The activity of a designer tissue inhibitor of metalloproteinases (TIMP)-1 against native membrane type 1 matrix metalloproteinase (MT1-MMP) in a cell-based environment
被引:20
作者:
Lee, Meng-Huee
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Univ Cambridge, Dept Oncol, Canc Res Inst, Li Ka Shing Ctr, Cambridge CB2 ORE, EnglandUniv Cambridge, Dept Oncol, Canc Res Inst, Li Ka Shing Ctr, Cambridge CB2 ORE, England
Lee, Meng-Huee
[1
]
Atkinson, Susan
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Univ Cambridge, Dept Oncol, Canc Res Inst, Li Ka Shing Ctr, Cambridge CB2 ORE, EnglandUniv Cambridge, Dept Oncol, Canc Res Inst, Li Ka Shing Ctr, Cambridge CB2 ORE, England
Atkinson, Susan
[1
]
Rapti, Magdalini
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Univ Cambridge, Dept Oncol, Canc Res Inst, Li Ka Shing Ctr, Cambridge CB2 ORE, EnglandUniv Cambridge, Dept Oncol, Canc Res Inst, Li Ka Shing Ctr, Cambridge CB2 ORE, England
Rapti, Magdalini
[1
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Handsley, Madeleine
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Univ E Anglia, Sch Biol Sci, Norwich NR4 7TJ, Norfolk, EnglandUniv Cambridge, Dept Oncol, Canc Res Inst, Li Ka Shing Ctr, Cambridge CB2 ORE, England
Handsley, Madeleine
[2
]
Curry, Valerie
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Univ Cambridge, Dept Oncol, Canc Res Inst, Li Ka Shing Ctr, Cambridge CB2 ORE, EnglandUniv Cambridge, Dept Oncol, Canc Res Inst, Li Ka Shing Ctr, Cambridge CB2 ORE, England
Curry, Valerie
[1
]
Edwards, Dylan
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Univ E Anglia, Sch Biol Sci, Norwich NR4 7TJ, Norfolk, EnglandUniv Cambridge, Dept Oncol, Canc Res Inst, Li Ka Shing Ctr, Cambridge CB2 ORE, England
Edwards, Dylan
[2
]
Murphy, Gillian
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Univ Cambridge, Dept Oncol, Canc Res Inst, Li Ka Shing Ctr, Cambridge CB2 ORE, EnglandUniv Cambridge, Dept Oncol, Canc Res Inst, Li Ka Shing Ctr, Cambridge CB2 ORE, England
Murphy, Gillian
[1
]
机构:
[1] Univ Cambridge, Dept Oncol, Canc Res Inst, Li Ka Shing Ctr, Cambridge CB2 ORE, England
[2] Univ E Anglia, Sch Biol Sci, Norwich NR4 7TJ, Norfolk, England
TIMP-1;
MT1-MMP;
Site directed mutagenesis;
Cell-based assays;
Cancer therapeutics;
ACTIVATION;
PROGELATINASE;
INVASION;
CLEAVES;
DOMAIN;
TIMP-2;
CD44;
GELS;
D O I:
10.1016/j.canlet.2009.08.029
中图分类号:
R73 [肿瘤学];
学科分类号:
100214 ;
摘要:
The surface-anchored membrane type 1 matrix metalloproteinase (MT1-MMP) degrades a wide range of extracellular matrix components that includes collagens, laminins, fibronectin and the structural proteoglycan aggrecan. The enzyme modulates cell motility and plays an important role in tumour invasion and proliferation. We have previously designed a variant of tissue inhibitor of metalloproteinase (TIMP)-1 bearing a triple mutation (V4A + P6V + T98L, or N-TIMP-1(mt1)) that forms tight binary complex with the soluble catalytic domain of MT1-MMP [M.H. Lee, M. Rapti, G. Murphy, J. Biol. Chem. 278 (2003) 40224-40230]. Here, we report our latest findings on the cellular potency of this mutant against native MT1-MMP in cell-based environment. We show that N-TIMP-1(mt1) is a highly potent inhibitor against the ectodomain form of MT1-MMP (K-i 9.53 nM) with potential for further development as a therapeutic agent. The mutant is devoid of pro-MMP-2-activating capability but is highly effective in blocking MT1-MMP-mediated FITC-labelled collagen and gelatin film degradation in HTC75 fibrosarcoma and MCF7 breast cancer models. Most encouragingly, N-TIMP-1(mt1) is also effective against CD44 shedding in HTC75 cells and able to prevent tubule formation in human umbilical vascular endothelial cells (HUVEC) in a 3D fibrin gel model. We are interested in the development of the TIMPs as therapeutic agents against MT1-MMP related disorders such as cancers. Our findings here indicate the potential for the design of selective TIMPs with refined specificity and possibility for future therapeutic application. (C) 2009 Elsevier Ireland Ltd. All rights reserved.
机构:
Univ Tokyo, Dept Canc Cell Res, Inst Med Sci, Minato Ku, Tokyo 1088639, JapanUniv Tokyo, Dept Canc Cell Res, Inst Med Sci, Minato Ku, Tokyo 1088639, Japan
Kajita, M
Itoh, Y
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Univ Tokyo, Dept Canc Cell Res, Inst Med Sci, Minato Ku, Tokyo 1088639, JapanUniv Tokyo, Dept Canc Cell Res, Inst Med Sci, Minato Ku, Tokyo 1088639, Japan
Itoh, Y
Chiba, T
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Univ Tokyo, Dept Canc Cell Res, Inst Med Sci, Minato Ku, Tokyo 1088639, JapanUniv Tokyo, Dept Canc Cell Res, Inst Med Sci, Minato Ku, Tokyo 1088639, Japan
Chiba, T
Mori, H
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Univ Tokyo, Dept Canc Cell Res, Inst Med Sci, Minato Ku, Tokyo 1088639, JapanUniv Tokyo, Dept Canc Cell Res, Inst Med Sci, Minato Ku, Tokyo 1088639, Japan
Mori, H
Okada, A
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Univ Tokyo, Dept Canc Cell Res, Inst Med Sci, Minato Ku, Tokyo 1088639, JapanUniv Tokyo, Dept Canc Cell Res, Inst Med Sci, Minato Ku, Tokyo 1088639, Japan
Okada, A
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Kinoh, H
Seiki, M
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Univ Tokyo, Dept Canc Cell Res, Inst Med Sci, Minato Ku, Tokyo 1088639, JapanUniv Tokyo, Dept Canc Cell Res, Inst Med Sci, Minato Ku, Tokyo 1088639, Japan
机构:
Univ Tokyo, Dept Canc Cell Res, Inst Med Sci, Minato Ku, Tokyo 1088639, JapanUniv Tokyo, Dept Canc Cell Res, Inst Med Sci, Minato Ku, Tokyo 1088639, Japan
Kajita, M
Itoh, Y
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Univ Tokyo, Dept Canc Cell Res, Inst Med Sci, Minato Ku, Tokyo 1088639, JapanUniv Tokyo, Dept Canc Cell Res, Inst Med Sci, Minato Ku, Tokyo 1088639, Japan
Itoh, Y
Chiba, T
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Univ Tokyo, Dept Canc Cell Res, Inst Med Sci, Minato Ku, Tokyo 1088639, JapanUniv Tokyo, Dept Canc Cell Res, Inst Med Sci, Minato Ku, Tokyo 1088639, Japan
Chiba, T
Mori, H
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Univ Tokyo, Dept Canc Cell Res, Inst Med Sci, Minato Ku, Tokyo 1088639, JapanUniv Tokyo, Dept Canc Cell Res, Inst Med Sci, Minato Ku, Tokyo 1088639, Japan
Mori, H
Okada, A
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Univ Tokyo, Dept Canc Cell Res, Inst Med Sci, Minato Ku, Tokyo 1088639, JapanUniv Tokyo, Dept Canc Cell Res, Inst Med Sci, Minato Ku, Tokyo 1088639, Japan
Okada, A
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Kinoh, H
Seiki, M
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Univ Tokyo, Dept Canc Cell Res, Inst Med Sci, Minato Ku, Tokyo 1088639, JapanUniv Tokyo, Dept Canc Cell Res, Inst Med Sci, Minato Ku, Tokyo 1088639, Japan