Plasminogen Activator Inhibitor-1 Represses Integrin- and Vitronectin-Mediated Cell Migration Independently of Its Function as an Inhibitor of Plasminogen Activation

Kjøller, Lars; Kanse, Sandip M.; Kirkegaard, Tove; Rodenburg, Kees W.; Rønne, Ebbe; Goodman, Simon L.; Preissner, Klaus T.; Ossowski, Lilliana; Andreasen, Peter A.

doi:10.1006/excr.1997.3540

Cited by 221 publications

(181 citation statements)

References 61 publications

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“…The balance between PAI-1 and uPA expression is delicate, but extremely important in regulating cell behavior. A shift in the balance towards PAI-1, whether due to an increase in PAI-1, a decrease in uPA or a combination of both, tends to prevent in vitro migration and invasion of cancer cells, as we and others have shown previously [30,[32][33][34][35]. Likewise, downregulation of PAI-1, up-regulation of uPA or both would shift the balance in favor of uPA and presumably increase in vitro migration and invasion.…”

Section: Discussionmentioning

confidence: 53%

Phosphatidylinositol 3-kinase/Akt regulates the balance between plasminogen activator inhibitor-1 and urokinase to promote migration of SKOV-3 ovarian cancer cells

Whitley

Beaulieu

Carter

et al. 2007

Gynecologic Oncology

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Objectives-Increased levels of urokinase-type plasminogen activator (uPA) are associated with shortened overall survival in ovarian cancer patients. Additionally, elevated levels of the serine protease inhibitor (serpin), plasminogen activator inhibitor-1 (PAI-1), a uPA inhibitor, have also been correlated with an unfavorable prognosis in ovarian cancer. Therefore, it is critical to understand the signaling pathways that regulate PAI-1 and uPA expression in cancer cell migration-invasion.Methods-We studied the PI3K/Akt, Rho kinase/ROCK, p38 MAPK and MEK pathways and their modulation of PAI-1 and uPA expression and wound-induced cell migration in SKOV-3 ovarian cancer cells. The PI3K/Akt pathway was further examined using pharmacological inhibitors (LY294002 and wortmannin), Akt siRNA, constitutively active Akt adenovirus and treatment with IGF-1/insulin in the SKOV-3 cells.Results-The PI3K/Akt pathway negatively regulates PAI-1 expression and positively correlates with migratory abilities and uPA expression in SKOV-3 cells. A reduction in active Akt results in an increase in PAI-1 expression coupled with a decrease in uPA expression to ultimately result in reduced cell migration and invasion. By contrast, an increase in Akt activity reduces PAI-1 expression and results in an increase in SKOV-3 wound-induced cell migration. Furthermore, IGF-1 and insulin stimulated SKOV-3 migration by altering the balance between uPA and PAI-1 to favor uPA, and the enhanced migration was attenuated by treatment with LY294002 indicating PI3K/Akt in this pathway. Conclusions-These results suggest an overall ovarian tumor-protective role for PAI-1, and that the PI3K/Akt signaling pathway regulates the ratio of PAI-1:uPA to either increase or decrease cell migration.

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Section: Discussionmentioning

confidence: 53%

Phosphatidylinositol 3-kinase/Akt regulates the balance between plasminogen activator inhibitor-1 and urokinase to promote migration of SKOV-3 ovarian cancer cells

Whitley

Beaulieu

Carter

et al. 2007

Gynecologic Oncology

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“…PAI-1 competes with the binding of vitronectin to different integrins such as α v β 1 , α v β 3 , α v β 5 , α 11b β 3 , and α 8 β 1 [49]. Accordingly, PAI-1 inhibits integrin-dependent migration of human amnion WISH cells, human carcinoma Hep-2 cells, and smooth muscle cells on vitronectin [50,51]. It also promotes cellular migration by decreasing cell adhesion to vitronectin [52].…”

Section: Physiological Inhibitors Of the Plasminogen Systemmentioning

confidence: 99%

Role of plasminogen activator-plasmin system in tumor angiogenesis

Rakic¹,

Maillard²,

Jost³

et al. 2003

Cellular and Molecular Life Sciences (CMLS)

119

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New blood formation or angiogenesis has become a key target in therapeutic strategies aimed at inhibiting tumor growth and other diseases associated with neovascularization. Angiogenesis is associated with important extracellular remodeling involving different proteolytic systems among which the plasminogen system plays an essential role. It belongs to the large serine proteinase family and can act directly or indirectly by activating matrix metalloproteinases or by liberating growth factors and cytokines sequestered within the extracellular matrix. Migration of endothelial cells is associated with significant upregulation of proteolysis and conversely, immunoneutralization or chemical inhibition of the system reduces angiogenesis in vitro. On the other hand genetically altered mice developed normally without overt vascular anomalies indicating the possibility of compensation by other proteases in vivo. Nevertheless, they have in some experimental settings revealed unanticipated roles for previously characterized proteinases or their inhibitors. In this review, the complex mechanisms of action of the serine proteases in pathological angiogenesis are summarized alongside possible therapeutic applications.

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“…The proteolytic activities of uPA and plasmin can be inhibited by the specific inhibitors plasminogen activator inhibitor-1 (PAI-1) and a2-antiplasmin, respectively (28). Apart from specifically blocking uPA proteolytic function, PAI-1 binds to vitronectin (29) and can competitively block the uPAR-and integrin-dependent interactions with vitronectin (14,30,31), allowing PAI-1 to block adhesion, induce cell detachment, and promote cell motility (14,23,27).…”

mentioning

confidence: 99%

Urokinase Plasminogen Activator Is a Central Regulator of Macrophage Three-Dimensional Invasion, Matrix Degradation, and Adhesion

Fleetwood

Achuthan

Schultz

et al. 2014

The Journal of Immunology

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Urokinase plasminogen activator (uPA) and its receptor (uPAR) coordinate a plasmin-mediated proteolytic cascade that has been implicated in cell adhesion, cell motility, and matrix breakdown, for example, during inflammation. As part of their function during inflammatory responses, macrophages move through tissues and encounter both two-dimensional (2D) surfaces and more complex three-dimensional (3D) interstitial matrices. Based on approaches employing uPA gene–deficient macrophages, plasminogen supplementation, and neutralization with specific protease inhibitors, it is reported in this study that uPA activity is a central component of the invasion of macrophages through a 3D Matrigel barrier; it also has a nonredundant role in macrophage-mediated matrix degradation. For murine macrophages, matrix metalloproteinase-9 activity was found to be required for these uPA-mediated effects. Evidence for a unique role for uPA in the inverse relationship between macrophage adhesion and 2D migration was also noted: macrophage adhesion to vitronectin was enhanced by uPA and blocked by plasminogen activator inhibitor-1, the latter approach also able to enhance in turn the 2D migration on this matrix protein. It is therefore proposed that uPA can have a key role in the inflammatory response at several levels as a central regulator of macrophage 3D invasion, matrix remodeling, and adhesion.

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Plasminogen Activator Inhibitor-1 Represses Integrin- and Vitronectin-Mediated Cell Migration Independently of Its Function as an Inhibitor of Plasminogen Activation

Cited by 221 publications

References 61 publications

Phosphatidylinositol 3-kinase/Akt regulates the balance between plasminogen activator inhibitor-1 and urokinase to promote migration of SKOV-3 ovarian cancer cells

Phosphatidylinositol 3-kinase/Akt regulates the balance between plasminogen activator inhibitor-1 and urokinase to promote migration of SKOV-3 ovarian cancer cells

Role of plasminogen activator-plasmin system in tumor angiogenesis

Urokinase Plasminogen Activator Is a Central Regulator of Macrophage Three-Dimensional Invasion, Matrix Degradation, and Adhesion

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