Inhibition of Furin-mediated Processing Results in Suppression of Astrocytoma Cell Growth and Invasiveness

Purpose: Astrocytoma arises in the central nervous system as a tumorof great lethality, in part because of the invasive potential of the neoplastic cells that are able to release extracellular matrix-degrading enzymes. Furin convertase activates several precursor matrix metalloproteases involved in the breakdown of the extracellular matrix. In the present study inhibition of furin was achieved by gene transfer of α 1 -antitrypsin Portland (PDX) cDNA. Experimental Design: This furin inhibitor was transfected into two tumorigenic astrocytoma cell lines. The inhibitory effect was evaluated using in vivo tumorigenicity, invasion, and proliferation assays, as well as by investigating impairment of furin substrate processing. Results: Expression of PDX prevented the s.c. growth of the transfected cells. Invasion assays demonstrated that PDX-transfected cells exhibited a reduced invasive ability in vitro and in vivo . Furthermore, s.c. growth of PDX transfectant xenotransplants showed a significant reduction in size that coincided with a significant decrease of the in vitro doubling time and of the in vivo cell proliferation ability. Additional studies showed that the furin substrates insulin-like growth factor IR, transforming growth factor β and membrane type 1-matrix metalloprotease were not activated in PDX-expressing astrocytoma cells. Conclusions: PDX expression in astrocytoma cells demonstrated a direct mechanistic link between furin inhibition, and decreased astrocytoma proliferation and invasive ability. Because furin inhibition inhibits both invasiveness and cell growth in astrocytoma, furin should be considered a promising target for glioblastoma therapy.