.1074/jbc.M303172200.
27. Tarui T., Mazar A. P., Cines D. B., Takada Y. Urokinase-type plasminogen activator receptor (CD87) is a ligand for integrins and mediates cell-cell interaction. J. Biol. Chem. 2001, V. 276, P. 3983‒3990. https://doi.org/10.1074/jbc.M008220200
28. Cao Y., Ji R.W., Davidson D., Schaller J., Marti D., Söhndel S., McCance S.G., O'Reilly M.S., Llinás M., Folkman J. Kringle domains of human angiostatin. Characterization of the anti-proliferative activity on endothelial cells. J. Biol. Chem. 1996, V. 271, P. 29461-29467. https://doi.org/10.1074/jbc.271.46.29461.
29. Llombart-Bosch A., López-Guerrero J. A., Felipo V. New trends in cancer for the 21st century. Springer Netherlands. 2006: 251‒275. https://doi.org/10.1007/978-1-4020-5133-3
30. Cao Y., Xue L. Angiostatin. Semin. Thromb. Hemost. 2004, 30(1), 83‒93. https://doi.org/10.1055/s-2004-822973.
31. Kapustianenko L.G., Iatsenko T.A., Iusova O.I., Grinenko T.V. Isolation and purification of a kringle 5 from human plasminogen using AH-Sepharose. Biotechnologia Acta. 2014, 7(4), 35‒42. https://doi.org/10.15407/biotech7.04.035
32. Shoshan-Barmatz V., De Pinto V., Zweckstetter M., Raviv Z., Keinan N., Arbel N. VDAC, a multi-functional mitochondrial protein regulating cell life and death. Mol. Aspects Med. 2010, 31(3), 227‒285. https://doi.org/10.1016/j.mam.2010.03.002
33. Li L., Yao Y.C., Gu X.Q., Che D., Ma C.-Q., Dai Zh.-Y., Li C., Zhou T., Cai W.-B., Yang Zh.-H., Yang X., Gao G.-Q. Plasminogen kringle 5 induces endothelial cell apoptosis by triggering a voltage-dependent anion channel 1 (VDAC1) positive feedback loop. J. Biol. Chem. 2014, 289, 32628‒32638. https://doi.org/10.1074/jbc.M114.567792
34. Gonzalez-Gronow M., Ray R., Wang F., Pizzo S.V. The voltage-dependent anion channel (VDAC) binds tissue-type plasminogen activator and promotes activation of plasminogen on the cell surface. J. Biol. Chem. 2013, 288(1), 498‒509. https://doi.org/10.1074/jbc.M112.412502
35. Gu X., Yao Y., Cheng R., Zhang Y., Dai Z., Wan G., Yang Z., Cai W., Gao G.,Yang X. Plasminogen K5 activates mitochondrial apoptosis pathway in endothelial cells by regulating Bak and Bcl-x(L) subcellular distribution. Apoptosis. 2011, 16(8), 846‒855. https://doi.org/10.1007/s10495-011-0618-9
36. Fang S., Hong H., Li L., He D., Xu Z., Zuo S., Han J., Wu Q., Dai Z., Cai W., Ma J, Shao C., Gao G., Yang X. Plasminogen kringle 5 suppresses gastric cancer via regulating HIF-1α and GRP78. Cell Death Dis. 2017, 8(10), e3144. https://doi.org/10.1038/cddis.2017.528.
37. Lu H., Dhanabal M., Volk R., Waterman M.J., Ramchandran R., Knebelmann B., Segal M., Sukhatme V.P. Kringle 5 causes cell cycle arrest and apoptosis of endothelial cells. Biochem. Biophys. Res. Commun. 1999, 258(3), 668‒673. https://doi.org/10.1006/bbrc.1999.0612.
38. Gao X., Jiang P., Wei X., Zhang W., Zheng J., Sun S., Yao H., Liu X., Zhang Q. Novel fusion protein PK5-RL-Gal-3C inhibits hepatocellular carcinoma via anti-angiogenesis and cytotoxicity. BMC Cancer. 2023, 23, 359. https://doi.org/10.1186/s12885-023-10843-0
39. Siegel R.L., Miller K.D., Jemal A. Cancer statistics, 2016. CA Cancer J. Clin. 2016, 66, 7‒30. https://doi.org/10.3322/caac.21332
40. Shah M.A. Gastrointestinal cancer: targeted therapies in gastric cancer-the dawn of a new era. Nat. Rev. Clin. Oncol. 2014, 11, 10–11. https://doi.org/10.1038/nrclinonc.2013.231
41. Cai W.-B., Zhang Y., Cheng R,. Wang Zh., Fang Sh.-H., Xu Z.-M., Yang X., Yang Zh.-H., Ma J.-X., Shao Ch.-K., Gao G.-Q. Dual Inhibition of Plasminogen Kringle 5 on Angiogenesis and Chemotaxis Suppresses Tumor Metastasis by Targeting HIF-1α Pathway. PLoS One. Editor: Anjali Jain, Cedars-Sinai Medical Center, USA. 2012, 7(12), e53152. https://doi.org/10.1371/journal.pone.0053152
42. Melillo G. Inhibiting hypoxia-inducible factor 1 for cancer therapy. Mol. Cancer Res. 2006, 4, 601‒605. https://doi.org/10.1158/1541-7786.MCR-06-0235
43. Nordgren I.K., Tavassoli A. Targeting tumor angiogenesis with small molecule inhibitors of hypoxia inducible factor. Chem. Soc. Rev. 2011, 40, 4307‒4317. https://doi.org/10.1039/c1cs15032d
44. Shin J., Lee H.J., Jung D.B., Jung J.H., Lee E.O., Lee S.G, Shim B.S., Choi S.H., Ko S.G., Ahn K.S., Jeong S.-J., Kim S.-H. Suppression of STAT3 and HIF-1 alpha mediates anti-angiogenic activity of betulinic acid in hypoxic pc-3 prostate cancer cells. PLoS One. Editor: Anjali Jain, Cedars-Sinai Medical Center, USA. 2011, 6(6), e21492. https://doi.org/10.1371/journal.pone.0021492
45. Salceda S., Caro J. Hypoxia-inducible factor 1alpha (hif-1alpha) protein is rapidly degraded by the ubiquitin-proteasome system under normoxic conditions. Its stabilization by hypoxia depends on redox-induced changes. J. Biol. Chem. 1997, 272, 22642‒22647. https://doi.org/10.1074/jbc.272.36.22642
46. Chilov D., Camenisch G., Kvietikova I., Ziegler U., Gassmann M., Wenger R.H. Induction and nuclear translocation of hypoxia-inducible factor-1 (hif-1): Heterodimerization with arnt is not necessary for nuclear accumulation of hif-1alpha. J. Cell Sci. 1999, 112(Pt8), 1203‒1212. https://doi.org/10.1242/jcs.112.8.1203
47. Zhang D., Kaufman P.L., Gao G., Saunders R.A., Ma J.X. Intravitreal injection of plasminogen kringle 5, an endogenous angiogenic inhibitor, arrests retinal neovascularization in rats. Diabetologia. 2001, 44(6), 757‒765. https://doi.org/10.1007/s001250051685
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