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Procathepsin D in breast cancer: What do we know? Effects of ribozymes and other inhibitors

Cancer Gene Therapy volume 9, pages 854–863 (2002)Cite this article

Abstract

Procathepsin D (pCD) is a major secreted glycoprotein in some human breast and other cancer cell lines. Several groups proposed that pCD served as a growth factor for these cell lines. Secreted pCD has been demonstrated in tissue section, tissue culture supernatants, carcinoma cytosols, and nipple aspirates. Moreover, several clinical studies suggested a potential role for this molecule in metastasis because its concentration in primary tumors correlated with an increased incidence of tumor metastases. In this paper, the effects of pCD were evaluated by proliferation in vitro and by mouse studies in vivo. Subsequent flow cytometry experiments showed the specificity of pCD binding to cancer cells. Cell cultivation showed that addition of either pCD or its activation peptide stimulates growth of cancer cells. These effects can be inhibited both in vitro and in vivo by anti-pCD antibodies. In addition, production of pCD can be inhibited by specifically designed ribozymes. This paper is focused on mitogenic effects of pCD, which seem to involve interaction of the activation peptide with as yet unidentified receptor. Different mechanisms by which pCD could promote development and spread of cancer cells are discussed.

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References

  1. Erickson AH, Blobel G . Early events in the biosynthesis of the lysosomal enzyme cathepsin D J Biol Chem 1979 254: 11771–11774

    CAS  PubMed  Google Scholar 

  2. Kornfeld R, Kornfeld S . Assembly of asparagine linked oligosaccharides Annu Rev Biochem 1985 54: 631–664

    Article  CAS  PubMed  Google Scholar 

  3. Tang J, Wong RNS . Evolution in the structure and function of aspartic proteases J Cell Biochem 1987 33: 53–63

    Article  CAS  PubMed  Google Scholar 

  4. Dingle JT, Poole AR, Lazarus GS et al. Immunoinhibition of intracellular protein digestion in macrophages J Exp Med 1973 137: 1124–1141

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Williams KP, Smith JA . Isolation of membrane-associated cathepsin D like enzyme from the model antigen presenting cell, A20, and its ability to generate antigenic fragments from protein antigen in a cell free system Arch Biochem Biophys 1993 305: 298–306

    Article  CAS  PubMed  Google Scholar 

  6. Baldocchi RA, Nicoll CS . Processing of rat prolactin by rat tissue explants and serum in vitro Endocrinology 1992 130: 1653–1659

    CAS  PubMed  Google Scholar 

  7. Loscalzo J . The macrophage and fibrinolysis Semin Thromb Haemost 1996 22: 503–506

    Article  CAS  Google Scholar 

  8. Podhajcer OL, Bover L, Bravo AL et al. Expression of cathepsin D in primary and metastatic human melanoma and dysplastic nevi J Invest Dermatol 1995 104: 340–344

    Article  CAS  PubMed  Google Scholar 

  9. Bazzett LB, Watkins CS et al. Modulation of proliferation and chemosensitivity by procathepsin D and its peptides in ovarian cancer Gynecol Oncol 1999 74: 181–187

    Article  CAS  PubMed  Google Scholar 

  10. Rochefort H . Cathepsin D in cancer metastasis: a protease and a ligand APMIS 1999 107: 86–95

    Article  CAS  PubMed  Google Scholar 

  11. Lorenzo K, Ton P, Clark JL et al. Invasive properties of murine squamous carcinoma cells: secretion of matrix-degrading cathepsins is attributable to a deficiency in the mannose 6-phosphate/insulin-like growth factor II receptor Cancer Res 2000 60: 4070–4076

    CAS  PubMed  Google Scholar 

  12. Rochefort H, Garcia M, Glondu M . Cathepsin D in breast cancer: mechanisms and clinical applications, a 1999 review Clin Chim Acta 2000 291: 157–170

    Article  CAS  PubMed  Google Scholar 

  13. Reid WA, Vallor MJ, Kay J . Immunolocalization of cathepsin D in normal and neoplastic tissues J Clin Pathol 1986 39: 1323–1330

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Spyratos F, Brouillet JP, Defrenne A et al. Cathepsin D: an independent prognostic factor for metastasis of breast cancer Lancet 1989 ii: 1115–1118

    Article  Google Scholar 

  15. Rochefort H . Biological and clinical significance of cathepsin D in breast cancer Acta Oncol 1992 31: 125–130

    Article  CAS  PubMed  Google Scholar 

  16. Vignon F, Capony F, Chambon M et al. Autocrine growth stimulation of the MCF 7 breast cancer cells by the estrogen-regulated 52 K protein Endocrinology 1986 118: 1537–1545

    Article  CAS  PubMed  Google Scholar 

  17. Elangovan S, Moulton BC . Progesterone and estrogen control of rates of synthesis of uterine cathepsin D J Biol Chem 1980 255: 7474–7479

    CAS  PubMed  Google Scholar 

  18. Westley B, Rochefort H . A secretion of glycoprotein induced by estrogens in human breast cancer cell lines Cell 1980 20: 352–362

    Article  Google Scholar 

  19. Cavailles V, Augreau P, Rochefort H . Cathepsin D gene is controlled by a mixed promoter, and estrogens stimulate only TATA-dependent transcription in breast cancer cells Proc Natl Acad Sci USA 1993 90: 203–207

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Krishnan V, Narasimhan T, Safe S . Development of gel staining techniques for detecting the secretion of procathepsin D (52-kDa protein) in MCF-7 human breast cancer cells Anal Biochem 1992 204: 137–142

    Article  CAS  PubMed  Google Scholar 

  21. Rochefort H, Capony F, Garcia M et al. Estrogen-induced lysosomal proteases secreted by breast cancer cells: a role in carcinogenesis? J Cell Biochem 1987 35: 17–29

    Article  CAS  PubMed  Google Scholar 

  22. Augereau P, Miralles F, Cavailles V . Characterization of the proximal estrogen-responsive element of human cathepsin D gene Mol Endocrinol 1994 8: 693–703

    CAS  PubMed  Google Scholar 

  23. Leto G, Gebbia N, Rausa L et al. Cathepsin D in the malignant progression of neoplastic diseases Anticancer Res 1992 12: 235–240

    CAS  PubMed  Google Scholar 

  24. Rochefort H . Cathepsin D in breast cancer: a tissue marker associated with metastasis Eur J Cancer 1992 28A: 1780–1783

    Article  CAS  PubMed  Google Scholar 

  25. Kute TE, Shao ZM, Sugg NK et al. Cathepsin D as a prognostic indicator for node-negative breast cancer patients using both immunoassays and enzymatic assays Cancer Res 1992 52: 5198–5203

    CAS  PubMed  Google Scholar 

  26. Pujol P, Maudelonde T, Daures JP et al. A prospective study of the prognostic value of cathepsin D levels in breast cancer cytosol Cancer 1993 71: 2006–2012

    Article  CAS  PubMed  Google Scholar 

  27. Schultz DC, Bazel S, Wright LM . Western blotting and enzymatic activity analysis of cathepsin D in breast tissue and sera of patients with breast cancer and benign breast disease and of normal controls Cancer Res 1994 54: 48–54

    CAS  PubMed  Google Scholar 

  28. Nazeer T, Church K, Amato C et al. Comparative quantitative immunohistochemical and immunoradiometric determinations of cathepsin D in endometrial adenocarcinoma: predictors of tumor aggressiveness Mod Pathol 1994 7: 469–474

    CAS  PubMed  Google Scholar 

  29. Inoue Y, Abe K, Obata K et al. Immunohistochemical studies concerning cathepsin D in endometrial carcinomas J Obstet Gynaecol Res 1999 25: 345–352

    Article  CAS  PubMed  Google Scholar 

  30. Huet G, Zerimech F, Dieu MC et al. The state of differentiation of HT-29 colon carcinoma cells alters the secretion of cathepsin D and of plasminogen activator Int J Cancer 1994 57: 875–882

    Article  CAS  PubMed  Google Scholar 

  31. Oh-e H, Tanaka S, Kitadai Y et al. Cathepsin D expression as a possible predictor of lymph node metastasis in submucosal colorectal cancer Eur J Cancer 2001 37: 180–188

    Article  CAS  PubMed  Google Scholar 

  32. Vigneswaran N, Zhao W, Dassanayake A et al. Variable expression of cathepsin B and D correlates with highly invasive and metastatic phenotype of oral cancer Hum Pathol 2000 31: 931–937

    Article  CAS  PubMed  Google Scholar 

  33. Ferrandina G, Scambia G, Panici P et al. Cathepsin D in primary squamous laryngeal tumors: correlation with clinico-pathological parameters and receptor status Cancer Lett 1992 67: 133–138

    Article  CAS  PubMed  Google Scholar 

  34. Goussia A, Ioachim E, Peschos D et al. Immunohistochemical expression of cathepsin D in laryngeal epithelial lesions: correlation with CD44 expression, p53 and Rb status and proliferation associated indices Anticancer Res 1999 19: 3055–3060

    CAS  PubMed  Google Scholar 

  35. Gandour-Edwards R, Trock B, Donald PJ . Predictive value of cathepsin D for cervical lymph node metastasis in head and neck squamous cell carcinoma Head Neck 1999 21: 718–722

    Article  CAS  PubMed  Google Scholar 

  36. Metaye T, Millet C, Kraimps JL et al. Estrogen receptors and cathepsin D in human thyroid tissue Cancer 1993 72: 1991–1996

    Article  CAS  PubMed  Google Scholar 

  37. Chambon M, Rebillard X, Rochefort H et al. Cathepsin D cytosolic assay and immunohistochemical quantification in human prostate tumors Prostate 1994 24: 320–325

    Article  CAS  PubMed  Google Scholar 

  38. Vetvicka V, Vetvickova J, Fusek M . Effect of procathepsin D and its activation peptide on prostate cancer cells Cancer Lett 1998 129: 55–59

    Article  CAS  PubMed  Google Scholar 

  39. Frohlich E, Schlagenhauff B, Mohrle M et al. Activity, expression, and transcription rate of the cathepsins B, D, H, and L in cutaneous malignant melanoma Cancer 2001 91: 972–982

    Article  CAS  PubMed  Google Scholar 

  40. Ikeguchi M, Fukuda K, Oka SI et al. Micro-lymph node metastasis and its correlation with cathepsin D expression in early gastric cancer J Surg Oncol 2001 77: 188–194

    Article  CAS  PubMed  Google Scholar 

  41. Chinni SR, Gercel-Taylor C, Conner GE et al. Cathepsin D antigenic epitopes identified by the humoral responses if ovarian cancer patients Cancer Immunol Immunother 1998 46: 48–54

    Article  CAS  PubMed  Google Scholar 

  42. Baekelandt H, Holm R, Trope CG et al. The significance of metastasis-related factors cathepsin D and nm23 in advanced ovarian cancer Ann Oncol 1999 10: 1335–1341

    Article  CAS  PubMed  Google Scholar 

  43. Tedone T, Correale M, Barbadossa G et al. Release of the aspartyl protease cathepsin D is associated with and facilitates human breast cancer cell invasion FASEB J 1997 11: 785–792

    Article  CAS  PubMed  Google Scholar 

  44. Johnson MD, Torri JA, Lippman ME et al. The role of cathepsin D in the invasiveness of human breast cancer cells Cancer Res 1993 53: 873–877

    CAS  PubMed  Google Scholar 

  45. Lah TT, Calaf G, Kalman E et al. Cathepsins D, B and L in breast carcinoma and in transformed human breast epithelial cells (HBEC) Biol Chem Hoppe-Seyler 1995 376: 357–363

    Article  CAS  PubMed  Google Scholar 

  46. Fusek M, Vetvicka V . Aspartic Proteinases: Physiology and Pathology Boca Raton: CRC Press 1995

    Google Scholar 

  47. Vetvicka V, Vetvickova J, Fusek M . Anti-human procathepsin D activation peptide antibodies inhibit breast cancer development Breast Cancer Res Treat 1999 57: 261–269

    Article  CAS  PubMed  Google Scholar 

  48. Koelsch G, Metcalf P, Vetvicka V et al. Human procathepsin D: three-dimensional model and isolation In: Takahaski K, ed Aspartic Proteinases: Structure, Function, Biology, and Biomedical Implications New York: Plenum 1995 273–278

    Chapter  Google Scholar 

  49. Scherr M, Rossi JJ . Rapid determination and quantitation of the accessibility to native RNAs by antisense oligodeoxynucleotides in murine cell extracts Nucleic Acids Res 1998 26: 5079–5085

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Biegelman L, McSwiggen JA, Draper KG et al. Chemical modification of hammerhead ribozymes J Biol Chem 1995 270: 2507–25780

    Google Scholar 

  51. Dawson PA, Marini JC . Hammerhead ribozymes selectively suppress mutant type I collagen mRNA in osteogenesis imperfecta fibroblasts Nucleic Acids Res 2000 28: 4013–4020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Golumbek PT, Azhari R, Jaffee EM et al. Controlled release, biodegradable cytokine depots: a new approach in cancer vaccine design Cancer Res 1993 53: 5841–5844

    CAS  PubMed  Google Scholar 

  53. Vetvicka V, Vetvickova J, Fusek M . Effect of human procathepsin D on proliferation of human cell lines Cancer Lett 1994 79: 131–135

    Article  CAS  PubMed  Google Scholar 

  54. Mathieu M, Rochefort H, Barenton B et al. Interaction of cathepsin D and insulin-like growth factor II (IGF-II) on the IGF-II/mannose-6-phosphate receptor in human breast cancer cells and possible consequences on mitogenic activity of IGF-II Mol Endocrinol 1990 4: 1327–1335

    Article  CAS  PubMed  Google Scholar 

  55. Vetvicka V, Fusek M . Activation of peripheral blood neutrophils and lymphocytes by human procathepsin D and insulin-like growth factor II Cell Immunol 1994 156: 332–341

    Article  CAS  PubMed  Google Scholar 

  56. Vetvicka V, Vetvickova J, Hilgert I et al. Analysis of the interaction of procathepsin D activation peptide with breast cancer cells Int J Cancer 1997 73: 402–409

    Article  Google Scholar 

  57. Vetvicka V, Vetvickova J, Fusek M . Role of procathepsin D activation peptide in prostate cancer growth Prostate 2000 44: 1–7

    Article  CAS  PubMed  Google Scholar 

  58. Bazzett LB, Watkins CS, Gercel-Taylor C et al. Modulation of proliferation and chemosensitivity by procathepsin D and its peptides in ovarian cancer Gynecol Oncol 1999 74: 181–187

    Article  CAS  PubMed  Google Scholar 

  59. Zuker M, Mathews DH, Turner DH . Algorithms and thermodynamics for RNA secondary structure prediction: a practical guide In: Barciszewski J, Clark BFC, eds RNA Biochemistry and Biotechnology NATO ASI Series vols. 11–43: Dordrecht: Kluwer Academic Publishing 1999

    Google Scholar 

  60. Shimayama T, Nishikawa S, Taira K . Generality of the NUX rule — kinetic analysis of the results of systematic mutations in the trinucleotide at the cleavage site of hammerhead ribozymes Biochemistry 1995 34: 3649–3654

    Article  CAS  PubMed  Google Scholar 

  61. Altschul SF, Gish W, Miller W et al. Basic local alignment search tool J Mol Biol 1990 215: 403–410

    Article  CAS  PubMed  Google Scholar 

  62. Streckfus C, Bigler L, Tucci M et al. A preliminary study of CA15-3, c-erbB-2, epidermal growth factor receptor, cathepsin-D, and p53 in saliva among women with breast carcinoma Cancer Invest 2000 18: 101–109

    Article  CAS  PubMed  Google Scholar 

  63. Thorpe SM, Rochefort H, Garcia M et al. Association between high concentration of 52,000 MW cathepsin D and poor prognosis in primary human breast cancer Cancer Res 1989 49: 6008–6014

    CAS  PubMed  Google Scholar 

  64. Garcia D, Dercoq Q, Pujol P et al. Overexpression of transfected cathepsin D in transformed cells increases their malignant phenotype and metastatic potency Oncogene 1990 5: 1809–1814

    CAS  PubMed  Google Scholar 

  65. Liaudet E, Garcia M, Rochefort H . Cathepsin D maturation and its stimulatory effect on metastasis are prevented by addition of KDEL retention signal Oncogene 1994 9: 1145–1154

    CAS  PubMed  Google Scholar 

  66. Rochefort H, Capony F . Alterations of cathepsin D in human breast cancer In: Bond JS, Barrett AJ, eds Proteolysis and Protein Turnover London: Portland Press 1993 233–238

    Google Scholar 

  67. Rochefort H . Oestrogens, proteases and breast cancer. From cell lines to clinical applications Eur J Cancer 1994 30A: 1583–1586

    Article  CAS  PubMed  Google Scholar 

  68. Briozzo P, Badet J, Capony F et al. MCF7 mammary cancer cells respond to bFGF and internalize it following its release from extracellular matrix: a permissive role of cathepsin D Exp Cell Res 1991 194: 252–259

    Article  CAS  PubMed  Google Scholar 

  69. Liaudet-Coopman E, Glondu M, Coopman P et al. A mutated cathepsin-D devoid of its catalytic activity stimulates the growth of cancer cells. 92nd Annual Meeting of the American Association for Cancer Research, New Orleans vol. 3826: 2001

  70. Von Figura K, Hasilik A . Lysosomal enzymes and their receptors Annu Rev Biochem 1986 55: 167–193

    Article  CAS  PubMed  Google Scholar 

  71. Von Figura K . Molecular recognition and targeting of lysosomal proteins Curr Opin Cell Biol 1991 3: 642–646

    Article  CAS  PubMed  Google Scholar 

  72. Kornfeld S, Mellman I . The biogenesis of lysosomes Annu Rev Cell Biol 1986 55: 167–193

    Google Scholar 

  73. Capony F, Braulke T, Tougeot C et al. Specific mannose-6-phosphate receptor-independent sorting of procathepsin D in breast cancer cells Exp Cell Res 1994 215: 154–163

    Article  CAS  PubMed  Google Scholar 

  74. Diment S, Leech MS, Stahl PD . Cathepsin D is membrane-associated in macrophage endosomes J Biol Chem 1998 263: 6901–6907

    Google Scholar 

  75. Rijnbout S, Aerts HMFG, Geuze HJ et al. Identification of subcellular compartments involved in biosynthetic processing of cathepsin D J Biol Chem 1991 266: 4862–4868

    Google Scholar 

  76. Isidoro C, Demoz M, De Stefanis D et al. Differential targeting and processing of procathepsin D in normal and transformed murine 3T3 fibroblasts Int J Cancer 1997 70: 310–314

    Article  CAS  PubMed  Google Scholar 

  77. Isidoro C, Baccino FM, Hasilik A . Human and hamster procathepsin D, although equally tagged with mannose-6-phosphate, are differentially targeted to lysosomes in transfected BHK cells Cell Tissue Res 1998 292: 303–310

    Article  CAS  PubMed  Google Scholar 

  78. Laurent-Matha V, Farnoud MR, Lucas A et al. Endocytosis of pro-cathepsin D into breast cancer cells is mostly independent of mannose-6-phosphate receptors J Cell Sci 1998 111: 2539–2549

    CAS  PubMed  Google Scholar 

  79. Fusek M, Vetvicka V . Mitogenic function of human procathepsin D: the role of the propeptide Biochem J 1994 303: 775–780

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Wu X, Craft N, Raitano A et al. Functional expression cloning identifies cathepsin D as a candidate for prostate cancer progression. 89th Annual Meeting of the American Association for Cancer Research, New Orleans vol. 878: 1998

  81. Jarosz DE, Hamer PJ, Tenney DY et al. Elevated levels of pro-cathepsin D in the plasma of breast cancer patients Int J Oncol 1995 6: 859–865

    CAS  PubMed  Google Scholar 

  82. Brouillet JP, Dufour F, Lemamy G et al. Increased cathepsin D level in the serum of patients with metastatic breast carcinoma detected wit ha specific procathepsin D immunoassay Cancer 1997 79: 2132–2136

    Article  CAS  PubMed  Google Scholar 

  83. Taylor DD . Tumor-reactive immunoglobulins in ovarian cancer: diagnostic and therapeutic significance? Oncol Rep 1998 5: 1519–1524 (Review)

    CAS  PubMed  Google Scholar 

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Acknowledgements

The work was supported in part by research grants from American Cancer Society, US Army Breast Cancer Research Program, and Phi Beta Psi Sorority.

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  1. Department of Pathology and Laboratory Medicine, School of Medicine, University of Louisville, Louisville, 40292, Kentucky, USA

    Vaclav Vetvicka & Petr Benes

  2. Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Prague, Czech Republic

    Martin Fusek

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  1. Vaclav Vetvicka
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Correspondence to Vaclav Vetvicka.

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Vetvicka, V., Benes, P. & Fusek, M. Procathepsin D in breast cancer: What do we know? Effects of ribozymes and other inhibitors. Cancer Gene Ther 9, 854–863 (2002). https://doi.org/10.1038/sj.cgt.7700508

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