Evaluation of MMP inhibitors for cancer treatment

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Matrix metalloproteinases (MMPs) degrade extracellular matrix (ECM) and support cancer cell invasion in tissue, and eventually metastasis formation. Inhibition of MMP activity is expected to prevent cancer cell growth, invasion and metastasis, and angiogenesis. Among the MMPs, membrane-type MMPs (MT-MMPs) are thought to be important for cancer cell invasiohbecause that are responsible for perice11ular degradation of ECM that is required for cells to traverse in tissue. So far five MT-MMPs are known. One of them, MT1-MMP, is frequently expressed in cancer cells and activates pro-gelatinase A which is able to degrade type IV collagen in the basement membrane.(1) Localization of MT1-MMP was found to be regulated by associating with actin cytoskelton within the cells.(2) To detect MT-MMP activities at subcellular level, we established an assay system by using either FITC-coated gelatin film or DQ-gelatin of which fuluorecense can be activated by proteolytic cleavage.(3) Preparation of catalitically active MT1, MT2, MT3, MT4 and MT5-MMPs were successful by using an expression system in E. coli.