title: A small-molecule furin inhibitor inhibits cancer cell motility and invasiveness.
abstract: 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).
authors.affiliation: Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Julia M
authors.initials: JM
authors.lastname: Coppola
authors.forename: Mahaveer S
authors.initials: MS
authors.lastname: Bhojani
authors.forename: Brian D
authors.initials: BD
authors.lastname: Ross
authors.forename: Alnawaz
authors.initials: A
authors.lastname: Rehemtulla
mesh_terms: D000818:Animals; D015153:Blotting, Western; D016466:CHO Cells; D019556:COS Cells; D002465:Cell Movement / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D006224:Cricetinae; D003412:Cricetulus; D004789:Enzyme Activation / Q000187:drug effects; D005354:Fibrosarcoma / Q000473:pathology*; D045683:Furin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D009361:Neoplasm Invasiveness; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*
chemical_list: D015842:Serine Proteinase Inhibitors; D045683:Furin; D020778:Matrix Metalloproteinase 2; C507086:MMP14 protein, human; D053511:Matrix Metalloproteinase 14