RRC ID 81458
Author Tezuka-Kagajo M, Maekawa M, Ogawa A, Hatta Y, Ishii E, Eguchi M, Higashiyama S.
Title Development of Human CBF1-Targeting Single-Stranded DNA Aptamers with Antiangiogenic Activity In Vitro.
Journal Nucleic Acid Ther
Abstract C promoter binding factor 1 (CBF1) (alias RBPJ) is a critical transcription factor involved in Notch signaling. The activation of Notch signaling through CBF1 maintains the angiostatic state of endothelial cells suppressing angiogenesis, that is, the formation of new blood vessels. Vascular endothelial growth factor (VEGF) induces angiogenesis by promoting the proteasomal degradation of CBF1, in addition to endothelial cell proliferation. To date, angiogenic inhibitors targeting VEGF have been successfully used in clinics for cancer and age-related macular degeneration. Most antiangiogenic drugs, however, only target VEGF or VEGF receptors. In this study, to expand the repertoire of antiangiogenic therapeutics, we developed 15 single-stranded deoxyribonucleic acid (ssDNA) aptamers capable of binding to CBF1 with high affinity (Kd; 10-300 nM). To this end, systematic evolution of ligands by the exponential enrichment (SELEX) method was applied. One of the CBF1-binding ssDNA aptamers, Apt-3, inhibited angiogenesis through the activation of Notch signaling in vitro. We found that Apt-3 directly interacted with the LAG1 domain of CBF1. We suggest that the Apt-3 ssDNA aptamer may contribute to the development of a novel angiogenic inhibitor, which does not target VEGF.
Volume 30(6)
Pages 365-378
Published 2020-12-1
DOI 10.1089/nat.2020.0875
PMID 32881630
MeSH Angiogenesis Inhibitors / pharmacology* DNA, Single-Stranded / genetics DNA, Single-Stranded / pharmacology Humans Immunoglobulin J Recombination Signal Sequence-Binding Protein / antagonists & inhibitors Immunoglobulin J Recombination Signal Sequence-Binding Protein / genetics* Neoplasms / drug therapy Neoplasms / genetics Neovascularization, Pathologic / drug therapy* Neovascularization, Pathologic / genetics Protein Binding / drug effects Receptors, Notch / genetics Receptors, Vascular Endothelial Growth Factor / antagonists & inhibitors Receptors, Vascular Endothelial Growth Factor / genetics SELEX Aptamer Technique* Signal Transduction / drug effects Vascular Endothelial Growth Factor A / antagonists & inhibitors Vascular Endothelial Growth Factor A / genetics
Resource
DNA material CSII-CMV-MCS-IRES2-Bsd (RDB04385) pCMV-VSV-G-RSV-Rev (RDB04393) pCAG-HIVgp (RDB04394)