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Role of Serine Proteases and Inhibitors in Cancer

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Proteases in Physiology and Pathology

Abstract

Serine proteases, the largest human protease family, are found in many key developmental and physiological processes in the biological system. Protease signalling pathways are stringently controlled, and deregulation of proteolytic activity results in the degradation of extracellular matrix which plays a major role in cancer progression. The Type II transmembrane serine protease, hepsin, matriptase-2 and TMPRSS4, and secreted serine protease, urokinase plasminogen activator (uPA), kallikreins and HtrA, are closely related to cancer-associated proteases and also involved in perturbation of uPA plasminogen system, matrix metalloproteases (MMPs), upregulation of adhesion molecules like integrin family, activation of intracellular signalling cascade, inhibition of apoptosis pathway in various types of cancers which causes cell proliferation, invasion and metastasis. Serpin, an endogenous serine protease inhibitor, regulates the homeostasis by maintaining a delicate balance with the serine protease and prevents the process of invasion and metastasis of cancer cells thus inhibiting tumour growth. This chapter focuses on the role of serine proteases and their inhibitors in different types of tumours associated with cancer prognostication and therapy.

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References

  1. Lin YC et al (1995) Activation of NF-kappa B requires proteolysis of the inhibitor I kappa B-alpha: signal-induced phosphorylation of I kappa B-alpha alone does not release active NF-kappa B. Proc Natl Acad Sci U S A 92:552–556

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Walsh PN, Ahmad SS (2002) Proteases in blood clotting. Essays Biochem 38:95–111

    Article  CAS  PubMed  Google Scholar 

  3. Borissenko L, Groll M (2007) Diversity of proteasomal missions: fine tuning of the immune response. Biol Chem 388:947–955

    Article  CAS  PubMed  Google Scholar 

  4. Roth S (2003) The origin of dorsoventral polarity in drosophila. Philos Trans R Soc Lond Ser B Biol Sci 358:1317–1329. discussion 1329

    Article  CAS  Google Scholar 

  5. Bastians H et al (1999) Cell cycle-regulated proteolysis of mitotic target proteins. Mol Biol Cell 10:3927–3941

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Turk B, Stoka V (2007) Protease signalling in cell death: caspases versus cysteine cathepsins. FEBS Lett 581:2761–2767

    Article  CAS  PubMed  Google Scholar 

  7. Rawlings ND et al (2008) MEROPS: the peptidase database. Nucleic Acids Res 36:D320–D325

    Article  CAS  PubMed  Google Scholar 

  8. Di Cera E (2009) Serine proteases. IUBMB Life 61:510–515

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Hedstrom L (2002) Serine protease mechanism and specificity. Chem Rev 102:4501–4524

    Article  CAS  PubMed  Google Scholar 

  10. Fastrez J, Fersht AR (1973) Demonstration of the acyl-enzyme mechanism for the hydrolysis of peptides and anilides by chymotrypsin. Biochemistry 12:2025–2034

    Article  CAS  PubMed  Google Scholar 

  11. Puente XS et al (2005) A genomic view of the complexity of mammalian proteolytic systems. Biochem Soc Trans 33:331–334

    Article  CAS  PubMed  Google Scholar 

  12. Stroud RM (1974) A family of protein-cutting proteins. Sci Am 231:74–88

    Article  CAS  PubMed  Google Scholar 

  13. Hooper JD et al (2001) Type II transmembrane serine proteases. Insights into an emerging class of cell surface proteolytic enzymes J Biol Chem 276:857–860

    CAS  PubMed  Google Scholar 

  14. Netzel-Arnett S et al (2003) Membrane anchored serine proteases: a rapidly expanding group of cell surface proteolytic enzymes with potential roles in cancer. Cancer Metastasis Rev 22:237–258

    Article  CAS  PubMed  Google Scholar 

  15. Chen LM et al (2001) Prostasin is a glycosylphosphatidylinositol-anchored active serine protease. J Biol Chem 276:21434–21442

    Article  CAS  PubMed  Google Scholar 

  16. Verghese GM et al (2006) Prostasin regulates epithelial monolayer function: cell-specific Gpld1-mediated secretion and functional role for GPI anchor. Am J Physiol Cell Physiol 291:C1258–C1270

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Hooper JD et al (1999) Testisin, a new human serine proteinase expressed by premeiotic testicular germ cells and lost in testicular germ cell tumors. Cancer Res 59:3199–3205

    CAS  PubMed  Google Scholar 

  18. Szabo R, Bugge TH (2008) Type II transmembrane serine proteases in development and disease. Int J Biochem Cell Biol 40:1297–1316

    Article  CAS  PubMed  Google Scholar 

  19. Lu P et al. (2011) Extracellular matrix degradation and remodeling in development and disease. Cold Spring Harb Perspect Biol 3: pii:a005058

    Google Scholar 

  20. Lopez-Otin C, Matrisian LM (2007) Emerging roles of proteases in tumour suppression. Nat Rev Cancer 7:800–808

    Article  CAS  PubMed  Google Scholar 

  21. Choi KY et al (2012) Protease-activated drug development. Theranostics 2:156–178

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Hildenbrand R et al (2008) The urokinase-system--role of cell proliferation and apoptosis. Histol Histopathol 23:227–236

    CAS  PubMed  Google Scholar 

  23. Collen D, Lijnen HR (1991) Basic and clinical aspects of fibrinolysis and thrombolysis. Blood 78:3114–3124

    CAS  PubMed  Google Scholar 

  24. Blasi F (1997) uPA, uPAR, PAI-1: key intersection of proteolytic, adhesive and chemotactic highways? Immunol Today 18:415–417

    Article  CAS  PubMed  Google Scholar 

  25. Gondi CS et al (2007) Down-regulation of uPAR and uPA activates caspase-mediated apoptosis and inhibits the PI3K/AKT pathway. Int J Oncol 31:19–27

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Andreasen PA et al (1997) The urokinase-type plasminogen activator system in cancer metastasis: a review. Int J Cancer 72:1–22

    Article  CAS  PubMed  Google Scholar 

  27. Fisher JL et al (2001) The expression of the urokinase plasminogen activator system in metastatic murine osteosarcoma: an in vivo mouse model. Clin Cancer Res 7:1654–1660

    CAS  PubMed  Google Scholar 

  28. Sidenius N, Blasi F (2003) The urokinase plasminogen activator system in cancer: recent advances and implication for prognosis and therapy. Cancer Metastasis Rev 22:205–222

    Article  CAS  PubMed  Google Scholar 

  29. Aguirre Ghiso JA et al (1999) Tumor dormancy induced by downregulation of urokinase receptor in human carcinoma involves integrin and MAPK signaling. J Cell Biol 147:89–104

    Article  CAS  PubMed  Google Scholar 

  30. Preissner KT et al (2000) Urokinase receptor: a molecular organizer in cellular communication. Curr Opin Cell Biol 12:621–628

    Article  CAS  PubMed  Google Scholar 

  31. Stillfried GE et al (2007) Plasminogen binding and activation at the breast cancer cell surface: the integral role of urokinase activity. Breast Cancer Res 9:R14

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Harbeck N et al (2002) Clinical utility of urokinase-type plasminogen activator and plasminogen activator inhibitor-1 determination in primary breast cancer tissue for individualized therapy concepts. Clin Breast Cancer 3:196–200

    Article  CAS  PubMed  Google Scholar 

  33. Oka T et al (1991) Immunohistochemical evidence of urokinase-type plasminogen activator in primary and metastatic tumors of pulmonary adenocarcinoma. Cancer Res 51:3522–3525

    CAS  PubMed  Google Scholar 

  34. Hasui Y et al (1992) The content of urokinase-type plasminogen activator antigen as a prognostic factor in urinary bladder cancer. Int J Cancer 50:871–873

    Article  CAS  PubMed  Google Scholar 

  35. Nekarda H et al (1994) Tumour-associated proteolytic factors uPA and PAI-1 and survival in totally resected gastric cancer. Lancet 343:117

    Article  CAS  PubMed  Google Scholar 

  36. Han Q et al (2002) Rac1-MKK3-p38-MAPKAPK2 pathway promotes urokinase plasminogen activator mRNA stability in invasive breast cancer cells. J Biol Chem 277:48379–48385

    Article  CAS  PubMed  Google Scholar 

  37. Borgono CA et al (2004) Human tissue kallikreins: physiologic roles and applications in cancer. Mol Cancer Res 2:257–280

    CAS  PubMed  Google Scholar 

  38. Borgono CA, Diamandis EP (2004) The emerging roles of human tissue kallikreins in cancer. Nat Rev Cancer 4:876–890

    Article  CAS  PubMed  Google Scholar 

  39. Schmitt M et al (2013) Emerging clinical importance of the cancer biomarkers kallikrein-related peptidases (KLK) in female and male reproductive organ malignancies. Radiol Oncol 47:319–329

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Milkiewicz M et al (2006) Regulators of angiogenesis and strategies for their therapeutic manipulation. Int J Biochem Cell Biol 38:333–357

    Article  CAS  PubMed  Google Scholar 

  41. Desrivieres S et al (1993) Activation of the 92 kDa type IV collagenase by tissue kallikrein. J Cell Physiol 157:587–593

    Article  CAS  PubMed  Google Scholar 

  42. Menashi S et al (1994) Regulation of 92-kDa gelatinase B activity in the extracellular matrix by tissue kallikrein. Ann N Y Acad Sci 732:466–468

    Article  CAS  PubMed  Google Scholar 

  43. Saunders WB et al (2005) MMP-1 activation by serine proteases and MMP-10 induces human capillary tubular network collapse and regression in 3D collagen matrices. J Cell Sci 118:2325–2340

    Article  CAS  PubMed  Google Scholar 

  44. Takayama TK et al (2001) Characterization of hK4 (prostase), a prostate-specific serine protease: activation of the precursor of prostate specific antigen (pro-PSA) and single-chain urokinase-type plasminogen activator and degradation of prostatic acid phosphatase. Biochemistry 40:15341–15348

    Article  CAS  PubMed  Google Scholar 

  45. Giusti B et al (2005) The antiangiogenic tissue kallikrein pattern of endothelial cells in systemic sclerosis. Arthritis Rheum 52:3618–3628

    Article  CAS  PubMed  Google Scholar 

  46. Frenette G et al (1997) Prostatic kallikrein hK2, but not prostate-specific antigen (hK3), activates single-chain urokinase-type plasminogen activator. Int J Cancer 71:897–899

    Article  CAS  PubMed  Google Scholar 

  47. Colman RW (2006) Regulation of angiogenesis by the kallikrein-kinin system. Curr Pharm Des 12:2599–2607

    Article  CAS  PubMed  Google Scholar 

  48. Emanueli C, Madeddu P (2001) Targeting kinin receptors for the treatment of tissue ischaemia. Trends Pharmacol Sci 22:478–484

    Article  CAS  PubMed  Google Scholar 

  49. Watt KW et al (1986) Human prostate-specific antigen: structural and functional similarity with serine proteases. Proc Natl Acad Sci U S A 83:3166–3170

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Peter A et al (1998) Semenogelin I and semenogelin II, the major gel-forming proteins in human semen, are substrates for transglutaminase. Eur J Biochem 252:216–221

    Article  CAS  PubMed  Google Scholar 

  51. Christensson A et al (1990) Enzymatic activity of prostate-specific antigen and its reactions with extracellular serine proteinase inhibitors. Eur J Biochem 194:755–763

    Article  CAS  PubMed  Google Scholar 

  52. Christensson A, Lilja H (1994) Complex formation between protein C inhibitor and prostate-specific antigen in vitro and in human semen. Eur J Biochem 220:45–53

    Article  CAS  PubMed  Google Scholar 

  53. Mackay AR et al (1990) Basement membrane type IV collagen degradation: evidence for the involvement of a proteolytic cascade independent of metalloproteinases. Cancer Res 50:5997–6001

    CAS  PubMed  Google Scholar 

  54. Webber MM, Waghray A (1995) Urokinase-mediated extracellular matrix degradation by human prostatic carcinoma cells and its inhibition by retinoic acid. Clin Cancer Res 1:755–761

    CAS  PubMed  Google Scholar 

  55. Lipinska B et al (1990) The HtrA (DegP) protein, essential for Escherichia coli survival at high temperatures, is an endopeptidase. J Bacteriol 172:1791–1797

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Spiess C et al (1999) A temperature-dependent switch from chaperone to protease in a widely conserved heat shock protein. Cell 97:339–347

    Article  CAS  PubMed  Google Scholar 

  57. Clausen T et al (2002) The HtrA family of proteases: implications for protein composition and cell fate. Mol Cell 10:443–455

    Article  CAS  PubMed  Google Scholar 

  58. Hu SI et al (1998) Human HtrA, an evolutionarily conserved serine protease identified as a differentially expressed gene product in osteoarthritic cartilage. J Biol Chem 273:34406–34412

    Article  CAS  PubMed  Google Scholar 

  59. Gray CW et al (2000) Characterization of human HtrA2, a novel serine protease involved in the mammalian cellular stress response. Eur J Biochem 267:5699–5710

    Article  CAS  PubMed  Google Scholar 

  60. Nie G et al (2006) Serine peptidase HTRA3 is closely associated with human placental development and is elevated in pregnancy serum. Biol Reprod 74:366–374

    Article  CAS  PubMed  Google Scholar 

  61. Inagaki A et al (2012) Upregulation of HtrA4 in the placentas of patients with severe pre-eclampsia. Placenta 33:919–926

    Article  CAS  PubMed  Google Scholar 

  62. Zurawa-Janicka D et al (2013) Temperature-induced changes of HtrA2(Omi) protease activity and structure. Cell Stress Chaperones 18:35–51

    Article  CAS  PubMed  Google Scholar 

  63. Canfield AE et al (2007) HtrA1: a novel regulator of physiological and pathological matrix mineralization? Biochem Soc Trans 35:669–671

    Article  CAS  PubMed  Google Scholar 

  64. Zumbrunn J, Trueb B (1996) Primary structure of a putative serine protease specific for IGF-binding proteins. FEBS Lett 398:187–192

    Article  CAS  PubMed  Google Scholar 

  65. Baldi A et al (2002) The HtrA1 serine protease is down-regulated during human melanoma progression and represses growth of metastatic melanoma cells. Oncogene 21:6684–6688

    Article  CAS  PubMed  Google Scholar 

  66. Kotliarov Y et al (2006) High-resolution global genomic survey of 178 gliomas reveals novel regions of copy number alteration and allelic imbalances. Cancer Res 66:9428–9436

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Chien J et al (2004) A candidate tumor suppressor HtrA1 is downregulated in ovarian cancer. Oncogene 23:1636–1644

    Article  CAS  PubMed  Google Scholar 

  68. Narkiewicz J et al (2009) Expression of human HtrA1, HtrA2, HtrA3 and TGF-beta1 genes in primary endometrial cancer. Oncol Rep 21:1529–1537

    CAS  PubMed  Google Scholar 

  69. Bowden MA et al (2006) Serine proteases HTRA1 and HTRA3 are down-regulated with increasing grades of human endometrial cancer. Gynecol Oncol 103:253–260

    Article  CAS  PubMed  Google Scholar 

  70. Esposito V et al (2006) Analysis of HtrA1 serine protease expression in human lung cancer. Anticancer Res 26:3455–3459

    CAS  PubMed  Google Scholar 

  71. Chien J et al (2006) Serine protease HtrA1 modulates chemotherapy-induced cytotoxicity. J Clin Invest 116:1994–2004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Oka C et al (2004) HtrA1 serine protease inhibits signaling mediated by Tgfbeta family proteins. Development 131:1041–1053

    Article  CAS  PubMed  Google Scholar 

  73. Fesik SW (2005) Promoting apoptosis as a strategy for cancer drug discovery. Nat Rev Cancer 5:876–885

    Article  CAS  PubMed  Google Scholar 

  74. Verhagen AM et al (2002) HtrA2 promotes cell death through its serine protease activity and its ability to antagonize inhibitor of apoptosis proteins. J Biol Chem 277:445–454

    Article  CAS  PubMed  Google Scholar 

  75. Suzuki Y et al (2001) A serine protease, HtrA2, is released from the mitochondria and interacts with XIAP, inducing cell death. Mol Cell 8:613–621

    Article  CAS  PubMed  Google Scholar 

  76. Antalis TM et al (2010) The cutting edge: membrane-anchored serine protease activities in the pericellular microenvironment. Biochem J 428:325–346

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Carter BS et al (1990) Epidemiologic evidence regarding predisposing factors to prostate cancer. Prostate 16:187–197

    Article  CAS  PubMed  Google Scholar 

  78. Moran P et al (2006) Pro-urokinase-type plasminogen activator is a substrate for hepsin. J Biol Chem 281:30439–30446

    Article  CAS  PubMed  Google Scholar 

  79. Kirchhofer D et al (2005) Hepsin activates pro-hepatocyte growth factor and is inhibited by hepatocyte growth factor activator inhibitor-1B (HAI-1B) and HAI-2. FEBS Lett 579:1945–1950

    Article  CAS  PubMed  Google Scholar 

  80. Kazama Y et al (1995) Hepsin, a putative membrane-associated serine protease, activates human factor VII and initiates a pathway of blood coagulation on the cell surface leading to thrombin formation. J Biol Chem 270:66–72

    Article  CAS  PubMed  Google Scholar 

  81. Chen Z et al (2003) Hepsin and maspin are inversely expressed in laser capture microdissectioned prostate cancer. J Urol 169:1316–1319

    Article  CAS  PubMed  Google Scholar 

  82. Magee JA et al (2001) Expression profiling reveals hepsin overexpression in prostate cancer. Cancer Res 61:5692–5696

    CAS  PubMed  Google Scholar 

  83. Tanimoto H et al (1997) Hepsin, a cell surface serine protease identified in hepatoma cells, is overexpressed in ovarian cancer. Cancer Res 57:2884–2887

    CAS  PubMed  Google Scholar 

  84. Lin B et al (1999) Prostate-localized and androgen-regulated expression of the membrane-bound serine protease TMPRSS2. Cancer Res 59:4180–4184

    CAS  PubMed  Google Scholar 

  85. Thiery JP, Sleeman JP (2006) Complex networks orchestrate epithelial-mesenchymal transitions. Nat Rev Mol Cell Biol 7:131–142

    Article  CAS  PubMed  Google Scholar 

  86. Peinado H et al (2007) Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype? Nat Rev Cancer 7:415–428

    Article  CAS  PubMed  Google Scholar 

  87. Kim S et al (2010) TMPRSS4 induces invasion and epithelial-mesenchymal transition through upregulation of integrin alpha5 and its signaling pathways. Carcinogenesis 31:597–606

    Article  CAS  PubMed  Google Scholar 

  88. Jung H et al (2008) TMPRSS4 promotes invasion, migration and metastasis of human tumor cells by facilitating an epithelial-mesenchymal transition. Oncogene 27:2635–2647

    Article  CAS  PubMed  Google Scholar 

  89. Cheng H et al (2009) Hepatocyte growth factor activator inhibitor type 1 regulates epithelial to mesenchymal transition through membrane-bound serine proteinases. Cancer Res 69:1828–1835

    Article  CAS  PubMed  Google Scholar 

  90. Min HJ et al (2014) TMPRSS4 upregulates uPA gene expression through JNK signaling activation to induce cancer cell invasion. Cell Signal 26:398–408

    Article  CAS  PubMed  Google Scholar 

  91. Wang CH et al (2015) TMPRSS4 facilitates epithelial-mesenchymal transition of hepatocellular carcinoma and is a predictive marker for poor prognosis of patients after curative resection. Sci Rep 5:12366

    Article  PubMed  PubMed Central  Google Scholar 

  92. Min HJ et al (2014) TMPRSS4 induces cancer cell invasion through pro-uPA processing. Biochem Biophys Res Commun 446:1–7

    Article  CAS  PubMed  Google Scholar 

  93. Ramsay AJ et al (2008) The type II transmembrane serine protease matriptase-2--identification, structural features, enzymology, expression pattern and potential roles. Front Biosci 13:569–579

    Article  CAS  PubMed  Google Scholar 

  94. Velasco G et al (2002) Matriptase-2, a membrane-bound mosaic serine proteinase predominantly expressed in human liver and showing degrading activity against extracellular matrix proteins. J Biol Chem 277:37637–37646

    Article  CAS  PubMed  Google Scholar 

  95. Webb SL et al (2012) The influence of matriptase-2 on prostate cancer in vitro: a possible role for beta-catenin. Oncol Rep 28:1491–1497

    Article  CAS  PubMed  Google Scholar 

  96. Shi YE et al (1993) Identification and characterization of a novel matrix-degrading protease from hormone-dependent human breast cancer cells. Cancer Res 53:1409–1415

    CAS  PubMed  Google Scholar 

  97. Ramsay AJ et al (2009) Matriptase-2 (TMPRSS6): a proteolytic regulator of iron homeostasis. Haematologica 94:840–849

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Ramsay AJ et al (2009) Matriptase-2 mutations in iron-refractory iron deficiency anemia patients provide new insights into protease activation mechanisms. Hum Mol Genet 18:3673–3683

    Article  CAS  PubMed  Google Scholar 

  99. Sanders AJ et al (2010) The type II transmembrane serine protease, matriptase-2: possible links to cancer? Anti Cancer Agents Med Chem 10:64–69

    Article  CAS  Google Scholar 

  100. Oberst M et al (2001) Matriptase and HAI-1 are expressed by normal and malignant epithelial cells in vitro and in vivo. Am J Pathol 158:1301–1311

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Riddick AC et al (2005) Identification of degradome components associated with prostate cancer progression by expression analysis of human prostatic tissues. Br J Cancer 92:2171–2180

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Tannock IF, Rotin D (1989) Acid pH in tumors and its potential for therapeutic exploitation. Cancer Res 49:4373–4384

    CAS  PubMed  Google Scholar 

  103. McQueney MS et al (1997) Autocatalytic activation of human cathepsin K. J Biol Chem 272:13955–13960

    Article  CAS  PubMed  Google Scholar 

  104. Richter C et al (1998) Mechanism of activation of the gastric aspartic proteinases: pepsinogen, progastricsin and prochymosin. Biochem J 335(Pt 3):481–490

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Tseng IC et al (2010) Matriptase activation, an early cellular response to acidosis. J Biol Chem 285:3261–3270

    Article  CAS  PubMed  Google Scholar 

  106. Lin CY et al (1997) Characterization of a novel, membrane-bound, 80-kDa matrix-degrading protease from human breast cancer cells. Monoclonal antibody production, isolation, and localization. J Biol Chem 272:9147–9152

    Article  CAS  PubMed  Google Scholar 

  107. Oberst MD et al (2003) The activation of matriptase requires its noncatalytic domains, serine protease domain, and its cognate inhibitor. J Biol Chem 278:26773–26779

    Article  CAS  PubMed  Google Scholar 

  108. Xu H et al (2012) Mechanisms for the control of matriptase activity in the absence of sufficient HAI-1. Am J Physiol Cell Physiol 302:C453–C462

    Article  CAS  PubMed  Google Scholar 

  109. Lee MS et al (2005) Simultaneous activation and hepatocyte growth factor activator inhibitor 1-mediated inhibition of matriptase induced at activation foci in human mammary epithelial cells. Am J Physiol Cell Physiol 288:C932–C941

    Article  CAS  PubMed  Google Scholar 

  110. Szabo R et al (2007) Matriptase inhibition by hepatocyte growth factor activator inhibitor-1 is essential for placental development. Oncogene 26:1546–1556

    Article  CAS  PubMed  Google Scholar 

  111. Kang JY et al (2003) Tissue microarray analysis of hepatocyte growth factor/met pathway components reveals a role for met, matriptase, and hepatocyte growth factor activator inhibitor 1 in the progression of node-negative breast cancer. Cancer Res 63:1101–1105

    CAS  PubMed  Google Scholar 

  112. Saleem M et al (2006) A novel biomarker for staging human prostate adenocarcinoma: overexpression of matriptase with concomitant loss of its inhibitor, hepatocyte growth factor activator inhibitor-1. Cancer Epidemiol Biomark Prev 15:217–227

    Article  CAS  Google Scholar 

  113. Bhatt AS et al (2005) Adhesion signaling by a novel mitotic substrate of src kinases. Oncogene 24:5333–5343

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Engh RA et al (1995) Divining the serpin inhibition mechanism: a suicide substrate ‘springe’? Trends Biotechnol 13:503–510

    Article  CAS  PubMed  Google Scholar 

  115. Irving JA et al (2000) Phylogeny of the serpin superfamily: implications of patterns of amino acid conservation for structure and function. Genome Res 10:1845–1864

    Article  CAS  PubMed  Google Scholar 

  116. Declerck PJ, Gils A (2013) Three decades of research on plasminogen activator inhibitor-1: a multifaceted serpin. Semin Thromb Hemost 39:356–364

    Article  CAS  PubMed  Google Scholar 

  117. Dass K et al (2008) Evolving role of uPA/uPAR system in human cancers. Cancer Treat Rev 34:122–136

    Article  CAS  PubMed  Google Scholar 

  118. Duffy MJ (2002) Urokinase plasminogen activator and its inhibitor, PAI-1, as prognostic markers in breast cancer: from pilot to level 1 evidence studies. Clin Chem 48:1194–1197

    CAS  PubMed  Google Scholar 

  119. Bajou K et al (2008) Plasminogen activator inhibitor-1 protects endothelial cells from FasL-mediated apoptosis. Cancer Cell 14:324–334

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Bajou K et al (1998) Absence of host plasminogen activator inhibitor 1 prevents cancer invasion and vascularization. Nat Med 4:923–928

    Article  CAS  PubMed  Google Scholar 

  121. Nishioka N et al (2012) Plasminogen activator inhibitor 1 RNAi suppresses gastric cancer metastasis in vivo. Cancer Sci 103:228–232

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Zou Z et al (1994) Maspin, a serpin with tumor-suppressing activity in human mammary epithelial cells. Science 263:526–529

    Article  CAS  PubMed  Google Scholar 

  123. Sheng S et al (1994) Production, purification, and characterization of recombinant maspin proteins. J Biol Chem 269:30988–30993

    CAS  PubMed  Google Scholar 

  124. Pemberton PA et al (1997) Maspin is an intracellular serpin that partitions into secretory vesicles and is present at the cell surface. J Histochem Cytochem 45:1697–1706

    Article  CAS  PubMed  Google Scholar 

  125. Bass R et al (2002) Maspin inhibits cell migration in the absence of protease inhibitory activity. J Biol Chem 277:46845–46848

    Article  CAS  PubMed  Google Scholar 

  126. McGowen R et al (2000) The surface of prostate carcinoma DU145 cells mediates the inhibition of urokinase-type plasminogen activator by maspin. Cancer Res 60:4771–4778

    CAS  PubMed  Google Scholar 

  127. Biliran H Jr, Sheng S (2001) Pleiotrophic inhibition of pericellular urokinase-type plasminogen activator system by endogenous tumor suppressive maspin. Cancer Res 61:8676–8682

    CAS  PubMed  Google Scholar 

  128. Sheng S et al (1998) Tissue-type plasminogen activator is a target of the tumor suppressor gene maspin. Proc Natl Acad Sci U S A 95:499–504

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Zhang M et al (1997) Transactivation through Ets and Ap1 transcription sites determines the expression of the tumor-suppressing gene maspin. Cell Growth Differ 8:179–186

    CAS  PubMed  Google Scholar 

  130. Domann FE et al (2000) Epigenetic silencing of maspin gene expression in human breast cancers. Int J Cancer 85:805–810

    Article  CAS  PubMed  Google Scholar 

  131. Qin L, Zhang M (2010) Maspin regulates endothelial cell adhesion and migration through an integrin signaling pathway. J Biol Chem 285:32360–32369

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Zhang M et al (2000) Maspin is an angiogenesis inhibitor. Nat Med 6:196–199

    Article  PubMed  CAS  Google Scholar 

  133. Wang MC et al (2004) Maspin expression and its clinicopathological significance in tumorigenesis and progression of gastric cancer. World J Gastroenterol 10:634–637

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Latha K et al (2005) Maspin mediates increased tumor cell apoptosis upon induction of the mitochondrial permeability transition. Mol Cell Biol 25:1737–1748

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Chen EI et al (2005) Maspin alters the carcinoma proteome. FASEB J 19:1123–1124

    CAS  PubMed  Google Scholar 

  136. Schwartz AL, Ciechanover A (1999) The ubiquitin-proteasome pathway and pathogenesis of human diseases. Annu Rev Med 50:57–74

    Article  CAS  PubMed  Google Scholar 

  137. Mercatali L et al (2006) RT-PCR determination of maspin and mammaglobin B in peripheral blood of healthy donors and breast cancer patients. Ann Oncol 17:424–428

    Article  CAS  PubMed  Google Scholar 

  138. Chim SS et al (2005) Detection of the placental epigenetic signature of the maspin gene in maternal plasma. Proc Natl Acad Sci U S A 102:14753–14758

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Shi HY et al (2003) Modeling human breast cancer metastasis in mice: maspin as a paradigm. Histol Histopathol 18:201–206

    CAS  PubMed  Google Scholar 

  140. Li Z et al (2005) Targeted expression of maspin in tumor vasculatures induces endothelial cell apoptosis. Oncogene 24:2008–2019

    Article  CAS  PubMed  Google Scholar 

  141. Ruegg MA et al (1989) Purification of axonin-1, a protein that is secreted from axons during neurogenesis. EMBO J 8:55–63

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Hastings GA et al (1997) Neuroserpin, a brain-associated inhibitor of tissue plasminogen activator is localized primarily in neurons. Implications for the regulation of motor learning and neuronal survival J Biol Chem 272:33062–33067

    CAS  PubMed  Google Scholar 

  143. Kaiserman D et al (2006) Mechanisms of serpin dysfunction in disease. Expert Rev Mol Med 8:1–19

    Article  PubMed  Google Scholar 

  144. Lloyd-Jones D et al (2009) Heart disease and stroke statistics--2009 update: a report from the American Heart Association statistics committee and stroke statistics subcommittee. Circulation 119:e21–181

    Article  PubMed  Google Scholar 

  145. Adibhatla RM, Hatcher JF (2008) Tissue plasminogen activator (tPA) and matrix metalloproteinases in the pathogenesis of stroke: therapeutic strategies. CNS Neurol Disord Drug Targets 7:243–253

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Lebeurrier N et al (2005) The brain-specific tissue-type plasminogen activator inhibitor, neuroserpin, protects neurons against excitotoxicity both in vitro and in vivo. Mol Cell Neurosci 30:552–558

    Article  CAS  PubMed  Google Scholar 

  147. Yepes M et al (2002) Regulation of seizure spreading by neuroserpin and tissue-type plasminogen activator is plasminogen-independent. J Clin Invest 109:1571–1578

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Chang WS et al (2000) Tissue-specific cancer-related serpin gene cluster at human chromosome band 3q26. Genes Chromosomes Cancer 29:240–255

    Article  CAS  PubMed  Google Scholar 

  149. Steele FR et al (1993) Pigment epithelium-derived factor: neurotrophic activity and identification as a member of the serine protease inhibitor gene family. Proc Natl Acad Sci U S A 90:1526–1530

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. He X et al (2015) PEDF and its roles in physiological and pathological conditions: implication in diabetic and hypoxia-induced angiogenic diseases. Clin Sci (Lond) 128:805–823

    Article  Google Scholar 

  151. Ide H et al (2015) Circulating pigment epithelium-derived factor (PEDF) is associated with pathological grade of prostate cancer. Anticancer Res 35:1703–1708

    CAS  PubMed  Google Scholar 

  152. Seruga B et al (2011) Drug resistance in metastatic castration-resistant prostate cancer. Nat Rev Clin Oncol 8:12–23

    Article  CAS  PubMed  Google Scholar 

  153. Dawson DW et al (1999) Pigment epithelium-derived factor: a potent inhibitor of angiogenesis. Science 285:245–248

    Article  CAS  PubMed  Google Scholar 

  154. Johnston EK et al (2015) Recombinant pigment epithelium-derived factor PEDF binds vascular endothelial growth factor receptors 1 and 2. In Vitro Cell Dev Biol Anim 51:730–738

    Article  CAS  PubMed  Google Scholar 

  155. Belkacemi L, Zhang SX (2016) Anti-tumor effects of pigment epithelium-derived factor (PEDF): implication for cancer therapy. A mini-review. J Exp Clin Cancer Res 35:4

    Google Scholar 

  156. Guan M et al (2007) Adenovirus-mediated PEDF expression inhibits prostate cancer cell growth and results in augmented expression of PAI-2. Cancer Biol Ther 6:419–425

    Article  CAS  PubMed  Google Scholar 

  157. Crawford SE et al (2001) Pigment epithelium-derived factor (PEDF) in neuroblastoma: a multifunctional mediator of Schwann cell antitumor activity. J Cell Sci 114:4421–4428

    CAS  PubMed  Google Scholar 

  158. Filleur S et al (2005) Two functional epitopes of pigment epithelial-derived factor block angiogenesis and induce differentiation in prostate cancer. Cancer Res 65:5144–5152

    Article  CAS  PubMed  Google Scholar 

  159. Abramson LP et al (2003) Wilms’ tumor growth is suppressed by antiangiogenic pigment epithelium-derived factor in a xenograft model. J Pediatr Surg 38:336–342

    Article  PubMed  Google Scholar 

  160. Mishur RJ et al (2008) Synthesis, X-ray crystallographic, and NMR characterizations of platinum(II) and platinum(IV) pyrophosphato complexes. Inorg Chem 47:7972–7982

    Article  CAS  PubMed  Google Scholar 

  161. Kazal LA et al (1948) Isolation of a crystalline trypsin inhibitor-anticoagulant protein from pancreas. J Am Chem Soc 70:3034–3040

    Article  CAS  PubMed  Google Scholar 

  162. Stenman UH et al (1982) Immunochemical demonstration of an ovarian cancer-associated urinary peptide. Int J Cancer 30:53–57

    Article  CAS  PubMed  Google Scholar 

  163. Kuwata K et al (2002) Functional analysis of recombinant pancreatic secretory trypsin inhibitor protein with amino-acid substitution. J Gastroenterol 37:928–934

    Article  CAS  PubMed  Google Scholar 

  164. Hirota M et al (2006) Genetic background of pancreatitis. Postgrad Med J 82:775–778

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Gaber A et al (2009) High expression of tumour-associated trypsin inhibitor correlates with liver metastasis and poor prognosis in colorectal cancer. Br J Cancer 100:1540–1548

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Soon WW et al (2011) Combined genomic and phenotype screening reveals secretory factor SPINK1 as an invasion and survival factor associated with patient prognosis in breast cancer. EMBO Mol Med 3:451–464

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Ateeq B et al. (2011) Therapeutic targeting of SPINK1-positive prostate cancer. Sci Transl Med 3: 72ra17

    Google Scholar 

  168. McKeehan WL et al (1986) Two apparent human endothelial cell growth factors from human hepatoma cells are tumor-associated proteinase inhibitors. J Biol Chem 261:5378–5383

    CAS  PubMed  Google Scholar 

  169. Ozaki N et al (2009) Serine protease inhibitor Kazal type 1 promotes proliferation of pancreatic cancer cells through the epidermal growth factor receptor. Mol Cancer Res 7:1572–1581

    Article  CAS  PubMed  Google Scholar 

  170. Stenman UH (2011) SPINK1: a new therapeutic target in cancer? Clin Chem 57:1474–1475

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Biotechnology, Invertis University, Bareilly, -243123, Uttar Pradesh, India

    Nitesh Kumar Poddar, Sanjeev Kumar Maurya & Vanshika Saxena

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  1. Nitesh Kumar Poddar
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  2. Sanjeev Kumar Maurya
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  3. Vanshika Saxena
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Correspondence to Nitesh Kumar Poddar .

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  1. Department of Biochemistry and Biophysics, University of Kalyani, Kalyani, West Bengal, India

    Sajal Chakraborti

  2. St. Boniface Hospital Research Centre, University of Manitoba, Faculty of Health Sciences, College of Medicine, Institute of Cardiovascular Sciences, Manitoba, Winnipeg, Canada

    Naranjan S. Dhalla

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Poddar, N.K., Maurya, S.K., Saxena, V. (2017). Role of Serine Proteases and Inhibitors in Cancer. In: Chakraborti, S., Dhalla, N. (eds) Proteases in Physiology and Pathology. Springer, Singapore. https://doi.org/10.1007/978-981-10-2513-6_12

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