Inhibition of matrix degrading enzymes and invasion in human glioblastoma (U87MG) Cells by isoflavones
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Glioblastoma multiforme is a primary brain tumor associated with extensive invasion into surrounding brain tissue. Matrix metalloproteinases (MMPs) and urokinase plasminogen activation (uPA) system are shown to be involved in tumor invasion as they help in degradation of extracellular matrix (ECM) proteins and thus assist in the movement of cells. MMP-2 and 9 were shown to be upregulated in gliomas, suggesting their involvement in invasion. Genistein and biochanin A are isoflavones commonly known as phytoestrogens and have some anticancer properties. We hypothesize that these two isoflavones can induce a lowering of tumor invasion by decreasing the activity of matrix degrading enzymes. In this study we investigated the effects of genistein and biochanin A on invasive activity of U87MG cells using the Calbiochem in vitro invasion assay system. Our results suggest that genistein and biochanin A induced a decrease in invasive activity of U87MG cells in a dose-related manner. Genistein also induced a decrease in EGF-stimulated invasion thereby implicating an involvement of EGF-mediated signaling in invasion. Our results also show that treatment of U87MG cells with the two isoflavones induced decreases in the enzymatic activity of MMP-9 and the protein levels of MT1-MMP and uPAR.
Keywordsglioblastoma invasion isoflavones MMPs uPAR
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Our work was supported in part, by grants from Faculty Research Committee grant # 937, and University Research Committee grant # FY2002-09 at Idaho State University, and NIH/NCRR INBRE grant # P20RR16454.
- 1.Central Brain Tumor Registry of the Unites States. Statistical report: primary brain tumors in the Unites States, 1995–1999. CBTRUS; 2002–2003Google Scholar
- 2.Kufe DW, Pollock RE, Weichselbaum RR, Bast RC, Gansler TS, Holland JF, Frei E: Cancer Medicine 6. BC Decker, New York, 2003, p1195–1231Google Scholar
- 3.Jeffrey Bruce: Glioblastoma Multiforme. eMedicine February, 2005Google Scholar
- 21.Ellerbroek SM, Halbleib JM, Benavidez M, Warmka JK, Wattenberg EV, Stack MS, Hudson LG: Phosphatidylinositol 3-kinase activity in epidermal growth factor-stimulated matrix metalloproteinase-9 production and cell surface association. Cancer Res (61): 1855–1861, 2001Google Scholar
- 22.Huang SM, Li J, Harari PM: Molecular inhibition of angiogenesis and metastatic potential in human squamous cell carcinomas after epidermal growth factor receptor blockade. Mol Cancer Ther 1(7): 507–514, 2002Google Scholar
- 49.Mikkelsen T, Bjerkvig R, Laerum OD, Rosenblum ML: Brain Tumor Invasion: Biological, Clinical, and Therapeutic Considerations. Wiley-Liss, 1998Google Scholar
- 57.Guo P, Imanishi Y, Cackowski FC, Jarzynka MJ, Tao HQ, Nishikawa R, Hirose T, Hu B, Cheng SY: Up-regulation of angiopoietin-2, matrix metalloprotease-2, membrane type 1 metalloprotease, and laminin 5 gamma 2 correlates with the invasiveness of human gliomaAm J Pathol 166(3):877–890, 2005PubMedGoogle Scholar
- 58.Lakka SS, Gondi CS, Yanamandra N, Dinh DH, Olivero WC, Gujrati M, Rao JS: Synergistic down-regulation of urokinase plasminogen activator receptor and matrix metalloproteinase-9 in SNB19 glioblastoma cells efficiently inhibits glioma cell invasion, angiogenesis, and tumor growth Cancer Res 63(10):2454–2461, 2003PubMedGoogle Scholar