title: Modulation of urokinase plasminogen activator system by poly(ADP-ribose)polymerase-1 inhibition.
abstract: The urokinase plasminogen activator (uPA) system is a complex regulator of extracellular proteolysis which is involved in various physiological and pathological processes. The major components of this system are the serine protease uPA, two inhibitors PAI-1 and PAI-2, and the receptor uPAR. It has been previously shown by several groups that the uPA system has an important role in cancer progression and therefore its possible prognostic and therapeutic value has been evaluated. The aim of this study is to tackle the role of poly(ADP-ribosyl)ation in the induction of uPA activity in a glioblastoma cell line, A1235. This cell line is sensitive to alkylation damage and is a model for drug treatment. The components of the uPA system and the level of DNA damage were analyzed after alkylation agent treatment in combination with poly(ADP-ribose)polymerase-1 (PARP-1) inhibition. Here we show that the increase in uPA activity results from the net balance change between uPA and its inhibitor at mRNA level. Further, PARP-1 inhibition exerts its influence on uPA activity through DNA damage increase. Involvement of several signaling pathways, as well as cell specific regulation influencing the uPA system are discussed.
authors.affiliation: Department of Molecular Biology, Faculty of Science, University of Zagreb, Horvatovac 102, 10000, Zagreb, Croatia.
authors.forename: Josip
authors.initials: J
authors.lastname: Madunić
authors.affiliation: Rudjer Boskovic Institute, Bijenička 56, 10000, Zagreb, Croatia.
authors.forename: Mariastefania
authors.initials: M
authors.lastname: Antica
authors.affiliation: Department of Molecular Biology, Faculty of Science, University of Zagreb, Horvatovac 102, 10000, Zagreb, Croatia.
authors.forename: Petra
authors.initials: P
authors.lastname: Cvjetko
authors.affiliation: Department of Molecular Biology, Faculty of Science, University of Zagreb, Horvatovac 102, 10000, Zagreb, Croatia.
authors.forename: Lidija
authors.initials: L
authors.lastname: Požgaj
authors.affiliation: Department of Molecular Biology, Faculty of Science, University of Zagreb, Horvatovac 102, 10000, Zagreb, Croatia. mmatulic@biol.pmf.hr.
authors.forename: Maja
authors.initials: M
authors.lastname: Matulić
keywords: DNA damage; Plasminogen activator inhibitor-1; Poly(ADP-ribose)polymerase-1; Urokinase plasminogen activator