engleski

Modulation of urokinase plasminogen activation system by PARP-1 inhibition

Plasminogen activation system is a complex system regulating extracellular proteolysis involved in various physiological and pathological processes. It is precisely regulated on the level of transcription and mRNA degradation and inhibition of its components, urokinase plasminogen activator, its inhibitors PAI-1 and PAI-2 and its receptor. Our aim was to elucidate the role of poly(ADP-ribosyl)ation in the induction of urokinase activity in A1235 glioblastoma cell line, after alkylation damage. A1235 glioblastoma cell line was treated with alkylating agent, alone or in combination with PARP-1 inhibitor, and the cell growth, cell cycle and appearance of senescent cells analyzed. Urokinase activity was determined in conditioned media and gene expression from isolated RNA. DNA damage was assessed by comet assay. As A1235 cells are DNA repair deficient and sensitive on alkylation agents, low doses of these agents caused growth arrest, changes in cell morphology and perturbances in cell cycle, as well as appearance of senescent cells. DNA damage caused by alkylation appeared proportional to the applied agent concentration, and PARP-1 inhibitor addition increased the level of damage. The pattern of modulation of urokinase activity after alkylation damage, caused by addition of PARP-1 inhibitor, indicate the indirect involvement of PARP-1 in urokinase induction, through influence on the DNA damage. We concluded that induction of urokinase activity resulted from the change in net balance between urokinase and PAI-1 transcription, and these processes are regulated through several different signaling pathways.

urokinase ; plasminogen activator ; PARP-1

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