Furin inhibition results in absent or decreased invasiveness and tumorigenicity of human cancer cells

Pro-protein convertases such as Turin are expressed in many human tumor lin es and primary tumors. Furin processes stromelysin-3, membrane type 1 matri x metalloproteinase (MMPs) involved in tumor cell invasiveness, as well as growth factors such as transforming growth factor beta1. Evaluation of furi n expression in head and neck squamous cell carcinoma (HNSCC) cells exhibit ing different invasive ability showed that furin overexpression correlated with their respective invasiveness. The use of a selective furin inhibitor, alpha 1-PDX (PDX) was studied in three Turin-expressing invasive HNSCC cel l lines. The effects of PDX transfection were evaluated in vivo and in vitr o to determine changes in the malignant phenotype. Transfection of HNSCC ce ll lines with PDX resulted in significant decrease or absence of tumorigeni city after s.c. inoculation into severe combined immunodeficient mice. Like wise, in vitro invasiveness was reduced approximate to 50%, The in vivo inv asion assay using tracheal xenotransplants showed even more drastic reducti ons of the invasive ability of PDX-transfected cells (up to an 80% decrease ). PDX-transfected cells did not invade or penetrated less into the trachea l wall tissues than their vector alone-transfected counterparts. In additio n, the former cells showed a remarkable decrease in MMP-2 processing and ac tivity. After PDX transfection the cells were less efficient in processing the tumor progression-associated furin substrates transforming growth facto r beta1 and pro-membrane type 1-MMP. These findings indicate that furin inh ibition is a feasible approach to attenuate and even abolish certain critic al attributes of the advanced malignant phenotype. Thus, furin should be co nsidered as a promising target for cancer therapy.