A Small-Molecule Furin Inhibitor Inhibits Cancer Cell Motility and Invasiveness 1

Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Neoplasia (New York, N.Y.) (Impact Factor: 4.25). 05/2008; 10(4):363-70. DOI: 10.1593/neo.08166
Source: PubMed


Furin, a member the proprotein convertase (PC) family, processes inactive precursor proteins to functional proteins within the Golgi/trans-Golgi network secretory pathway. Furin and other PC family members (furin/PCs) activate proteins vital to proper physiological functioning, including growth factors and hormones, receptors, plasma proteins, and matrix metalloproteases (MMPs). Additionally, the expression and activity of furin/PC are necessary for processing substrates important for cell transformation and tumor progression, metastasis, and angiogenesis. Furin processing of the remodeling protease membrane type-1 matrix metalloproteinase (MT1-MMP) enhances cellular motility and invasiveness, contributing to aggression and metastatic potential cancer cells. Whereas overexpression and activity of furin/PC exacerbate the cancer phenotype, inhibition of its activity decreases or nullifies furin/PC-mediated effects, and thus, inhibition of furin may be a viable route to cancer therapy. Recently, we identified a small-molecule inhibitor of furin, named B3, by high-throughput screening with a K(i) and IC(50) of 12 microM. Here, we show that this cell-permeable, small-molecule compound inhibits furin-mediated cleavage of proMT1-MMP, resulting in decreased MMP-2 activation and cell motility in CHO cells expressing proMT1-MMP. Additionally, this molecule inhibited proMT1-MMP processing, complete MMP-2 maturation, and invasiveness of human fibrosarcoma cells (HT1080).

1 Follower
12 Reads
  • Source
    • "The plasmin is generated from plasminogen in the vicinity of the cancer cells by the action of urokinase plasminogen activator (uPA) which is often localized in the invading front via its receptor (uPAR) [10]. Membrane tethered forms of MMPs like MT1-MMP are another class of proteins present on the membrane in the active form (due to the action of furin), that convert proMMPs into active forms [11] [12]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Abstract Matrix remodeling and invasion of basement membrane are the major determinants of malignant progression. Matrix degrading enzymes play a pivotal role in this process and have been shown to be regulated at multiple levels. Using high metastatic B16F10 and its invasive variant B16BL6 cells, we previously demonstrated that the expression of β1,6 branched N-oligosaccharides promotes cellular adhesion on different matrix components which in turn induces secretion of MMP9. The present investigations report that although the two cell lines do not differ in the expression of uPAR, expression of MT1-MMP is significantly higher on B16BL6 cells. Analysis of the transcripts of tissue inhibitors of matrix metalloproteinases (TIMPs) showed that expression of both TIMP1 and 2 correlates negatively with the invasive potential of cells. CD44 and β1 integrin, the two important receptors involved in motility were identified to carry β1,6 branched N-oligosaccharides in an invasive potential dependent manner. However, their glycosylation status did not appear to influence their surface expression. Although, glycosylation on CD44 had no effect, that on β1 integrin significantly affected association of β1 integrin with MT1-MMP. The results thus demonstrate that the cancer cells use multiple mechanisms for degradation of matrix in a controlled manner to couple it with movement for effective invasion.
    BioMed Research International 08/2014; 2014. DOI:10.1155/2014/804680 · 2.71 Impact Factor
  • Source
    • "We showed that the antigenic CTL epitope could be loaded onto tumor cells following selective cleavage of the amino acid sequence RVKR by furin. Many tumors, including ovarian tumors (for review, see [7]), highly express furin on the cell surface and in the extracellular space [8-12]. We showed that meso-scFv preferentially delivered OVA to mesothelin-expressing ovarian cancer cells, where cleavage by furin released the foreign immunogenic CTL epitope to be loaded on MHC class I molecules of tumor cells [4]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: There is an urgent need to develop targeted therapies for the control of advanced stage ovarian cancer because it is the most deadly gynecologic cancer. Antigen-specific immunotherapy is a promising approach because of the potential of the immune system to specifically target tumors without the toxicity associated with traditional chemoradiation. However, one of the major limitations for antigen-specific cancer immunotherapy is the pre-existing immune tolerance against endogenous targeted tumor antigens that frequently evolves during carcinogenesis. Here, we described the creation of a therapeutic agent comprised of a tumor-homing module fused to a functional domain capable of selectively rendering tumor cells sensitive to foreign antigen-specific CD8+ T cell-mediated immune attack, thereby circumventing many aspects of immune tolerance. The tumor-homing module, NKG2D, specifically binds to NKG2D ligand that is commonly overexpressed in ovarian tumors. The functional domain is comprised of the Fc portion of IgG2a protein and foreign immunogenic CD8+ T cell epitope flanked by furin cleavage sites (R), which can be recognized and cleaved by furin that is highly expressed in the tumor microenvironment. We show that this therapeutic chimeric protein specifically loaded antigenic epitope onto the surface of NKG2D ligand-expressing ovarian tumor cells, rendering ovarian tumors susceptible to antigen-specific CTL-mediated killing in vitro. Furthermore, we show that intraperitoneal administration of our therapeutic chimeric protein followed by adoptive transfer of antigen-specific CD8+ T cells generates potent antitumor effects and significant accumulation of antigen-specific CD8+ T cells in the tumor loci. Our findings have promise for bypassing immune tolerance to enhance cancer immunotherapy.
    Cell and Bioscience 12/2013; 3(1):48. DOI:10.1186/2045-3701-3-48 · 3.63 Impact Factor
  • Source
    • "It is thought that MT1-MMP is activated by the proprotein convertase furin, although furin-independent activation of MT1-MMP has been reported [8–10]. Golubkov et al. demonstrated the importance of the furin-mediated activation of MT1-MMP for tumorigenicity [11], while others used a small molecule inhibitor of the process to reduce the invasiveness of HT1080 cells [12]. Active furin cycles between the Golgi and the cell surface leading to MT1-MMP activation at both locations [9,13,14]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: To test if proteolysis is involved in tumor cell extravasation, we developed an in vitro model where tumor cells cross an endothelial monolayer cultured on a basement membrane. Using this model we classified the ability of the cells to transmigrate through the endothelial cell barrier onto the underlying matrix, and scored this invasion according to the stage of passage through the endothelium. Metalloproteinase inhibitors reduced tumor cell extravasation by at least 35%. Visualization of protease and cell adhesion molecules by confocal microscopy demonstrated the cell surface localization of MMP-2, MMP-9, MT1-MMP, furin, CD44 and αvβ3, during the process of transendothelial migration. By the addition of inhibitors and bio-modulators we assessed the functional requirement of the aforementioned molecules for efficient migration. Proteolytic digestion occurred at the cell-matrix interface and was most evident during the migratory stage. All of the inhibitors and biomodulators affected the transition of the tumor cells into the migratory stage, highlighting the most prevalent use of proteolysis at this particular step of tumor cell extravasation. These data suggest that a proteolytic interface operates at the tumor cell surface within the tumor-endothelial cell microenvironment.
    PLoS ONE 10/2013; 8(10):e78413. DOI:10.1371/journal.pone.0078413 · 3.23 Impact Factor
Show more


12 Reads
Available from

Alnawaz Rehemtulla