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

Abstract

Pro-protein convertases such as furin are expressed in many human tumor lines and primary tumors. Furin processes stromelysin-3, membrane type 1 matrix metalloproteinase (MMPs) involved in tumor cell invasiveness, as well as growth factors such as transforming growth factor ␤1. Evaluation of furin expression in head and neck squamous cell carcinoma (HNSCC) cells exhibiting 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 furin-expressing invasive HNSCC cell lines. The effects of PDX transfection were evaluated in vivo and in vitro to determine changes in the malignant phenotype. Transfection of HNSCC cell lines with PDX resulted in significant decrease or absence of tumorigenicity after s.c. inoculation into severe combined immunodeficient mice. Likewise, in vitro invasiveness was reduced Ϸ50%. The in vivo invasion assay using tracheal xenotransplants showed even more drastic reductions of the invasive ability of PDX-transfected cells (up to an 80% decrease). PDX-transfected cells did not invade or penetrated less into the tracheal wall tissues than their vector alone-transfected counterparts. In addition, the former cells showed a remarkable decrease in MMP-2 processing and activity. After PDX transfection the cells were less efficient in processing the tumor progressionassociated furin substrates transforming growth factor ␤1 and pro-membrane type 1-MMP. These findings indicate that furin inhibition is a feasible approach to attenuate and even abolish certain critical attributes of the advanced malignant phenotype. Thus, furin should be considered as a promising target for cancer therapy.alpha1-PDX ͉ squamous cell carcinoma ͉ invasion ͉ tumor progression

Inhibition of Proprotein Convertases Enhances Cell Migration and Metastases Development of Human Colon Carcinoma Cells in a Rat Model

“…We, and others, previously observed that PCs inhibition leads to delayed tumor development and reduced tumor volume in nude or immunodeficient mice. [22][23][24][25] However, herein we used immunosuppressed newborn rats to test the metastatic dissemination. Results obtained with this animal model show that the role of PCs in tumor development and progression is far from being as simple as suggested by previous observations.…”

“…49 Differences in stromal microenvironment might thus explain the discrepancies between the present in vivo results and invasion assays using tracheal xenotransplants. 22,25 Given the role of PCs in biological activation of inactive precursors, their inhibition could be an interesting clinical strategy against cancers by simultaneously disrupting the function of numerous proteins involved in tumor cell invasion and tumor progression. 15,20 However, the effect of ␣1-PDX on certain convertase substrates, like adhesion molecules, MMPs or other proteases, that could potentially contribute to tumorigenesis should be taken into account when considering PC inhibitors as therapeutic tools for a variety of diseases, including cancer.…”

“…22 Conversely, inhibition of PCs resulted in reduced in vivo tumorigenicity and in vitro cell proliferation. [23][24][25] We have recently reported that the absence of endoproteolytic cleavage of ␣v integrins, by overexpression of ␣1-PDX in colonic cancer cells, has important consequences on signal transduction pathways leading to alterations in integrin function such as cell adhesion. 10 PCs inhibition also leads to reduced cell proliferation in vitro and delayed tumor growth in nude mice inoculated with tumor cells.…”

Furin regulates the intracellular activation and the uptake rate of cell surface-associated MT1-MMP

“…There is evidence that a portion of the cellular MT1-MMP pool is processed by additional PCs and also by autocatalysis directly at the cell surface (Sato et al, 1999;Yana and Weiss, 2000;Rozanov and Strongin, 2003;Deryugina et al, 2004). Inhibition of MT1-MMP activation by furin inhibitors, including a nanomolar range a1-anti-trypsin variant Portland (PDX) inhibitor repressed motility and tumorigenicity of cancer cells (Bassi et al, 2001).…”

Increased Furin Activity Enhances the Malignant Phenotype of Human Head and Neck Cancer Cells

“…11 Furin inhibition with ␣-1 PDX, a specific inhibitor of this PC, 12 demonstrated that the levels of processed MT1-MMP as well as the invasion ability of cells was greatly diminished in head and neck squamous cell carcinoma (HNSCC) cell lines. 13 On the other hand, some reports argue that MT1-MMP can be activated in a furin-independent manner suggesting that, at least in some systems, furin may not be crucial to tumor progression. 14 Furin can process another metalloproteinase, stromelysin-3, 15 which is able to degrade ␣-1 proteinase inhibitor, a serin protease inhibitor, 16 contributing to enhance extracellular matrix turnover.…”