title: Molecular competition between plasminogen activator inhibitors type -1 and -2 for urokinase: Implications for cellular proteolysis and adhesion in cancer.
abstract: Up-regulation of the urokinase plasminogen activation (uPA) system leads to increased cancer invasion and metastasis. Plasminogen activator inhibitors type-1 (PAI-1/SERPINE1) and type-2 (PAI-2/SERPINB2) have similar uPA inhibitory properties yet PAI-1 promotes cell invasion by modulating cell adhesion and migration. High tumour PAI-2 levels are associated with improved prognoses. Herein we show that PAI-2 is capable of inhibiting uPA in the presence of PAI-1, particularly on adherent cells in the presence of vitronectin. This suggests that elevated levels of PAI-2 in the tumour microenvironment could outcompete PAI-1 for uPA inhibition through its inhibitory serpin function. However, PAI-1 modulated cell adhesion in a largely uPA-independent manner consequently PAI-2 could not counteract the effects of PAI-1 on adhesion/migration. Thus studies aimed at further characterising the interplay between PAI-1 and PAI-2 on uPA-dependent pro-invasive processes are warranted.
authors.affiliation: School of Biological Sciences and Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, 2522 NSW, Australia.
authors.forename: Sergei
authors.initials: S
authors.lastname: Lobov
authors.forename: Marie
authors.initials: M
authors.lastname: Ranson
mesh_terms: D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D002633:Chemotaxis; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D006801:Humans; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism*; D017396:Plasminogen Activator Inhibitor 2 / Q000378:metabolism*; D015843:Serpins / Q000378:metabolism; D013997:Time Factors; D059016:Tumor Microenvironment; D020298:U937 Cells; D014568:Urokinase-Type Plasminogen Activator / Q000096:biosynthesis*; D019096:Vitronectin / Q000378:metabolism
chemical_list: D017395:Plasminogen Activator Inhibitor 1; D017396:Plasminogen Activator Inhibitor 2; D015843:Serpins; D019096:Vitronectin; D014568:Urokinase-Type Plasminogen Activator