Inhibition of Matrix Metalloproteinase 14 (MMP-14)-mediated Cancer Cell Migration

Abstract

Matrix metalloproteinases (MMPs) have been shown to be key players in both extracellular matrix remodeling and cell migration during cancer metastasis. MMP-14, a membraneanchored MMP, in particular, is closely associated with these processes. The hemopexin (PEX) domain of MMP-14 has been proposed as the modulating region involved in the molecular cross-talk that initiates cell migration through homodimerization of MMP-14 as well as heterodimerization with the cell surface adhesion molecule CD44. In this study, minimal regions required for function within the PEX domain were investigated through a series of substitution mutations. Blades I and IV were found to be involved in cell migration. We found that blade IV is necessary for MMP-14 homodimerization and that blade I is required for CD44 MMP-14 heterodimerization. Cross-talk between MMP-14 and CD44 results in phosphorylation of EGF receptor and downstream activation of the MAPK and PI3K signaling pathways involved in cell migration. Based on these mutagenesis analyses, peptides mimicking the essential outermost strand motifs within the PEX domain of MMP-14 were designed. These synthetic peptides inhibit MMP-14-enhanced cell migration in a dose-dependent manner but have no effect on the function of other MMPs. Furthermore, these peptides interfere with cancer metastasis without affecting primary tumor growth. Thus, targeting the MMP-14 hemopexin domain represents a novel approach to inhibit MMP-14-mediated cancer dissemination.

The impact of TGF-β1 on the mRNA expression of TβR I, TβR II, Smad4 and the invasiveness of the JEG-3 placental choriocarcinoma cell line

“…They are involved in the degradation of the extracellular matrix (ECM) and play a role in the invasion and metastasis of tumor cells (3,4). Previous studies (36)(37)(38) have suggested that disruption to the ECM during tumor progression is due to an imbalance in the MMP/TIMP ratio. Our study revealed that a significant upregulation of MMP-9 and TIMP-1 protein expression in JEG-3 cells was observed following treatment with TGF-β1 at concentrations of 100 and 200 µg/l.…”

Alteration of MMP-2 and -14 expression by imatinib in HPV-positive and -negative squamous cell carcinoma

“…Invasion through collagen networks and subsequent collagenolysis relies principally on MMP-14, not on secreted MMPs (32). It has now been shown, that MMP-14 interacts with CD44, a membrane-associated glycoprotein, which has also been shown to be a cancer stem cell marker in HNSCC (31,55,56). By this interaction a migratory front is created, which enables the cells to migrate through the tissue in the direction led by MMP-14 (31).…”

“…It has now been shown, that MMP-14 interacts with CD44, a membrane-associated glycoprotein, which has also been shown to be a cancer stem cell marker in HNSCC (31,55,56). By this interaction a migratory front is created, which enables the cells to migrate through the tissue in the direction led by MMP-14 (31). To minimize the remodeling of extracellular matrix necessary for tissue invasion, MMP-14 is localized at the leading edge of the cell, the invadopodia (31,57).…”

“…MMP-14, a membrane-type-MMP, is a critical protein in cancer invasion and metastasis (31). Invasion through collagen networks and subsequent collagenolysis relies principally on MMP-14, not on secreted MMPs (32).…”

“…Most MMPs are destined for secretion into the extracellular milieu. In contrast to this, MMP-14 is a membrane type-MMP (31). It is a critical protein in cancer invasion and metastasis.…”