Epidermal growth factor induces matrix metalloproteinase-1 (MMP-1) expression and invasion in glioma cell lines via the MAPK pathway

Abstract

Glioblastoma multiforme (GBM) is an aggressive cancer with a poor survival rate. A key component that contributes to the poor prognosis is the capacity of glioma cells to invade local brain tissue in a diffuse manner. Among various proteases that aid in the process of invasion, matrix metalloproteinase-1 (MMP-1) has been identified as an important contributory factor in various cancers. Apart from its traditional role in cleaving its primary extracellular matrix (ECM) substrates, and like other members of the matrix metalloproteinase family, MMP-1 can activate latent forms of bio-active molecules initiating downstream pro-invasive and pro-oncogenic signaling mechanisms. MMP-1 expression is regulated by several growth factors including epidermal growth factor (EGF). Due to the fact that the epidermal growth factor receptor (EGFR) is aberrantly overexpressed in GBM, we wanted to examine in greater detail the signaling mechanisms by which MMP-1 expression and invasion is driven by EGF in GBM cells. T98G cells treated with EGF resulted in an induction of MMP-1 expression following EGFR activation. Inhibition of EGFR by both pharmacologic and genetic approaches abrogated this induction. Repression of the mitogen activated protein kinase (MAPK) signaling led to the inhibition of EGF-induced MMP-1 whereas the PI3-kinase/AKT signaling was not associated with EGFR-mediated MMP-1 induction. Inhibition of EGFR signaling also led to a decrease in T98G invasion. These data suggest that EGFR mediated MMP-1 regulation is mainly via the MAPK pathway in T98G cells and inhibition of EGFR and MMP-1 results in a decrease in T98G cell invasion.

EphrinA1 Is Released in Three Forms from Cancer Cells by Matrix Metalloproteases

“…Additionally, expression of collagenases, such as MMP-1 and MMP-13, is deregulated in various cancers (9). MMP-1 expression has been documented to occur in GBM cells (4,21), and increased expression correlates with increased tumor grade (58,71) and tumorigenicity (52), and decreased survival in GBM patients (71). Moreover, increased MMP-13 production in glioma cells in response to various stimuli leads to an increase in migration and invasion (43).…”

Fluid shear stress regulates metalloproteinase-1 and 2 in human periodontal ligament cells: Involvement of extracellular signal-regulated kinase (ERK) and P38 signaling pathways

“…MAP Kinases were considered as the most important kinases involved in mechanotransduction (Wang and Thampatty, 2006). Many evidences showed that MMPs expression induced by chemical and physical factors were related to MAP Kinases pathway (Anand et al, 2011;Brauchle et al, 2000;Kook et al, 2011). Indeed, fluid shear stress rapidly activated ERK, P38 and JNK in 5-10 min.…”

Novel Carboxamide-Based Allosteric MEK Inhibitors: Discovery and Optimization Efforts toward XL518 (GDC-0973)

“…Controlled by activation of RAS at the cell surface interior, the subsequent stimulation of Raf and then MEK and ERK serves to regulate a range of key intracellular effectors associated with cell proliferation, 1 invasion, 2 angiogenesis, 3 and apoptotic resistance. 4 Mutated RAS is associated with almost one-third of human cancers, and a majority of malignant melanomas and papillary thyroid cancers harbor B-Raf mutations.…”