© 2004 by Society
© 2004 by the Society forNeuro-Oncology
Induction of membrane-type-1 matrix metalloproteinase by epidermal growthfactor-mediated signaling in gliomas
Department of Neurosurgery, Medical College ofVirginia Campus, Virginia Commonwealth University, Richmond, VA 23298, USA(T.E.V., W.C.B., H.L.F); Institute of Biomedical andBiomolecular Sciences, University of Portsmouth, School of Pharmacy andBiomedical Sciences, St. Michael's Building, White Swan Road, Portsmouth,Hampshire PO1 2DT, England (H.K.R., G.J.P.); Cellularand 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, WestHospital 8th Floor, 1200 East Broad Street, Richmond, VA 23298, USA(hfillmor{at}hsc.vcu.edu).
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Abstract |
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Increased expression of membrane-type matrix metalloproteinases (MT-MMPs)has previously been reported to correlate with increasing grade of malignancyin gliomas, a relationship shared with alterations in epidermal growth factorreceptor (EGFR) signaling. To investigate the possibility of a causative rolefor EGFR signaling in increasing MT-MMP expression and subsequent peritumoralproteolysis, we characterized glioma cell lines for expression of MT1-MMP,MT2-MMP, MT3-MMP, and MT5-MMP by Western blotting and by quantitativereal-time polymerase chain reaction analysis, and for MMP-2 activity followingepidermal growth factor (EGF) stimulation. EGF stimulation of glioma celllines resulted in a 2- to 4-fold increase in MT1-MMP mRNA levels. Althoughthere were slight differences in MT2-, MT3-, and MT5-MMP mRNA expressionfollowing EGF stimulation, none of these demonstrated an increase similar tothat of MT1-MMP expression. Treatment of high-grade glioma cell lines U251MGand IPSB-18 with EGF for 24 h resulted in a several-fold increase in MT1-MMPprotein (2.5- and 5.1-fold, respectively) and in cyclin D1 (2.9-fold), ascompared to untreated controls. No significant increase was detected in otherMT-MMPs at the protein level. Although there was no detectable increase inproMMP-2 protein, there was an increase in MMP-2 activity. Furthermore, theMT1-MMP induction by EGF was prevented by pretreatment with the EGFR-specifictyrphostin inhibitor AG1478. Similarly, treatment with thephosphatidylinositol 3-kinase inhibitor LY294002 prevented the induction ofMT1-MMP protein by EGF stimulation. These compounds additionally inhibitedEGF-stimulated invasion in Matrigel Transwell assays. Our results indicatethat one mechanism of EGFR-mediated invasiveness in gliomas may involve theinduction of MT1-MMP.
Received August 22, 2003; Accepted March 3, 2004
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