Advertisement

Proteases and Their Role in Drug Development with an Emphasis in Cancer

Chapter
Part of the Advances in Biochemistry in Health and Disease book series (ABHD, volume 8)

Abstract

Proteases play a fundamental role in multiple biological and pathological conditions including cancer. They contribute to cancer development and promotion by regulating the activities of growth factors/cytokines and signalling receptors, as well as the composition of the extracellular matrix, thereby suppressing cell death pathways and activating cell survival pathways. With strong evidence of protease involvement in cancer, proteases serve an important role in anticancer drug development. In this review we will first introduce key proteases along with their function in tumorigenesis. Finally we will discuss the key proteases as viable therapeutic targets for anticancer drug development. Further elucidation of the role of proteases in cancer will allow us to design more effective inhibitors and novel protease-based drugs for clinical use.

Keywords

Caspases Cysteine cathepsins Urokinase-type plasminogen activator Kallikreins Matrix metalloproteinases A disintegrin and metalloproteinases A disintegrin and metalloproteinase with thrombospondin motifs Protease-activated prodrugs 

References

  1. 1.
    Lopez-Otin C, Matrisian LM (2007) Emerging roles of proteases in tumour suppression. Nat Rev Cancer. 7(10): 800-808PubMedCrossRefGoogle Scholar
  2. 2.
    Lopez-Otin C, Overall CM (2002) Protease degradomics: a new challenge for proteomics. Nat Rev. Mol. Cell Biol. 3(7): 509-519PubMedCrossRefGoogle Scholar
  3. 3.
    Turk B (2006) Targeting proteases: successes, failures and future prospects. Nature Rev. Drug Discov. 5(9): 785-799CrossRefGoogle Scholar
  4. 4.
    Fisher A (1946) Mechanism of proteolytic activity of malignant tissue cells. Nature. 157: 442CrossRefGoogle Scholar
  5. 5.
    Mohamed MM, Sloane BF (2006) Cysteine cathepsins: multifunctional enzymes in cancer. Nat Rev Cancer. 6(10): 764-775PubMedCrossRefGoogle Scholar
  6. 6.
    Teitz T, Wei T, Valentine MB et al (2000) Caspase 8 is deleted or silenced preferentially in childhood neuroblastomas with amplification of MYCN. Nature Med. 6(5): 529-535PubMedCrossRefGoogle Scholar
  7. 7.
    Marino G, Uría JA, Puente XS et al (2003) Human autophagins, a family of cysteine proteases potentially implicated in cell degradation by autophagy. J. Biol. Chem. 278(6): 3671-3678PubMedCrossRefGoogle Scholar
  8. 8.
    Hoeller D, Hecker CM, Dikic I (2006) Ubiquitin and ubiquitin-like proteins in cancer pathogenesis. Nature Rev. Cancer. 6(10): 776-788CrossRefGoogle Scholar
  9. 9.
    Egeblad M, Werb Z (2002) New functions for matrix metalloproteinases in cancer progression. Nature Rev. Cancer. 2(3): 161-174CrossRefGoogle Scholar
  10. 10.
    Koblinskia JE, Ahrama M, Sloane BF (2000) Unraveling the role of proteases in cancer. Clinica Chimica Acta. 291(2): 113-135CrossRefGoogle Scholar
  11. 11.
    Lippens S, Kockx M, Knaapen M et al (2000) Epidermal differentiation does not involve the pro-apoptotic executioner caspases, but is associated with caspase-14 induction and processing. Cell Death and Differentiation. 7(12): 1218–1224PubMedCrossRefGoogle Scholar
  12. 12.
    Eckhart L, Ballaun C, Uthman A et al (2005) Identification and characterization of a novel mammalian caspase with proapoptotic activity. J Biol Chem. 280(42): 35077-80PubMedCrossRefGoogle Scholar
  13. 13.
    Sakata S, Yan Y, Satou Y et al (2007) Conserved function of caspase-8 in apoptosis during bony fish evolution. Gene. 396(1): 134-48PubMedCrossRefGoogle Scholar
  14. 14.
    Eckhart L, Ballaun C, Hermann M et al (2008) Identification of novel mammalian caspases reveals an important role of gene loss in shaping the human caspase repertoire. Mol Biol Evol. 25(5): 831-41PubMedCrossRefGoogle Scholar
  15. 15.
    Masumoto J, Zhou W, Chen FF et al (2003) Caspy, a zebrafish caspase, activated by ASC oligomerization is required for pharyngeal arch development. J Biol Chem. 278(6): 4268-76PubMedCrossRefGoogle Scholar
  16. 16.
    Sakamaki K, Nozaki M, Kominami K et al (2007) The evolutionary conservation of the core components necessary for the extrinsic apoptotic signaling pathway, in Medaka fish. BMC Genomics. 8: 141PubMedCrossRefGoogle Scholar
  17. 17.
    Shaham S (1998) Identification of multiple Caenorhabditis elegans caspases and their potential roles in proteolytic cascades. J Biol Chem. 273(52): 35109-17PubMedCrossRefGoogle Scholar
  18. 18.
    Cikala M, Wilm B, Hobmayer E et al (1999) Identification of caspases and apoptosis in the simple metazoan Hydra. Curr Biol. 9:959-62PubMedCrossRefGoogle Scholar
  19. 19.
    Lamkanfi M, Declercq W, Kalai M et al (2002) Alice in caspase land. A phylogenetic analysis of caspases from worm to man. Cell Death Differ. 9(17): 358-61PubMedCrossRefGoogle Scholar
  20. 20.
    Terajima D, Shida K, Takada N et al (2003) Identification of candidate genes encoding the core components of the cell death machinery in the Ciona intestinalis genome. Cell Death Differ. 10(6): 749-53PubMedCrossRefGoogle Scholar
  21. 21.
    Wiens M, Krasko A, Perovic S et al (2003) Caspase-mediated apoptosis in sponges: cloning and function of the phylogenetic oldest apoptotic proteases from Metazoa. Biochim Biophys Acta. 1593(2-3): 179-89PubMedCrossRefGoogle Scholar
  22. 22.
    Weill M, Philips A, Chourrout D et al (2005) The caspase family in urochordates: distinct evolutionary fates in ascidians and larvaceans. Biol Cell. 97(11): 857-66PubMedCrossRefGoogle Scholar
  23. 23.
    Dunn SR, Phillips WS, Spatafora JW et al (2006) Highly conserved caspase and Bcl-2 homologues from the sea anemone Aiptasia pallida: lower metazoans as models for the study of apoptosis evolution. J Mol Evol. 63(1): 95-107PubMedCrossRefGoogle Scholar
  24. 24.
    Robertson AJ, Croce J, Carbonneau S et al (2006) The genomic underpinnings of apoptosis in Strongylocentrotus purpuratus. Dev Biol. 300(1): 321-34PubMedCrossRefGoogle Scholar
  25. 25.
    Kumar S (2007) Caspase function in programmed cell death. Cell Death Differ. 14(1): 32-43PubMedCrossRefGoogle Scholar
  26. 26.
    Olsson M and Zhivotovsky B (2011) Caspases and cancer. Cell Death Differ. 18(9): 1441-1449PubMedCrossRefGoogle Scholar
  27. 27.
    Stupack DG, Teitz T, Potter MD et al (2006) Potentiation of neuroblastoma metastasis by loss of caspase-8. Nature. 439(7072): 95-99PubMedCrossRefGoogle Scholar
  28. 28.
    Mandruzzato S, Brasseur F, Andry G et al (1997) CASP-8 mutation recognized by cytosolic T lymphocytes on a human head and neck carcinoma. J. Exp. Med. 186: 785-793PubMedCrossRefGoogle Scholar
  29. 29.
    Soung YH, Lee JW, Kim SY et al (2005) CASPASE-8 gene is inactivated by somatic mutations in gastric carcinomas. Cancer Res. 65(3): 815-821PubMedGoogle Scholar
  30. 30.
    Shin MS, Kim HS, Kang CS et al (2002) Inactivating mutations of CASP 10 gene in non-Hodgkin lymphomas. Blood. 99(11): 4094-4099PubMedCrossRefGoogle Scholar
  31. 31.
    Park WS, Lee JH, Shin MS et al (2002) Inactivating mutations of caspase- 10 gene in gastric cancer. Oncogene. 21(18): 2919-2925PubMedCrossRefGoogle Scholar
  32. 32.
    Kataoka T (2005) The caspase-8 modulator c-FLIP. Crit Rev Immunol. 25(1): p. 31-58PubMedCrossRefGoogle Scholar
  33. 33.
    Gyrd-Hansen M, Meier P (2010) IAPs: from caspase inhibitors to modulators of NF-kappaB, inflammation and cancer. Nat Rev Cancer. 10(8): 561-574PubMedCrossRefGoogle Scholar
  34. 34.
    Rawlings ND, Morton FR, Kok CY et al (2008) MEROPS: the peptidase database. Nucleic Acids Res. 36(Database issue): D320–D325Google Scholar
  35. 35.
    Xia L, Kilb J, Wex H et al (1999) Localization of rat cathepsin K in osteoclasts and resorption pits: inhibition of bone resorption and cathepsin K-activity by peptidyl vinyl sulfones. Biol. Chem. 380(6): 679–687PubMedCrossRefGoogle Scholar
  36. 36.
    Shuja S, Murnane MJ (1996) Marked increases in cathepsin B and L activities distinguish papillary carcinoma of the thyroid from normal thyroid or thyroid with non-neoplastic disease. Int J Cancer. 66(4): 420–6PubMedCrossRefGoogle Scholar
  37. 37.
    Hughes SJ, Glover TW, Zhu XX et al (1998) A novel amplicon at 8p22–23 results in overexpression of cathepsin B in esophageal adenocarcinoma. Proc. Natl Acad. Sci. USA. 95(21): 12410–12415PubMedCrossRefGoogle Scholar
  38. 38.
    Linnerth NM, Sirbovan, K, Moorehead RA (2005) Use of a transgenic mouse model to identify markers of human lung tumors. Int. J. Cancer. 114(6): 977–982PubMedCrossRefGoogle Scholar
  39. 39.
    Allinen, M, Beroukhim R, Cai L et al (2004) Molecular characterization of the tumor microenvironment in breast cancer. Cancer Cell. 6(1): 17–32PubMedCrossRefGoogle Scholar
  40. 40.
    Flannery T, Gibson D, Mirakhur M et al (2003) The clinical significance of cathepsin S expression in human astrocytomas. Am. J. Pathol. 163(1): 175–182PubMedCrossRefGoogle Scholar
  41. 41.
    Reinheckel T, Hagemann S, Dollwet-Mack S et al (2005) The lysosomal cysteine protease cathepsin L regulates keratinocyte proliferation by control of growth factor recycling. J. Cell Sci. 118(Pt 15): 3387-3395PubMedCrossRefGoogle Scholar
  42. 42.
    Andreasen PA, Kjoller L, Christensen L et al (1997) The urokinase type plasminogen activator system in cancer metastasis: a review. Int J Cancer. 72(1): 1-22PubMedCrossRefGoogle Scholar
  43. 43.
    Dano K, Andreasen PA, Grondahl-Hansen K et al (1985) Plasminogen activators, tissue degradation and cancer. Adv Cancer Res. 44: 139-266PubMedCrossRefGoogle Scholar
  44. 44.
    Plough M, Ellis V, Dano K (1994) Ligand interaction between urokinase type plasminogen activator and its receptor probed with 8-anilino- 1-naphthalenesulfonate: evidence for a hydrophobic binding site exposed only on the intact receptor. Biochemistry. 33(30): 8991- 8997CrossRefGoogle Scholar
  45. 45.
    Zhou HM, Nichols A, Meda P et al (2000) Urokinase-type plasminogen activator and its receptor synergize to promote pathogenic proteolysis. EMBO J. 19(17): 4817-4826PubMedCrossRefGoogle Scholar
  46. 46.
    Rifkin DB (1997) Cross-talk among proteases and matrix in the control of growth factor action. Fibrinol Proteolysis. 11: 3-9CrossRefGoogle Scholar
  47. 47.
    Plouet J, Moro F, Bertagnolli S et al (1997) Extracellular cleavage of the vascular endothelial growth factor 189-amino acid form by urokinase is required for its mitogenic effect. J Biol Chem. 272: 13390-13396PubMedCrossRefGoogle Scholar
  48. 48.
    Mars WM, Zarnegar R, Michalopoulos GK (1993) Activation of hepatocyte growth factor by the plasminogen activators uPA and tPA. Am J Path. 143(3): p. 949-958PubMedGoogle Scholar
  49. 49.
    Cross MJ, Claesson-Welsh L (2001) FGF and VEGF function in angiogenesis: signalling pathways, biological responses and therapeutic inhibition. Trends Pharmacol Sci. 22(4): 201-207.PubMedCrossRefGoogle Scholar
  50. 50.
    Tyndall JDA, Kelso MJ, Clingan P et al (2008) Peptides and Small Molecules Targeting the Plasminogen Activation System: Towards Prophylactic Anti-Metastasis Drugs for Breast Cancer. Recent Patents on Anti-Cancer Drug Discovery. 3(1): 1-13PubMedCrossRefGoogle Scholar
  51. 51.
    Hayes DF, Bast RC, Desch CE et al (1996) Tumor marker utility grading system: a framework to evaluate clinical utility of tumor markers. J Natl Cancer Inst. 88(20): 1456-66PubMedCrossRefGoogle Scholar
  52. 52.
    Shapiro RL, Duquette JG, Roses DF et al (1996) Induction of primary cutaneous melanocytic neoplasms in urokinase-type plasminogen activator (uPA)-deficient and wild type mice: cellular blue nevi invade but do not progress to malignant melanoma in uPA-deficient animals. Cancer Res. 56: 3597-3604PubMedGoogle Scholar
  53. 53.
    Cao R, Wu HL, Veitonmaki N et al (1996) Suppression of angiogenesis and tumor growth by the inhibitor K1-5 generated by plasmin-mediated proteolysis. Proc Natl Acad Sci USA. 96(10): 5728-5733CrossRefGoogle Scholar
  54. 54.
    Duggan C, Maguire T, McDermott E et al (1995) Urokinase plasminogen activator and urokinase plasminogen activator receptor in breast cancer. Int J Cancer. 61(5): 597-600PubMedCrossRefGoogle Scholar
  55. 55.
    Grondahl-Hansen J, Peters HA, van Putten WLJ et al (1995) Prognostic significance of the receptor for urokinase type plasminogen activator in breast cancer. Clin Cancer Res. 1: 1079-1087PubMedGoogle Scholar
  56. 56.
    Paliouras M, Borgono C, Diamandis EP (2007) Human tissue kallikreins: The cancer biomarker family. Cancer Lett. 249: 61-79PubMedCrossRefGoogle Scholar
  57. 57.
    Scorilas A, Gregorakis AK (2006) mRNA expression analysis of human kallikrein 11 (KLK11) may be useful in the discrimination of benign prostatic hyperplasia from prostate cancer after needle prostate biopsy. Biol. Chem. 387(6): 789–793PubMedCrossRefGoogle Scholar
  58. 58.
    Stavropoulou P, Gregorakis AK, Plebani M et al (2005) Expression analysis and prognostic significance of human kallikrein 11 in prostate cancer. Clin. Chim. Acta 357(2): 190–195PubMedCrossRefGoogle Scholar
  59. 59.
    Obiezu CV, Soosaipillai A, Jung K et al (2002) Detection of human kallikrein 4 in healthy and cancerous prostatic tissues by immunofluorometry and immunohistochemistry. Clin. Chem. 48(8): 1232–1240PubMedGoogle Scholar
  60. 60.
    Obiezu CV, Shan SJ, Soosaipillai A et al (2005) Human kallikrein 4: quantitative study in tissues and evidence for its secretion into biological fluids. Clin. Chem. 51(8): 1432–1442PubMedCrossRefGoogle Scholar
  61. 61.
    Borgono CA, Michael IP, Diamandis EP (2004) Human tissue kallikreins: physiologic roles and applications in cancer. Mol. Cancer Res. 2: 257–280PubMedGoogle Scholar
  62. 62.
    Borgono CA, Diamandis EP (2004) The emerging roles of human tissue kallikreins in cancer. Nat. Rev. Cancer 4: 876–890PubMedCrossRefGoogle Scholar
  63. 63.
    Obiezu CV, Diamandis EP (2005) Human tissue kallikrein gene family: applications in cancer. Cancer Lett. 224(1): 1–22PubMedGoogle Scholar
  64. 64.
    Obiezu CV, Scorilas A, Katsaros D et al (2001) Higher human kallikrein gene 4 (KLK4) expression indicates poor prognosis of ovarian cancer patients. Clin. Cancer Res. 7: 2380–2386PubMedGoogle Scholar
  65. 65.
    Kim H, Scorilas A, Katsaros D et al (2001) Human kallikrein gene 5 (KLK5) expression is an indicator of poor prognosis in ovarian cancer. Br. J. Cancer 84(5): 643–650PubMedCrossRefGoogle Scholar
  66. 66.
    Sher YP, Chou CC, Chou RH et al (2006) Human kallikrein 8 protease confers a favourable clinical outcome in non-small cell lung cancer by suppressing tumor cell invasiveness. Cancer Res. 66: 11763-11770PubMedCrossRefGoogle Scholar
  67. 67.
    Goyal J, Smith KM, Cowan JM et al (1998) The role of NES1 serine protease as a novel tumor suppressor. Cancer Res. 58: 4782-4786PubMedGoogle Scholar
  68. 68.
    Beaufort N, Debela M, Creutzburg S et al (2006) Interplay of human tissue kallikrein 4 (hK4) with the plasminogen activation system: hK4 regulates the structure and functions of the urokinase-type plasminogen activator receptor (uPAR). Biol Chem. 387(2): 217-22PubMedCrossRefGoogle Scholar
  69. 69.
    Page-McCaw A, Ewald AJ, Werb Z (2007) Matrix metalloproteinases and the regulation of tissue remodelling. Nat Rev Mol Cell Biol. 8: 221–233PubMedCrossRefGoogle Scholar
  70. 70.
    Parks WC, Wilson CL, Lopez-Boado YS (2004) Matrix metalloproteinases as modulators of inflammation and innate immunity. Nat Rev Immunol. 4: 617–629PubMedCrossRefGoogle Scholar
  71. 71.
    Nagase H, Visse R, Murphy G (2006) Structure and function of matrix metalloproteinases and TIMPs. Cardiovasc Res. 69(3): 562–573PubMedCrossRefGoogle Scholar
  72. 72.
    Egeblad M, Werb Z (2002) New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer. 2: 161–174PubMedCrossRefGoogle Scholar
  73. 73.
    Genersch E, Haye K, Neuenfeld Y et al (2000) Sustained ERK phosphorylation is necessary but not sufficient for MMP-9 regulation in endothelial cells: involvement of Ras-dependent and independent pathways. J. Cell Sci. 113: 4319-4330PubMedGoogle Scholar
  74. 74.
    Stetler-Stevenson WG (1999) Matrix metalloproteinases in angiogenesis: a moving target for therapeutic intervention. J Clin Invest. 103(9): 1237–1241PubMedCrossRefGoogle Scholar
  75. 75.
    Balbín M, Fueyo A, Tester AM et al (2003) Loss of collagenase-2 confers increased skin tumor susceptibility to male mice. Nature Genet. 35: 252-257PubMedCrossRefGoogle Scholar
  76. 76.
    Gorrin-Rivas MJ, Arii S, Furutani M et al (2000) Mouse macrophage metalloelastase gene transfer into a murine melanoma suppresses primary tumor growth by halting angiogenesis. Clin. Cancer Res. 6: 1647-1654PubMedGoogle Scholar
  77. 77.
    Gorrin-Rivas MJ, Arii S, Mori A et al (2001) Implications of human macrophage metalloelastase and vascular endothelial growth factor gene expression in angiogenesis of hepatocellular carcinoma. Ann. Surg. 231(1): 67-73CrossRefGoogle Scholar
  78. 78.
    Hofmann HS, Hansen G, Richter G et al (2005) Matrix metalloproteinase-12 expression correlates with local recurrence and metastatic disease in non-small cell lung cancer patients. Cancer Res. 11: 1086-1092Google Scholar
  79. 79.
    Sternlicht MD, Lochter A, Sympson CJ et al (1999) The stromal proteinase MMP3/stromelysin-1 promotes mammary carcinogenesis. Cell. 98(2): 137-146PubMedCrossRefGoogle Scholar
  80. 80.
    Ichikawa Y, Ishikawa T, Momiyama N et al (2006) Matrilysin (MMP-7) degrades VE-cadherin and accelerates accumulation of beta-catenin in the nucleus of human umbilical vein endothelial cells. Oncol. Rep. 15: 311-315PubMedGoogle Scholar
  81. 81.
    Stetler-Stevenson WG (1999) Matrix metalloproteinases in angiogenesis: a moving target for therapeutic intervention. J Clin Invest. 103: 1237–1241PubMedCrossRefGoogle Scholar
  82. 82.
    Rojiani MV, Alidina J, Esposito N et al (2010) Expression of MMP-2 correlates with increased angiogenesis in CNS metastasis of lung carcinoma. Int J Clin Exp Pathol. 3: 775–781PubMedGoogle Scholar
  83. 83.
    Noël A, Jost M, Maquoi E (2008) Matrix metalloproteinases at cancer tumor-host interface. Semin Cell Dev Biol. 19(1): 52–60Google Scholar
  84. 84.
    Murphy G (2008) The ADAMs: signalling scissors in the tumour microenvironment. Nat Rev Cancer. 8: 932– 941CrossRefGoogle Scholar
  85. 85.
    Rocks N, Paulissen G, El Hour M et al (2008) Emerging roles of ADAM and ADAMTS metalloproteinases in cancer. Biochimie. 90(2): 369–379PubMedCrossRefGoogle Scholar
  86. 86.
    Boutet P, Agüera-González S, Atkinson S et al (2009) Cutting edge: the metalloproteinase ADAM17/TNF-alpha-converting enzyme regulates proteolytic shedding of the MHC class I-related chain B protein. J Immunol. 1: 182(1): p. 49-53Google Scholar
  87. 87.
    Gialeli C, Theocharis AD, Karamanos NK (2011) Roles of matrix metalloproteinases in cancer progression and their pharmacological targeting. FEBS J. 278(1): 16-27PubMedCrossRefGoogle Scholar
  88. 88.
    Iruela-Arispe ML, Carpizo D, Luque A (2003) ADAMTS1: a matrix metalloprotease with angioinhibitory properties. Ann. NY. Acad. Sci. 995: 183-190PubMedCrossRefGoogle Scholar
  89. 89.
    Kuno K, Bannai K, Hakozaki M et al (2004) The carboxy-terminal half region of ADAMTS-1 suppresses both tumorigenicity and experimental tumor metastatic potential. Biochem. Biophys. Res. Commun. 319: 1327-1333PubMedCrossRefGoogle Scholar
  90. 90.
    Masui T, Hosotani R, Tsuji S et al (2001) Expression of METH-1 and METH-2 in pancreatic cancer. Clin. Cancer Res. 7: 3437-3443PubMedGoogle Scholar
  91. 91.
    Cheung HH, St Jean M, Beug ST et al (2011) SMG1 and NIK regulate apoptosis induced by Smac mimetic compounds. Cell Death Dis. 2: e146PubMedCrossRefGoogle Scholar
  92. 92.
    Hengartner MO (2000) The biochemistry of apoptosis. Nature. 407: 770-776PubMedCrossRefGoogle Scholar
  93. 93.
    MacKenzie SH, Schipper JL, Clark AC (2010) The potential for caspases in drug discovery. Curr Opin Drug Discov Devel. 13(5): 568–576PubMedGoogle Scholar
  94. 94.
    Los M, Burek CJ, Stroh C, Benedyk K et al (2003) Anticancer drugs of tomorrow: apoptotic pathways as targets for drug design. Drug Discov Today. 8(2): 67-77PubMedCrossRefGoogle Scholar
  95. 95.
    Choi KY, Swierczewska M, Lee S et al (2012) Protease-Activated Drug Development. Theranostics. 2(2): 156-178PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Functional Genomics UnitCSIR-Institute of Genomics and Integrative BiologyNew DelhiIndia

Personalised recommendations