Increased furin activity enhances the malignant phenotype of human head and neck cancer cells.
Many proteins are synthesized as inactive proforms requiring a proteolytic processing to render them active. A variety of proteases catalyze these cleavage reactions. Proprotein convertases are a family of serine proteases capable of activating substrates that will subsequently intervene in extracellular matrix (ECM) degradation, cell growth, differentiation and viral pathogenesis. Furin, the prototype of this family, has been implicated in many physiological and pathological processes. Some of its substrates such as TGF-beta, MT-MMP's, and IGFR-1 have been identified. Overexpression of furin has been observed in several human tumors. In this report we demonstrate that overexpression of furin causes a significant increase in the invasive potential of human tumor cells of low and moderate aggressive potential in vitro and in vivo. SCC12 and SCC15 were transfected with furin cDNA, resulting in efficient processing of furin substrates. An in vivo invasion assay showed enhancement of invasive ability. Inhibition of furin activity with the synthetic inhibitor decanoyl-Arg-Val-Lys-Arg-chloromethyl-ketone, CMK, showed a significant decrease in both processing and in vitro invasiveness. A moderate enhancement in proliferation rate was observed when cells were transfected with furin. CMK treatment resulted in a marked reduction of this effect. Tumors obtained after subcutaneous (s.c.) inoculation of furin-overexpressing cells were larger and developed earlier than the controls. Furin overexpression caused an imbalance in the activation of invasion and proliferation-related substrates leading to the acquisition of an advanced malignant phenotype. In addition, inhibition of furin activity decreases substrate activation, proliferation rate, and invasive potential of cancer cells, suggesting that furin is a potentially useful target for therapeutics.
Bassi
Daniel E
DE
Department of Pathology, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.
Mahloogi
Haleh
H
Lopez De Cicco
Ricardo
R
Klein-Szanto
Andres
A
D002294:Carcinoma, Squamous Cell; D002455:Cell Division; D004791:Enzyme Inhibitors / Q000494:pharmacology; D045683:Furin; D006258:Head and Neck Neoplasms / Q000201:enzymology / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D009361:Neoplasm Invasiveness; D009842:Oligopeptides / Q000494:pharmacology; D011994:Recombinant Proteins / Q000378:metabolism; D013381:Subtilisins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014407:Tumor Cells, Cultured
D004791:Enzyme Inhibitors; D009842:Oligopeptides; D011994:Recombinant Proteins; D013381:Subtilisins; D045683:Furin