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Induction of membrane-type-1 matrix metalloproteinase by epidermal growth factor-mediated signaling in gliomas

Department of Neurosurgery, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA 23298, USA (T.E.V., W.C.B., H.L.F); Institute of Biomedical and Biomolecular Sciences, University of Portsmouth, School of Pharmacy and Biomedical Sciences, St. Michael's Building, White Swan Road, Portsmouth, Hampshire PO1 2DT, England (H.K.R., G.J.P.); Cellular and Molecular Neuro-Oncology Research Group (H.K.R., G.J.P.)

² Address correspondence to Helen L. Fillmore, Department of Neurosurgery, Virginia Commonwealth University, Medical College of Virginia Campus, West Hospital 8th Floor, 1200 East Broad Street, Richmond, VA 23298, USA (hfillmor{at}hsc.vcu.edu).

Abstract

Increased expression of membrane-type matrix metalloproteinases (MT-MMPs) has previously been reported to correlate with increasing grade of malignancy in gliomas, a relationship shared with alterations in epidermal growth factor receptor (EGFR) signaling. To investigate the possibility of a causative role for EGFR signaling in increasing MT-MMP expression and subsequent peritumoral proteolysis, we characterized glioma cell lines for expression of MT1-MMP, MT2-MMP, MT3-MMP, and MT5-MMP by Western blotting and by quantitative real-time polymerase chain reaction analysis, and for MMP-2 activity following epidermal growth factor (EGF) stimulation. EGF stimulation of glioma cell lines resulted in a 2- to 4-fold increase in MT1-MMP mRNA levels. Although there were slight differences in MT2-, MT3-, and MT5-MMP mRNA expression following EGF stimulation, none of these demonstrated an increase similar to that of MT1-MMP expression. Treatment of high-grade glioma cell lines U251MG and IPSB-18 with EGF for 24 h resulted in a several-fold increase in MT1-MMP protein (2.5- and 5.1-fold, respectively) and in cyclin D1 (2.9-fold), as compared to untreated controls. No significant increase was detected in other MT-MMPs at the protein level. Although there was no detectable increase in proMMP-2 protein, there was an increase in MMP-2 activity. Furthermore, the MT1-MMP induction by EGF was prevented by pretreatment with the EGFR-specific tyrphostin inhibitor AG1478. Similarly, treatment with the phosphatidylinositol 3-kinase inhibitor LY294002 prevented the induction of MT1-MMP protein by EGF stimulation. These compounds additionally inhibited EGF-stimulated invasion in Matrigel Transwell assays. Our results indicate that one mechanism of EGFR-mediated invasiveness in gliomas may involve the induction of MT1-MMP.

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