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.

Induction of Urokinase Activity by Retinoic Acid in Two Cell Lines of Neuronal Origin

“…Our previous experiments showed that A1235 cells had the ability to increase the activity of urokinase plasminogen activator (uPA) when treated with certain drugs [23,24]. We hypothesized that these cells possibly began the process of epithelial-mesenchymal transition, with changes in the uPA activity as a sign of reprogramming.…”