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Thromb Haemost 2008; 100(06): 1041-1046
DOI: 10.1160/TH08-04-0266
Theme Issue Article
Schattauer GmbH

Regulation of programmed cell death by plasminogen activator inhibitor type 1 (PAI-1)

Ulrik A. Lademann
1   Department of Disease Biology, Section for Biomedicine, Faculty of Life Sciences, University of Copenhagen, Frederiksberg C., Denmark
,
Maria Unni Rømer
1   Department of Disease Biology, Section for Biomedicine, Faculty of Life Sciences, University of Copenhagen, Frederiksberg C., Denmark
› Author AffiliationsFinancial support: This work was supported by grants from The IMK Foundation, Købmand I Odense Johann og Hanne Weimann, f. Seedorff Legat, the Danish Cancer Society, The A.P. Møller Foundation for the Advancement of Medical Science, The Danish Foundation for Cancer Research and The Danish Medical Research Council.
Further Information

Publication History

Received: 29 April 2008

Accepted after major revision: 09 November 2008

Publication Date:
23 November 2017 (online)

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Summary

Elevated levels of plasminogen activator inhibitor-1 (PAI-1) are associated with poor prognosis in cancer. An explanation to the elevated levels of PAI-1 could be a protective response to the increased proteolytic activity, caused by elevated levels of urokinase-type plasminogen activator (uPA) observed in tumours; however, several lines of evidence suggest that PAI-1 may contribute directly to the pathology of the disease. PAI-1 has been reported to have an effect on most of the basic cellular processes including cell adhesion, cell migration, cell invasion, and cell proliferation and increasing numbers of reports suggest that PAI-1 also can regulate programmed cell death (PCD) in cancer cells and normal cells.A number of reports suggest that PAI-1 can inhibit PCD through its pro-adhesive/anti-proteolytic property whereas other reports suggest that PAI-1 induces PCD through its anti-adhesive property.Furthermore,it has been suggested that PAI-1 can either induce or inhibit PCD though activation of cell signalling pathways.This review will focus on the regulation of programmed cell death by PAI-1 in both normal cells and cancer cells.

Keywords

Apoptosis - cancer - PAI-1 - normal cells
 

  • References

  • 1 Beyer BCM, Heiss MM, Simon EH. et al. Urokinase system expression in gastric carcinoma – Prognostic impact in an independent patient series and first evidence of predictive value in preoperative biopsy and intestinal metaplasia specimens. Cancer 2006; 106: 1026-1035.
    CrossrefPubMedGoogle Scholar
  • 2 Grondahl H, Christensen IJ, Rosenquist C. et al. High levels of urokinase-type plasminogen activator and its inhibitor PAI-1 in cytosolic extracts of breast carcinomas are associated with poor prognosis. Cancer Res 1993; 53: 2513-2521.
    PubMedGoogle Scholar
  • 3 Hofmann R, Lehmer A, Buresch M. et al. Clinical relevance of urokinase plasminogen activator, its receptor, and its inhibitor in patients with renal cell carcinoma. Cancer 1996; 78: 487-492.
    CrossrefPubMedGoogle Scholar
  • 4 Pedersen H, Brunner N, Francis D. et al. Prognostic impact of urokinase, urokinase receptor, and type-1 plasminogen-activator inhibitor in squamous and large-cell lung-cancer tissue. Cancer Res 1994; 54: 4671-4675.
    PubMedGoogle Scholar
  • 5 Stahl A, Mueller BM. Melanoma cell migration on vitronectin: Regulation by components of the plasminogen activation system. Int J Cancer 1997; 71: 116-122.
    CrossrefPubMedGoogle Scholar
  • 6 Bajou K, Noel A, Gerard RD. et al. Absence of host plasminogen activator inhibitor 1 prevents cancer invasion and vascularization. Nature Med 1998; 04: 923-928.
    CrossrefPubMedGoogle Scholar
  • 7 Gutierrez LS, Schulman A, Brito-Robinson T. et al. Tumor development is retarded in mice lacking the gene for urokinase-type plasminogen activator or its inhibitor, plasminogen activator inhibitor-1. Cancer Res 2000; 60: 5839-5847.
    PubMedGoogle Scholar
  • 8 Maillard C, Jost M, Romer MU. et al. Host plasmi-nogen activator inhibitor-1 promotes human skin carcinoma progression in a stage-dependent manner. Neoplasia 2005; 07: 57-66.
    CrossrefPubMedGoogle Scholar
  • 9 Palmieri D, Lee JW, Juliano RL, Church FC. Plas-minogenActivator Inhibitor-1 and -3 Increase Cell Adhesion and Motility of MDA-MB-435 Breast Cancer Cells. J Biol Chem 2002; 277: 40950-40957.
    CrossrefPubMedGoogle Scholar
  • 10 Andreasen PA. PAI-1 - a potential therapeutic target in cancer. Curr Drug Targets 2007; 08: 1030-1041.
    CrossrefPubMedGoogle Scholar
  • 11 Cao C, Lawrence DA, Li Y. et al. Endocytic receptor LRP together with tPA and PAI-1 coordinates Mac-1-dependent macrophage migration. EMBO J 2006; 25: 1860-1870.
    CrossrefPubMedGoogle Scholar
  • 12 Huntington JA, Read RJ, Carrell RW. Structure of a serpin-protease complex shows inhibition by deformation. Nature 2000; 407: 923-926.
    CrossrefPubMedGoogle Scholar
  • 13 Cubellis MV, Wun TC, Blasi F. Receptor-mediated internalization and degradation of urokinase is caused by its specific inhibitor PAI-1. EMBO J 1990; 09: 1079-1085.
    PubMedGoogle Scholar
  • 14 Nykjaer A, Conese M, Christensen EI. et al. Recycling of the urokinase receptor upon internalization of the uPA:serpin complexes. EMBO J 1997; 16: 2610-2620.
    CrossrefPubMedGoogle Scholar
  • 15 Heegaard CW, Simonsen AC, Oka K. et al. Very low density lipoprotein receptor binds and mediates endocytosis of urokinase-type plasminogen activatortype-1 plasminogen activator inhibitor complex. J Biol Chem 1995; 270: 20855-20861.
    CrossrefPubMedGoogle Scholar
  • 16 Stefansson S, Muhammad S, Cheng XF. et al. Plasminogen activator inhibitor-1 contains a cryptic high affinity binding site for the low density lipoprotein receptor-related protein. J Biol Chem 1998; 273: 6358-6366.
    CrossrefPubMedGoogle Scholar
  • 17 Skeldal S, Larsen JV, Pedersen KE. et al. Binding areas of urokinase-type plasminogen activator-plasmi-nogen activator inhibitor-1 complex for endocytosis receptors of the low-density lipoprotein receptor family, determined by site-directed mutagenesis. FEBS J 2006; 273: 5143-5159.
    CrossrefPubMedGoogle Scholar
  • 18 Webb DJ, Thomas KS, Gonias SL. Plasminogen activator inhibitor 1 functions as a urokinase response modifier at the level of cell signaling and thereby promotes MCF-7 cell growth. J Cell Biol 2001; 152: 741-752.
    CrossrefPubMedGoogle Scholar
  • 19 Campana WM, Li X, Dragojlovic N. et al. The low-density lipoprotein receptor-related protein is a pro-survival receptor in Schwann cells: possible implications in peripheral nerve injury. J Neurosci 2006; 26: 11197-1207.
    CrossrefPubMedGoogle Scholar
  • 20 Montel V, Gaultier A, Lester RD. et al. The low-density lipoprotein receptor-related protein regulates cancer cell survival and metastasis development. Cancer Res 2007; 67: 9817-9824.
    CrossrefPubMedGoogle Scholar
  • 21 Germer M, Kanse SM, Kirkegaard T. et al. Kinetic analysis of integrin-dependent cell adhesion on vitronectin--the inhibitory potential of plasminogen activator inhibitor-1 and RGD peptides. Eur J Biochem 1998; 253: 669-674.
    CrossrefPubMedGoogle Scholar
  • 22 Seiffert D, Smith JW. The cell adhesion domain in plasma vitronectin is cryptic. J Biol Chem 1997; 272: 13705-13710.
    CrossrefPubMedGoogle Scholar
  • 23 Stefansson S, Lawrence DA. The serpin PAI-1 inhibits cell migration by blocking integrin alpha V beta 3 binding to vitronectin. Nature 1996; 383: 441-443.
    CrossrefPubMedGoogle Scholar
  • 24 Lazar MH, Christensen PJ, Du M. et al. Plasminogen Activator Inhibitor-1 Impairs Alveolar Epithelial Repair by Binding to Vitronectin. Am J Respir Cell Mol Biol 2004; 31: 672-678.
    CrossrefPubMedGoogle Scholar
  • 25 Deng G, Curriden SA, Hu G. et al. Plasminogen activator inhibitor-1 regulates cell adhesion by binding to the somatomedin B domain of vitronectin. J Cell Physiol 2001; 189: 23-33.
    CrossrefPubMedGoogle Scholar
  • 26 Schar CR, Blouse GE, Minor KH. et al. A deletion mutant of vitronectin lacking the somatomedin B domain exhibits residual plasminogen activator inhibitor-1-binding activity. J Biol Chem 2008; 283: 10297-10309.
    CrossrefPubMedGoogle Scholar
  • 27 Schar CR, Jensen JK, Christensen A. et al. Characterization of a site on PAI-1 that binds to vitronectin outside of the somatomedin B domain. J Biol Chem 2008; 283: 28487-28496.
    CrossrefPubMedGoogle Scholar
  • 28 Chen SC, Henry DO, Reczek PR. et al. Plasminogen activator inhibitor-1 inhibits prostate tumor growth through endothelial apoptosis. Mol Cancer Ther 2008; 07: 1227-1236.
    CrossrefPubMedGoogle Scholar
  • 29 Jacobson MD, Weil M, Raff MC. Programmed cell death in animal development. Cell 1997; 88: 347-354.
    CrossrefPubMedGoogle Scholar
  • 30 Thompson CB. Apoptosis in the pathogenesis and treatment of disease. Science 1995; 267: 1456-1462.
    CrossrefPubMedGoogle Scholar
  • 31 Hengartner MO. The biochemistry of apoptosis. Nature 2000; 407: 770-776.
    CrossrefPubMedGoogle Scholar
  • 32 Krammer PH. CD95’s deadly mission in the immune system. Nature 2000; 407: 789-795.
    CrossrefPubMedGoogle Scholar
  • 33 Nicholson DW. From bench to clinic with apoptosis-based therapeutic agents. Nature 2000; 407: 810-816.
    CrossrefPubMedGoogle Scholar
  • 34 Jaattela M. Multiple cell death pathways as regulators of tumour initiation and progression. Oncogene 2004; 23: 2746-2756.
    CrossrefPubMedGoogle Scholar
  • 35 Jaattela M. Escaping cell death: survival proteins in cancer. Exp Cell Res 1999; 248: 30-43.
    CrossrefPubMedGoogle Scholar
  • 36 Boudreau N, Sympson CJ, Werb Z. et al. Suppression of ICE and apoptosis in mammary epithelial cells by extra-cellular matrix. Science 1995; 267: 891-893.
    CrossrefPubMedGoogle Scholar
  • 37 Raff MC, Barres BA, Burne JF. et al. Programmed Cell-Death and the Control of Cell-Survival - Lessons from the Nervous-System. Science 1993; 262: 695-700.
    CrossrefPubMedGoogle Scholar
  • 38 Cheng GZ, Park S, Shu SK. et al. Advances of AKT pathway in human oncogenesis and as a target for anticancer drug discovery. Current Cancer Drug Ta rgets 2008; 08: 2-6.
    PubMedGoogle Scholar
  • 39 Henson ES, Gibson SB. Surviving cell death through epidermal growth factor (EGF) signal trans-duction pathways: Implications for cancer therapy. Cell Signalling 2006; 18: 2089-2097.
    CrossrefPubMedGoogle Scholar
  • 40 Li HC, Fan XL, Houghton J. Tumor microenvironment: The role of the tumor stroma in cancer. J Cell Biochem 2007; 101: 805-815.
    CrossrefPubMedGoogle Scholar
  • 41 Liotta LA, Kohn EC. The microenvironment of the tumour-host interface. Nature 2001; 411: 375-379.
    CrossrefPubMedGoogle Scholar
  • 42 Usher PA, Thomsen OF, Iversen P. et al. Expression of urokinase plasminogen activator, its receptor and type-1 inhibitor in malignant and benign prostate tissue. Int J Cancer 2005; 113: 870-880.
    CrossrefPubMedGoogle Scholar
  • 43 Offersen BV, Nielsen BS, Hoyer-Hansen G. et al. The myofibroblast is the predominant plasminogen activator inhibitor-1-expressing cell type in human breast carcinomas. Am J Pathol 2003; 163: 1887-1899.
    CrossrefPubMedGoogle Scholar
  • 44 Illemann M, Hansen U, Nielsen HJ. et al. Leadingedge myofibroblasts in human colon cancer express plasminogen activator inhibitor-1. Am J Clin Pathol 2004; 122: 256-265.
    CrossrefPubMedGoogle Scholar
  • 45 Lindberg P, Larsson A, Nielsen BS. Expression of plasminogen activator inhibitor-1, urokinase receptor and laminin gamma-2 chain is an early coordinated event in incipient oral squamous cell carcinoma. Int J Cancer 2006; 118: 2948-2956.
    CrossrefPubMedGoogle Scholar
  • 46 Hundsdorfer B, Zeilhofer HF, Bock KP. et al. Tumour-associated urokinase-type plasminogen activator (uPA) and its inhibitor PAI-1 in normal and neoplastic tissues of patients with squamous cell cancer of the oral cavity - clinical relevance and prognostic value. J Cranio-Maxillofacial Surg 2005; 33: 191-196.
    CrossrefPubMedGoogle Scholar
  • 47 Providence K, Higgins S, Mullen A. et al. SER-PINE1 (PAI-1) is deposited into keratinocyte migration “trails” and required for optimal monolayer wound repair. Arch Dermatol Res 2008; 300: 303-310.
    CrossrefPubMedGoogle Scholar
  • 48 Kwaan HC, Wang J, Svoboda K. et al. Plasminogen activator inhibitor 1 may promote tumour growth through inhibition of apoptosis. Br J Cancer 2000; 82: 1702-1708.
    CrossrefPubMedGoogle Scholar
  • 49 Kimura M, Soeda S, Oda M. et al. Release of plasminogen activator inhibitor-1 from human astrocytes is regulated by intracellular ceramide. J Neurosci Res 2000; 62: 781-788.
    CrossrefPubMedGoogle Scholar
  • 50 Soeda S, Shinomiya K, Ochiai T. et al. Plasminogen activator inhibitor-1 aids nerve growth factor-induced differentiation and survival of pheochromocytoma cells by activating both the extra-cellular signal-regulated kinase and c-Jun pathways. Neuroscience 2006; 141: 101-108.
    CrossrefPubMedGoogle Scholar
  • 51 Soeda S, Oda M, Ochiai T. et al. Deficient release of plasminogen activator inhibitor-1 from astrocytes triggers apoptosis in neuronal cells. Mol Brain Res 2001; 91: 96-103.
    CrossrefPubMedGoogle Scholar
  • 52 Gill JS, Schenone AE, Podratz JL. et al. Autocrine regulation of neurite outgrowth from PC12 cells by nerve growth factor. Mol Brain Res 1998; 57: 123-131.
    CrossrefPubMedGoogle Scholar
  • 53 Greene LA, Tischler AS. Establishment of a noradrenergic clonal line of rat adrenal pheochromocytoma cells which respond to nerve growth-factor. Proceedings of the National Academy of Sciences of the United States of America 1976; 73: 2424-2428.
    CrossrefPubMedGoogle Scholar
  • 54 Zielke A, Bresalier RS, Siperstein AE. et al. A unique allogenic model of metastatic pheochromocytoma: PC12 rat pheochromocytoma xenografts to nude mice and establishment of metastases-derived PC12 variants. Clin Exp Metastasis 1998; 16: 341-352.
    PubMedGoogle Scholar
  • 55 Lademann U, Romer MU, Jensen PB. et al. Malignant transformation of wild-type but not plasminogen activator inhibitor-1 gene-deficient fibroblasts decreases cellular sensitivity to chemotherapy-mediated apoptosis. Eur J Cancer 2005; 417: 1095-100.
    PubMedGoogle Scholar
  • 56 Romer MU, Kirkebjerg DA, Knud LJ. et al. Indication of a role of plasminogen activator inhibitor type I in protecting murine fibrosarcoma cells against apoptosis. Thromb Haemost 2005; 94: 859-866.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 57 Romer MU, Larsen L, Offenberg H. et al. Plasminogen activator inhibitor 1 protects fibrosarcoma cells from etoposide-induced apoptosis through activation of the PI3K/Akt cell survival pathway. Neoplasia 2008; 10: 1083-1091.
    CrossrefPubMedGoogle Scholar
  • 58 Han BH, Holtzman DM. BDNF protects the neonatal brain from hypoxic-ischemic injury in vivo via the ERK pathway. J Neurosci 2000; 20: 5775-5781.
    CrossrefPubMedGoogle Scholar
  • 59 Buisson A, Nicole O, Docagne F. et al. Up-regulation of a serine protease inhibitor in astrocytes mediates the neuroprotective activity of transforming growth factor beta 1. Faseb J 1998; 12: 1683-1691.
    CrossrefPubMedGoogle Scholar
  • 60 Gabriel C, Ali C, Lesne S. et al. Transforming growth factor alpha-induced expression of type-1 plas-minogen activator inhibitor in astrocytes rescues neurons from excitotoxicity. Faseb J 2003; 16: 277-279.
    PubMedGoogle Scholar
  • 61 Thornton P, Pinteaux E, Allan SM. et al. Matrix metalloproteinase-9 and urokinase plasminogen activator mediate interleukin-1-induced neurotoxicity. Mol Cell Neurosci 2008; 37: 135-142.
    CrossrefPubMedGoogle Scholar
  • 62 Rossignol P, Luttun A, Martin-Ventura JL. et al. Plasminogen activation: a mediator of vascular smooth muscle cell apoptosis in atherosclerotic plaques. J Thromb Haemost 2006; 04: 664-670.
    CrossrefPubMedGoogle Scholar
  • 63 Rossignol P, Angles-Canos E, Lijnen HR. Plasminogen activator inhibitor-I impairs plasminogen activation-mediated vascular smooth muscle cell apoptosis. Thromb Haemost 2006; 96: 665-670.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 64 Horowitz JC, Rogers DS, Simon RH. et al. Plasmi-nogen activation-induced pericellular fibronectin proteolysis promotes fibroblast apoptosis. Am J Respir Cell Mol Biol 2008; 38: 78-87.
    CrossrefPubMedGoogle Scholar
  • 65 Al-Fakhri N, Chavakis T, Schmidt-Woll T. et al. Induction of apoptosis in vascular cells by plasminogen activator inhibitor-1 and high molecular weight kininogen correlates with their anti-adhesive properties. Biol Chem 2003; 384: 423-435.
    PubMedGoogle Scholar
  • 66 Chen YB, Kelm RJ, Budd RC. et al. Inhibition of apoptosis and caspase-3 in vascular smooth muscle cells by plasminogen activator inhibitor type-1. J Cell Biochem 2004; 92: 178-188.
    CrossrefPubMedGoogle Scholar
  • 67 Das F, Ghosh-Choudhury N, Venkatesan B. et al. Akt kinase targets association of CBP with SMAD 3 to regulate TGF betainduced expression of plasminogen activator inhibitor-1. J Cell Physiol 2008; 214: 513-527.
    CrossrefPubMedGoogle Scholar
  • 68 Kietzmann T, Jungermann K, Gorlach A. Regulation of the hypoxia-dependent plasminogen activator inhibitor I expression by MAP kinases. Thromb Haemost 2003; 89: 666-673.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 69 Mukai Y, Wang CY, Rikitake Y, Liao JK. Phosphati-dylinositol 3-kinase/protein kinase Akt negatively regulates plasminogen activator inhibitor type 1 expression in vascular endothelial cells. Am J Physiol-Heart Circul Physiol 2007; 292: H1937-H1942.
    PubMedGoogle Scholar
  • 70 Whitley BR, Beaulieu LM, Carter JC. et al. Phosphatidylinositol 3-kinase/Akt regulates the balance between plasminogen activator inhibitor-1 and urokinase to promote migration of SKOV - 3 ovarian cancer cells. Gynecol Oncol 2007; 104: 470-479.
    CrossrefPubMedGoogle Scholar
  • 71 Balsara RD, Castellino FJ, Ploplis VA. A novel function of plasminogen activator inhibitor-1 in modulation of the AKT pathway in wild-type and plasminogen activator inhibitor-1-deficient endothelial cells. J Biol Chem 2006; 281: 22527-22536.
    CrossrefPubMedGoogle Scholar
  • 72 Kortlever RM, Higgins PJ, Bernards R. Plas-minogen activator inhibitor-1 is a critical downstream target of p53 in the induction of replicative senescence. Nature Cell Biol 2006; 08: 877-U155.
    CrossrefPubMedGoogle Scholar
  • 73 Alfano D, Iaccarino I, Stoppelli MP. Urokinase signaling through its receptor protects against anoikis by increasing BCL-xL expression levels. J Biol Chem 2006; 281: 17758-17767.
    CrossrefPubMedGoogle Scholar
  • 74 Jensen JK, Durand MK, Skeldal S. et al. Construction of a plasminogen activator inhibitor-1 variant without measurable affinity to vitronectin but otherwise normal. FEBS Lett 2004; 556: 175-179.
    CrossrefPubMedGoogle Scholar
  • 75 Xu Z, Balsara RD, Gorlatova NV. et al. Conservation of critical functional domains in murine plasminogen activator inhibitor-1. J Biol Chem 2004; 279: 17914-17920.
    CrossrefPubMedGoogle Scholar