A Mini-Review Towards the Assessment of two Natural Anticoagulants Protein C And Antithrombin III

Introduction

During the past decades several new anticoagulative proteins have been identified that play an important role in the regulation of hemostatic balance [1]. These proteins included antithrombin III(ATIII), protein C and its inhibitor, protein S, and thrombomodulin. In except for ATIII, the others form the components of the protein C pathway. The cDNA codes for human protein C protein which consists of a preproleader sequene of 42 amino acids, a light chain region of 155 amino acids, a connecting dipeptide of lys-Arg, and a heavy chain region of 262 amino acids [2,3]. During intracellular processing, the prepare leader sequence is removed, protein C is secreted as a mature protein of 419 amino acids. Protein C (PC), a vitamin K-dependent plasma protein, and its inhibitor of activated protein C (APCI) are part of a major regulatory system of hemostasis. Activated protein C destroys the activity of activated factor V and VIII. Protein S as cofactor of activated protein C (APC) is due to the inability of APC to prolong the APTT or the Va-induced clotting time in protein S deficient plasma [4]. APC and protein S complex could inactivate factor Va and VIIIa more rapidly under the condition of calcium and phospholipids than did APC alone [5,6]. More recent, it has been found that protein S drives cancer cell proliferation and cell survival via oncogenic receptor Axl [7-12]. Aberrant activation of RTKs often leads to malignant transformation, whereas PI3K/ Axl is required for this oncogenic receptor signaling [13]. Targeting against a deregulated dominant oncogenic receptor such as the oncogenic estrogen receptor (ER) pathway (tamoxifen), and blocking oncogenic receptor HER3/HER2 agent trastuzumab is enough to slow tumor progression [14-32].

At present,the oncogenic receptors and their target antibodies (Abs) [33]strategies have been widely extended to CD44 oncogenic receptor of hyaluronic acid(HA) [34], RAGE oncogenic receptor [35-38], the oncogenic receptor platelet-derived growth factor receptor-β (PDGFRβ) or PDGFRa linked to the pathogenesis of myeloproliferative neoplasm or chronic leukemia [26,39,40], cytokine IL-3/oncogenic receptor IL3R IL-6/IL6R- STAT3-ADAR1 (P150) oncogenic transcription factors [41], oncogenic IL7R [42], IL-11/IL-11 gp130 receptor pro-oncogenic signaling [24,43-45] and oncogenic receptor IL17rb [46,47]. Intriguing, in Wilmes’ article [48,49], homodimeric class I cytokine receptors TpoR, EpoR and GHR are normally dimerized by their ligands. These receptors lack intrinsic kinase activity, relying on the associated pseudo kinase domain (PK) of Janus kinase 2(JAK2) proteins to initiate signal transduction. Notably, oncogenic receptors (TpoR W515L, oncogenic EpoR and GHR mutant) and hyperactive JAK2 mutants (TpoR TM-JM and JAK2 PK domain) promoted stronger and stable ligand-dimerization as prerequisite for signal activation. Ligand-independent dimerization was in further enhanced upon coexpression of TpoR W515L and JAK2 V617F, which exerts their additive signaling activities. In the presence of JAK2 V617F ligandindependent dimerization reached to -50% of the maximum level for TpoR,-25% for EpoR,and -10% for GHR,respectively.

In clinics,decreased plasma PC levels can predispose an individual to thrombotic disease, whereas decreased levels of APCI can cause hemorrhages. Patients with recurrent thromboembolic episodes of unknown etiology would be monitored for the assessment of protein C deficiency. Congenital protein C deficiencies were reported at earlist by Griffin JH in 1981 [50], and by Bertina RM in 1982 [51,52]. Hereditary protein S deficiency was identified in three Dutch families by Broekmans AW in 1985 [53]. At present, protein C antigen was determined by electroimmuno- assay as described elsewhere. The term “antithrombin” was first postulated by Morawitz in 1905 [54]. Antithrombin III(ATIII) is an a2- globulin with ellipsoid form. The single polypeptide chain contains 425 amino acids. Heparin belongs to the glycosaminoglycans (GAGs), which are sulphated carbohydrates widely distributed in human [55]. The binding of heparin to ATIII induce conformational changes which facilitate the binding of thrombin. Upon the formation of a stable thrombin-ATIII complex,heparin is released and joins another AT molecule [56-59]. The data suggested that lysine was required for heparin binding. Another intact serine at the active site of thrombin was also essential for reaction with ATIII [56]. Thrombin and ATIII form an inactive complex in a 1:1 molar ratio. ATIII also inactivates factor IXa, Xa, XIa and XIIa at slow rates [56,57].

In clinical aspects, regarding the assay method for routine work,the clotting assays for determing ATIII activity(ATIII:C) is to be complicated. ATIII antigen (ATIII:Ag) was measured using immunoassays(EIA). The method is simple, cheap and requires about 20 hours, but cannot detect all congenital ATIII deficiencies. Egeberg O and Abildgaard U (1965,1970) [60,61] reported the results that mean ATIII activity (ATIII:C) were about half the normal in the classical ATIII deficiency and the affected family members. In cirrhosis of the liver, the protein C antigen and the ATIII concentration are often low and was positively correlation with serum albumin levels [12,62-65]. In biliary tract occlusion and primary biliary cirrhosis, normal PC and ATIII concentrations were found. This data indicated that two natural anticoagulants (PC and ATIII) deficiencies occur the dysregulation of hepatic PC and ATIII synthesis and might play a central role as a predictor index in liver diseases.

In recent many topics were focused on coagulation and malignancy. Some haemorrhagic and thromboembolic complications are frequent in patients with malignancy. Acute leukemias varied in PC and ATIII level [12,63,66]. The decreased PC concentration was frequently found in individuals with M5 subtype and hyper- leukocytic acute leukemias. Plasma PC: Ag and ATIII: Ag level had no significant lower in some patients with acute promyelocytic leukemia (APL) complicated by DIC, which suggested the coagulopathy in APL might be due to mechanisms different from other forms of DIC such as infectious disease (e.g., septic shock) [12,62,66]. Many authors [67] described that a procoagulant activity was in term of ‘cancer coagulative factor’, ‘cancer cell procoagulant activities’, ‘leukemic cell mediated procoagulant activities’ [66], ‘cancer procoagulant A(CPA)’ which was presented in malignant cells. The most prevalences are that low PC and ATIII levels were detected both in clinical infectious and experimental DIC, and the term ‘consumption coagulopathy’ characterized this PC and ATIII decrease [68]. Thus, the PC and ATIII assays are helpful to monitoring the disease progress and act as an important biomarker or predictable marker..

References

• Stenflo J (1976) A new vitamin K-dependent protein. Purification from bovine plasma and preliminary characterization. J Biol Chem 251(2): 355-363.
• Foster DC, Yoshitake S, Davie EW (1985) The nucleotide sequence of the gene for human protein C. Proc Natl Acad Sci USA 82(14): 4673-4677.
• Foster D, Davie EW (1984) Characterization of a cDNA coding for human protein C. Proc Natl Acad Sci 81(15): 4766-4770
• Bertina RM, Reinalda Poot J, Van Wijngaarden A (1985) Determination of plasma protein S-the protein co-factor of activated protein C. Thromb Haemost 53(2): 268-272.
• Suzuki K, Nishioka J, Hashimoto S (1983) Regulation of acitivated protein C by thrombin-modified protein S. J Biochem 94(3): 699-705.
• Lawrence JE, Batard MA, Berridge CW (1985) Protein S enhances the inactivation of factor VIII by activated protein C. Thromb Haemost 54: 83.
• Abboud Jarrous G, Burstyn Cohen T, Shivam Priya, Avi Maimon, Stuart Fischman, et al. (2017) Protein S drives oral squamous cell carcinoma tumorigenicity through regulation of Axl. Oncotarget 8(8): 13986-14002.
• Lee N, Jang WJ, Seo JH, ChulHo Jeong (2019) 2-Deoxy-D-glucose-induced metabolic alteration in human oral sequamous SCC15 cells: involvement of N-glycosylation of Axl and Met. Metabolites 9(9): 188.
• Song XZ, Akasaka H, Wang HM, Hua Wang, Anirban Maitra, et al. (2020) Hematopoietic progenitor kinase 1 down-regulates the oncogenic receptor tyrosine kinase Axl in pancreatic cancer. J Biol Chem 295(8): 2348-2358.
• Nuzzo S, Catuogno S, Capuozzo M, Alfonso Fiorelli, Carla Lucia Esposito, et al. (2019) Axl-targeted delivery of the oncosuppressor miR-137 in non-small-cell lung cancer. Mol Ther Nucleic Acids 17: 256-263.
• Wimmel A, Rohner I, M Schuermann, Ramaswamy A, R Seitz, et al. (1999) Synthesis and secretion of the anticoagulant protein S and coexpression of the Tyro3 in human lung carcinoma cells. Cancer 86(1): 43-9.
• Zhu G, Broekmans AW, Bertina RM (2020) Clinical application of plasma protein C determination. Univ J Pharm Res 5(6): 29-35.
• Utermark T, Rao T, Jean J Zhao, William J Muller, Cheng H, et al. (2012) The p110α and p110β isoforms of PI3K play divergent roles in mammary gland development and tumorigenesis. Genes Dev 26(14): 1573-1586.
• Green S, Chambon P (1986) Carcinogenesis: A superfamily of potentially oncogenic hormone receptors. Nature 324(6098): 615-617.
• Chin HMS, Nandra K, Clark J, Draviam VM (2014) Need for multi-scale systems to identify spindle orientation regulators relevant to tissue disorganization in solid cancers. Front Physiol 5: 278.
• Singh RR, Kumar R (2005) Steroid hormone receptor signalling in tumorigenesis. J Cell Biochem 96(3): 490-505.
• Elangovan S, Ramachandran S, Venkatesan N, Sudha Ananth, Muthusamy Thangaraju, et al. (2011) SIRT1 is essential for oncogenic signaling by estrogen/estrogen receptor α in breast cancer. Cancer Res 71(21): 6654-6664.
• Zinger L, Merenbakh Lamin K, Klein A, Adi Elazar, Shani Journo, et al. (2019) Ligand-binding domain-activating mutations of ESR1 rewire cellular metabolism of breast cancer cells. Clin Cancer Res 25(9): 2900-2914.
• Ludwik KA, McDonald OG, Brenin DR, Deborah A Lannigan (2018) ERα-mediated nuclear sequestration of RSK2 is required for ER+ breast cancer tumorigenesis. Cancer Res 78(8): 2014-2025.
• Veeraraghavan J, Tan Y, Kim JA, Alejandro Contreras, Xiao Song Wang, et al. (2014) Recurrent ESR1-CCDC170 rearrangements in an aggressive subset of oestrogen receptor-positive breast cancers. Nat Commun 7(5): 4577.
• Tilli MT, Frech MS, Steed ME, Kathleen S Hruska, Michael D Johnson, et al. (2003) Introduction of ERα into the tTA/TAg conditional mouse model precipitates the development of estrogen-responsive mammary adenocarcinoma. Am J Pathol 163(5): 17130-1719.
• Davis VL, Retha R Newbold, John F Couse, Sheri L Rea, Kenneth S Korach, et al. (2012) Expression of a dominant negative estrogen receptor alpha variant in transgenic mice accelerates uterine cancer induced by the potent estrogen diethylstilbestrol. Reprod Toxicol 34(4): 512-521.
• Yue W, Yager JD, Santen R, Ji Ping Wang, Richard J Santen, et al. (2013) Estrogen receptor-dependent and independent mechanisms of breast cancer carcinogenesis. Steroids 78(2): 161-170.
• Zhu G (2018) EpCAM, an old cancer antigen turned oncogenic receptor and its targeting immunotherapy. Univ J Pharma Res 3(2): 41-46.
• Marx C, Yau C, Banwalt S, Yamei Zhou, Gary K Scott, et al. (2007) Proteasome-regulated ERBB2 and estrogen receptor pathways in breast cancer. Mol Pharmacol 71(6): 1525-1534.
• Zhu G (2017) Targeting oncogenic receptor: From molecular physiology to currently the standard of target therapy. Adv Pharm J 2(1): 10-28.
• Hickey TE, Dwyer AR, Tilley WD (2021) Arming androgen receptors to oppose oncogenic estrogen receptor activity in breast cancer. Br J Cancer 125(12): 1599-1601.
• De Bacco F, Fassetta M, Rasola A (2004) Receptor tyrosine kinases as targets for cancer therapy. Cancer Therapy 2: 317-328.
• Moody P, Sayers EJ, Magnusson JP, Cameron Alexander, Paola Borri, et al. (2015) Receptor crosslinking: A general method to trigger internalization and lysosomal targeting of therapeutic receptor: ligand complexes. Mol Ther 23(12): 1888-1898.
• del Mar Maldonado M, Medina JI, Velazquez L, Dharmawardhane S (2020) Targeting Rac and Cdc42 GEFs in metastatic cancer. Front Cell Dev Biol 8(8): 201.
• Duarte HO, Balmafia M, Mereiter S, Hugo Osório, Joana Gomes, et al. (2017) Gastric cancer cell glycosylation as a modulator of the ErbB2 oncogenic receptor. Int J Med Sci 18(11): 2262.
• Jenke R, Holzhauser Rein M, Mueller Wilke S, Florian Lordick, Achim Aigne, et al. (2021) SATB1-mediated upregulation of the oncogenic receptor tyrosine kinase HER3 antagonizes Met inhibition in gastric cancer cells. Int J Mol Sci 22(1): 82.
• Yang XM, Zhang XM, Fu ML, Weichselbaum RR, Gajewski TF, et al. (2014) Targeting the Tumor Micro-environment with Interferon-b Bridges Innate and Adaptive Immune Responses. Cancer Cell 25(1): 37-48.
• He H, Maruta H (2013) Oncogenicity of PAKs and their substrates. In Merlin-an overview. Emery and Rimoin’s Principles and Practice of Medical Genetics (6^th Edn). pp.266-268
• Radia AM, Yaser AM, Ma X, Juan Zhang, Cejun Yang, et al. (2013) Specific siRNA targeting receptor for advanced glycation and products (RAGE) decreases proliferation in human breast cancer cell lines. Int J Mol Sci 14(4): 7959-7978.
• Xu XC, Abuduhadeer X, Wang YH, H Gao, T Li, et al. (2013) Knockdown of RAGE inhibits growth and invasion of gastric cancer cells. Eur J Histochem 57(4): e36.
• Wang D, Li T, Ye G, Zhiyong Shen, Yanfeng Hu, et al. (2015) Overexpression of the receptor for advanced glycation end products (RAGE) is associated with poor prognosis in gastric cancer. PLoS One 10(4): e0122697.
• Zhang Q, Jin Y, Zhao CF, Liu GY (2016) Receptor for advanced glycation end-products (RAGE) is over-expressed in human osteosarcoma and promotes the proliferation of osteosarcoma U-20S cells in vitro. Genet Mol Res 15(2).
• Esposito CL, Catuogno S, Condorelli G (2018) Aptamer Chimeras for Therapeutic Delivery: The Challenging Perspectives. Genes 9(11): 529.
• Zhu G (2018) Use of traditional medicine in severe edema amelioration of refractory congestive heart failure-case report. Blood Heart Circ 2(1): 1-2.
• Teoh PJ , Chung TH , Chng P , Wee Joo Chng (2020) IL6R-STAT3-ADAR1 (P150) interplay promotes oncogenicity in multiple myeloma with 1q21 amplification. Haematologica 105(5): 1391-1404.
• Mansour MR, Reed C, Eisenberg AR, Jen Chieh Tseng, Jean Claude Twizere, et al. (2015) Targeting Oncogenic Interleukin-7 Receptor Signalling with Nacetylcysteine in T-cell acute lymphoblastic leukaemia. Br J Haematol 168(2): 230-238.
• Ernst M, Putoczki T (2014) Molecular pathways: IL11 as a tumor-promoting cytokine-translational implications for cancers. Clin Cancer Res 20(22): 5579-88.
• Merchant JL (2008) What lurks beneath: IL-11, via stat-3, promotes inflammation-associated gastric tumorigenesis. J Clin Invest 118(5): 1628-1631.
• Ernst M, Najdovska M, Grail D (2008) STAT3 and STAT1 mediate IL-11-dependent and inflammation-associated gastric tumorigenesis in gp130 receptor mutant mice. J Clin Invest 118:1727-38.
• Huang SC, Wei PC, Hwang verslues WW, Wen Hung Kuo, King Jen Chang, et al. (2017) TGF-beta1 secreted by Tregs in lymph nodes promotes breast cancer malignancy via upregulation of IL-17RB. EMBO Mol Med 9(12): 1660-1680.
• Poultsidi A, Dimopoulos Y, He TF, Triantafyllos Chavakis, Constantinos Petrovas, et al. (2018) Lymph node cellular dynamics in cancer and HIV: what can we learn for the follicular CD4(Tfh) cells?. Front Immunol 9: 2233.
• Staerk J, Defour JP, Pecquet C, Emilie Leroy, Steven O Smith, et al. (2011) Orientation-specific signalling by thrombopoietin receptor dimers. EMBO J 30(21): 4398-4413.
• Wilmes S, Hafer M, Vuorio J, Tucker JA, Winkelmann H, et al. (2020) Mechanism of homodimeric cytokine receptor activation and dysregulation by oncogenic mutations. Science 367(6478): 643-652.
• Griffin JH, Evatt B, Zimmerman TS, C Wideman, Kleiss AJ, et al. (1981) Deficiency of protein C in congenital thrombotic disease. J Clin Invest 68(5): 1370-1373.
• Bertina RM, Broekmans AW, Van der Linden IK (1982) Protein C deficiency in a Dutch family with thrombotic disease. Thromb Haemost 48(1): 1-5.
• Broekmans AW, Veltkamp JJ, Bertina RM (1983) Congenital protein C deficiency and venous thrombo-embolism. A study in three Dutch families. N Engl J Med 309(6): 340-344.
• Broekmans AW, Bertina RM, Reinalda Poot J, L Engesser, Michiels JJ, et al. (1985) Hereditary protein S deficiency and venous thrombo-embolism. A study in three Dutch families. Thromb Haemost 53: 273-277.
• Morawitz P (1905) Die Chemie der Blurgerinnung. Ergebnisse der Physiologie, biologischen Chemie und experimentellen Pharmakologie(Berlin). 4: 307-422.
• Danishefsky I, Zweben A, Slomiany BL (1978) Human antithrombin III. Carbohydrate components and associated glycolipid. J Biol Chem 253(1): 32-37.
• Abildgaard U (1969) Binding of thrombin to antithrombin III. Scand J Clin Lab Invest 24(1): 23-27.
• Rosenberg RD, Damus PS (1973) The purification and mechanism of action of human antithrombin-heparin cofactor. J Biol Chem 248(18): 6490-6505.
• Li EHH, Fenton II JW, Feinman RD (1976) The role of heparin in the thrombin-antithrombin III Archives of Biochemistry and Biophysics 175:153-159.
• Machovich R, Blasko G, Palos LA (1975) Action of heparin on thrombin-antithrombin reaction. Biochim Biophys Acta 379(1): 193-200.
• Egeberg O (1965) Inherited antithrombin deficiency causing thrombophilia. Thromb Diath Haemorrh 13: 516-530.
• Abildgaard U, Gravem K, Godal HC (1970) Assay of progressive antithrombin in plasma. Thrombosis et Diathesis Haemorrhagica (Stuttgart). 24: 224-229
• Griffin JH, Mosher DF, Zimmerman TS (1982) Protein C,an antithrombotic protein is reduced in hospitalized patients deficiencies of protein C,an inhibitor of blood coagulation. Blood 60(1): 261-264.
• Mannucci PM, S Vigano (1982) Deficiencies of protein C, an inhibitor of blood coagulation. Lancet 2(8296): 463-467.
• Mannucci L, Dioguardi N, Mannucci PM (1973) Value of Normotest and antithrombin III in the assessment of liver function. Scandinavian Journal of Gastroenterology & supplement 19: 103-107.
• Nagy I, Losonczy H, Par A (1976) Heparin induced change of antithrombin III (AT III) activity in chronic active hepatitis and liver cirrhosis. Proceedings, Symposis and Round Table Conferences of the 10^th International Congress of Gastroenterology, Budapest.
• Zhu G, Li JX (1985) Plasma concentration of the natural anti-coagulants protein C and antithrombin III in leukemia. Thromb Haemost 62: 391.
• Donati MB, Poggi A Semeraro N (1981) Coagulation and malignancy. In Poller L (ed) Recent advances in blood coagulation. pp. 227-259.
• Fourrier F, Chopin C, Goudemand J, S Hendrycx, C Caron, et al. (1992) Septic shock,multiple organ failure,and disseminated intravascular coagulation. Compared patterns of antithrombin III,protein C,and protein S deficiencies. Chest 101(3): 816-823.