02 May 2003
PARP inhibitors modulate upregulation of uPA gene expression in transformed endothelial cellsR. Caldini, L. Ciarpallini, M. Del Rosso, E. Barletta, M. Chevanne
Med Sci Monit 2003; 9(1): 6-0 :: ID: 14991
Tumor growth and metastasis are complex processes which involve cell adhesion, proteolytic degradation of extracellular matrix and basement membrane, and cell migration. Several studies have demonstrated a pivotal role of the urokinase-type plasminogen activator (uPA) system in tumor growth, angiogenesis, and metastasis. In fact uPA and uPA receptor (uPAR) are overexpressed by many tumors and their expression correlates with tumor progression and poor prognosis, while downregulation of uPA or uPAR reduces invasiveness and tumorigenesis. In this study we demonstrate that FGF2 upregulation of uPA gene expression is mediated by poly(ADP-ribose) polymerase(PARP) activity. In fact. A specific inhibitor of PARP activity such as 3-aminobenzamide, as well as NAD+ deprivation, prevents FGF2-mediated uPA gene upregulation and cell-associated uPA production in transformed foetal bovine aortic endothelial cells GM7373. We also provide evidence that FGF2 enhances PARP activity by MAPK-dependent phosphorylation. It is noteworthy that also uPA-uPAR interaction controls uPA production through MAPK-dependent activation.Identification of the pathway which modulates upregulation of uPA gene expression, following MAPK activation, may be a new therapeutic target in anticancer therapy. In particular drugs which inhibit PARP activity could be relevant in the control of tumor angiogenesis and metastasis.
Keywords: PARP, uPA, FGF2, MAPK, GM7373 cells
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