Abstract
Current understanding of key transcription factors regulating angiogenesis is limited. Here we show that RNA-cleaving phosphodiester-linked DNA-based enzymes (DNAzymes), targeting a specific motif in the 5' untranslated region of early growth response (Egr-1) mRNA, inhibit Egr-1 protein expression, microvascular endothelial cell replication and migration, and microtubule network formation on basement membrane matrices. Egr-1 DNAzymes blocked angiogenesis in subcutaneous Matrigel plugs in mice, an observation that was independently confirmed by plug analysis in Egr-1-deficient animals, and inhibited MCF-7 human breast carcinoma growth in nude mice. Egr-1 DNAzymes suppressed tumor growth without influencing body weight, wound healing, blood coagulation or other hematological parameters. These agents inhibited endothelial expression of fibroblast growth factor (FGF)-2, a proangiogenic factor downstream of Egr-1, but not that of vascular endothelial growth factor (VEGF). Egr-1 DNAzymes also repressed neovascularization of rat cornea. Thus, microvascular endothelial cell growth, neovascularization, tumor angiogenesis and tumor growth are processes that are critically dependent on Egr-1.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Breast Neoplasms
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Cell Division / physiology
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Cell Movement / physiology
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DNA, Catalytic / metabolism*
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Early Growth Response Protein 1
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Endothelial Growth Factors / metabolism
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Endothelium, Vascular / cytology
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Endothelium, Vascular / metabolism*
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Female
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Fibroblast Growth Factor 2 / metabolism*
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Humans
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Immediate-Early Proteins*
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Intercellular Signaling Peptides and Proteins / metabolism
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Lymphokines / metabolism
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Mice, Nude
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Microtubules / metabolism
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Neoplasm Transplantation / pathology*
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Neoplasms, Experimental / blood supply
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Neoplasms, Experimental / pathology*
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Neovascularization, Pathologic*
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Neovascularization, Physiologic*
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Rats
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Rats, Sprague-Dawley
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Transplantation, Heterologous
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Tumor Cells, Cultured
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors
Substances
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DNA, Catalytic
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DNA-Binding Proteins
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EGR1 protein, human
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Early Growth Response Protein 1
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Egr1 protein, mouse
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Egr1 protein, rat
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Endothelial Growth Factors
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Immediate-Early Proteins
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Intercellular Signaling Peptides and Proteins
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Lymphokines
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Transcription Factors
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors
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Fibroblast Growth Factor 2