Abstract
α1(IV)NC1 inhibits angiogenesis by regulating MAPK activation, this biological function was partly attributed α1(IV)NC1 binding to α1β1-integrin. However, its potent antiangiogenic activity and the molecular targets of α1(IV)NC1 has not been investigated. In the present study, the regulation of MMP-2 activation by α1(IV)NC1 was evaluated. α1β1-integrin which is required for inhibition of angiogenesis is not playing a role in cellular invasion and inhibition of MMP-2 activation by α1(IV)NC1. We found that α1(IV)NC1 binds the CBD of MMP-2 and forming a stable complex that prevents activation of MMP-2. The antiangiogenic activity of α1(IV)NC1 is mediated, in part, by this binding activity. In addition, up-regulation of TIMP-2 by α1(IV)NC1 led to saturation of MT1-MMP binding sites, which in turn led to inhibition of MMP-2 activation. In-vivo studies using α1-integrin null-mice treated with higher doses of α1(IV)NC1 showed integrin independent inhibition of tumor growth and active-MMP-2, without affecting MMP-9, MMP-7 and angiostatin.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Retracted Publication
MeSH terms
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Angiostatins / metabolism
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Animals
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Collagen Type IV / chemistry
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Collagen Type IV / genetics
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Collagen Type IV / metabolism*
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Enzyme Activation / drug effects
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Human Umbilical Vein Endothelial Cells / drug effects
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Human Umbilical Vein Endothelial Cells / metabolism
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Humans
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Integrin alpha1 / genetics
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Matrix Metalloproteinase 14 / metabolism
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Matrix Metalloproteinase 2 / metabolism*
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Matrix Metalloproteinase 7 / metabolism
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Matrix Metalloproteinase 9 / metabolism
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Mice
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Mice, Knockout
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Neoplasms / drug therapy
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Neoplasms / genetics
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Neoplasms / metabolism
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Neoplasms / pathology
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Neovascularization, Pathologic / drug therapy
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Neovascularization, Pathologic / metabolism
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Neovascularization, Physiologic / drug effects
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Phenylmercuric Acetate / analogs & derivatives
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Phenylmercuric Acetate / pharmacology
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Protein Interaction Domains and Motifs* / genetics
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Recombinant Proteins / genetics
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Recombinant Proteins / isolation & purification
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Recombinant Proteins / pharmacology
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Vascular Endothelial Growth Factor A / pharmacology
Substances
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Collagen Type IV
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Integrin alpha1
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Recombinant Proteins
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Vascular Endothelial Growth Factor A
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4-aminophenylmercuriacetate
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Angiostatins
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Matrix Metalloproteinase 7
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Matrix Metalloproteinase 2
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Matrix Metalloproteinase 9
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Matrix Metalloproteinase 14
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Phenylmercuric Acetate