Summary
Angiostatin, a potent inhibitor of angiogenesis, tumour growth and metastasis, is a biologically active fragment of plasminogen, containing the kringle domains 1–4. It is generated from plasminogen by limited proteolysis. We show that prostate-specific antigen (PSA), a serine proteinase secreted by human prostate and human prostate cancer cells, is able to convert Lys-plasminogen to biologically active angiostatin-like fragments, containing kringles 1–4, by limited proteolysis of peptide bond Glu439–Ala440 in vitro. In an in vitro morphogenesis assay, the purified angiostatin-like fragments inhibited proliferation and tubular formation of human umbilical vein endothelial cells with the same efficacy as angiostatin. This finding might help to understand growth characteristics of prostate cancer, which usually has low microvessel density and slow proliferation.
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16 November 2011
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References
Cao, Y, Chen, A, An, SSA, Ji, RW, Davidson, D, Cao, Y & Llinás, M (1997). Kringle 5 of plasminogen is a novel inhibitor of endothelial cell growth. J Biol Chem 272: 22924–22928.
Christensson, A, Laurell, C & Lilja, H (1990). Enzymatic activity of prostate-specific antigen and its reactions with extracellular serine proteinase inhibitors. Eur J Biochem 194: 755–763.
Dong, Z, Kumar, R, Yang, X & Fidler, IJ (1997). Macrophage-derived metalloelastase is responsible for the generation of angiostatin in Lewis lung carcinoma. Cell 88: 801–810.
Gately, S, Twardowski, P, Stack, MS, Patrick, M, Boggio, L, Cundiff, DL, Schnaper, HW, Madison, L, Volpert, O, Bouck, N, Enghild, J, Kwaan, HC & Soff, GA (1996). Human prostate carcinoma cells express enzymatic activity that converts human plasminogen to the angiogenesis inhibitor, angiostatin. Cancer Res 56: 4887–4890.
Gately, S, Twardowski, P, Stack, MS, Cundiff, DL, Grella, D, Castellino, FJ, Enghild, J, Kwaan, HC, Lee, F, Kramer, RA, Volpert, O, Bouck, N & Soff, GA (1997). The mechanism of cancer-mediated conversion of plasminogen to the angiogenesis inhibitor angiostatin. Proc Natl Acad Sci USA 94: 10868–10872.
Hasenson, M, Lundh, B, Stege, R, Carlstrom, K & Pousette, A (1989). PAP and PSA in prostatic carcinoma cell lines and aspiration biopsies: relation to hormone sensitivity and to cytological grading. Prostate 14: 83–90.
Hayes, ML & Castellino, FJ (1979). Carbohydrate of the human plasminogen variants. J Biol Chem 254: 8772
Kumar, R, Yoneda, J, Bucana, CD & Fidler, IJ (1998). Regulation of distinct steps of angiogenesis by different angiogenic molecules. Int J Oncol 12: 749–757.
Laemmli UK: Cleavage of structural proteins during the assembly of the head of bacteriophage T4 (1970). Nature, (Lond.)227: 680–685.
Leinonen, J, Zhang, WM & Stenman, UH (1996). Complex formation between PSA isoenzymes and protease inhibitors. J Urol 155: 1099–1103.
Lilja, HR, Abrahamsson, P-A & Lundwall, A (1989). Semenogelin, the predominant protein in human semen. J Biol Chem 264: 18894–1900.
Lilja, HR, Christensson, A, Dahlen, U, Matikainen, MT, Nilsson, O, Pettersson, K & Lövgren, T (1991). Prostate specific antigen in human serum occurs predominantly in complex with alpha-1-antichymotrypsin. Clin Chem 37: 1618–1625.
Lijnen, HR, Uguwu, F, Bini, A & Collen, D (1998). Generation of an angiostatin-like fragment from plasminogen by stromelysin-1 (MMP-3). Biochemistry 37: 4699–4702.
Malm, J, Hellman, J & Lilja, H (1997). Mapping of the unique enzyme characteristics of PSA. J Urol 157: 345
O'Reilly, MS, Holmgren, L, Shing, Y, Chen, C, Rosenthal, RA, Moses, M, Lane, WS, Cao, Y, Sage, EH & Folkman, J (1994). Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell 79: 315–328.
O'Reilly, MS, Holmgren, L, Chen, C & Folkman, J (1996). Angiostatin induces and sustains dormnacy of human primary tumours in mice. Nat Med 2: 689–692.
Patterson, BC & Sang, QA (1997). Angiostatin-converting enzyme activities of human matrilysin (MMP-7) and gelatinase B/type IV collagenase (MMP-9). J Biol Chem 272: 28823–28825.
Shi, GY & Wu, HL (1988). Isolation and characterization of microplasminogen. A low molecular weight form of plasminogen. J Biol Chem 263: 17071–17075.
Sottrup-Jensen, L, Claeys, H, Zajdel, M, Petersson, TE & Magnusson, S (1978). The primary structure of human plasminogen: isolation of two lysine-binding fragments and one ‘mini’-plasminogen (MW 38 000) by elastase- catalyzed-specific limited proteolysis. In:Progress in Chemical Fibrinolysis and Thrombolysis 3, Davidson JF, Rowan RM, Samama MM, Desnoyers PC 191 Raven Press: New York
Sottrup-Jensen, L, Lonblad, PB, Stepanik, TM, Petersen, TE, Magnusson, S & Jornvall, H (1981). Primary structure of the ‘bait’ region for proteinases in alpha 2-macroglobulin. Nature of the complex. FEBS Lett 127: 167–173.
Wallén, P & Wiman, B (1972). Characterization of human plasminogen. II. Separation and partial characterization of different molecular forms of human plasminogen. Biochem Biophys Acta 257: 122–129.
Zhang, WM, Leinonen, J, Kalkkinen, N, Dowell, B & Stenman, UH (1995). Purification and characterization of different forms of prostate-specific antigen in human seminal fluid. Clin Chem 41: 1567–1573.
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Heidtmann, HH., Nettelbeck, D., Mingels, A. et al. Generation of angiostatin-like fragments from plasminogen by prostate-specific antigen. Br J Cancer 81, 1269–1273 (1999). https://doi.org/10.1038/sj.bjc.6692167
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DOI: https://doi.org/10.1038/sj.bjc.6692167
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