TY - JOUR
T1 - Antisense Oligonucleotides Targeting Y-Box Binding Protein-1 Inhibit Tumor Angiogenesis by Downregulating Bcl-xL-VEGFR2/-Tie Axes
AU - Setoguchi, Kiyoko
AU - Cui, Lin
AU - Hachisuka, Nobutaka
AU - Obchoei, Sumalee
AU - Shinkai, Kentaro
AU - Hyodo, Fuminori
AU - Kato, Kiyoko
AU - Wada, Fumito
AU - Yamamoto, Tsuyoshi
AU - Harada-Shiba, Mariko
AU - Obika, Satoshi
AU - Nakano, Kenji
N1 - Funding Information:
We thank Dr. Hirokazu Nankai (GeneDesign, Inc.) and Izumi Nakamura and Masako Naito (Kyushu University) for technical assistance. We thank Drs. Masao Tanaka and Michihiko Kuwano (Kyushu University) for providing the pancreatic cancer Suit2-GR cell line and YB-1 antibody, respectively. This study was supported by a Health Labour Sciences Research Grant (14524896 to K.N.) from the Japanese Ministry of Health, Labour and Welfare and Project for Development of Innovative Research on Cancer Therapeutics from Japan Agency for Medical Research and Development (16ck0106082h0003 to K.N.) and KAKENHI (Grand-in-Aid for Scientific Research (B) (16H05402 to K.N.) from the Japan Society for the Promotion of Science (JSPS). K. Setoguchi was supported by a grant from the Research Resident Development Program of the Foundation for Promotion of Cancer Research, Japan.
Funding Information:
We thank Dr. Hirokazu Nankai (GeneDesign, Inc.) and Izumi Nakamura and Masako Naito (Kyushu University) for technical assistance. We thank Drs. Masao Tanaka and Michihiko Kuwano (Kyushu University) for providing the pancreatic cancer Suit2-GR cell line and YB-1 antibody, respectively. This study was supported by a Health Labour Sciences Research Grant (14524896 to K.N.) from the Japanese Ministry of Health, Labour and Welfare and Project for Development of Innovative Research on Cancer Therapeutics from Japan Agency for Medical Research and Development ( 16ck0106082h0003 to K.N.) and KAKENHI (Grand-in-Aid for Scientific Research (B) ( 16H05402 to K.N.) from the Japan Society for the Promotion of Science (JSPS). K. Setoguchi was supported by a grant from the Research Resident Development Program of the Foundation for Promotion of Cancer Research, Japan .
Publisher Copyright:
© 2017 The Authors
PY - 2017/12
Y1 - 2017/12
N2 - Y-box binding protein-1 (YB-1), involved in cancer progression and chemoradiation resistance, is overexpressed in not only cancer cells but also tumor blood vessels. In this study, we investigated the potential value of amido-bridged nucleic acid (AmNA)-modified antisense oligonucleotides (ASOs) targeting YB-1 (YB-1 ASOA) as an antiangiogenic cancer therapy. YB-1 ASOA was superior to natural DNA-based ASO or locked nucleic acid (LNA)-modified YB-1 ASO in both knockdown efficiency and safety, the latter assessed by liver function. YB-1 ASOA administered i.v. significantly inhibited YB-1 expression in CD31-positive angiogenic endothelial cells, but not in cancer cells, in the tumors. With regard to the mechanism of its antiangiogenic effects, YB-1 ASOA downregulated both Bcl-xL/VEGFR2 and Bcl-xL/Tie signal axes, which are key regulators of angiogenesis, and induced apoptosis in vascular endothelial cells. In the xenograft tumor model that had low sensitivity to anti-VEGF antibody, YB-1 ASOA significantly suppressed tumor growth; not only VEGFR2 but also Tie2 expression was decreased in tumor vessels. In conclusion, YB-1/Bcl-xL/VEGFR2 and YB-1/Bcl-xL/Tie signal axes play pivotal roles in tumor angiogenesis, and YB-1 ASOA may be feasible as an antiangiogenic therapy for solid tumors.
AB - Y-box binding protein-1 (YB-1), involved in cancer progression and chemoradiation resistance, is overexpressed in not only cancer cells but also tumor blood vessels. In this study, we investigated the potential value of amido-bridged nucleic acid (AmNA)-modified antisense oligonucleotides (ASOs) targeting YB-1 (YB-1 ASOA) as an antiangiogenic cancer therapy. YB-1 ASOA was superior to natural DNA-based ASO or locked nucleic acid (LNA)-modified YB-1 ASO in both knockdown efficiency and safety, the latter assessed by liver function. YB-1 ASOA administered i.v. significantly inhibited YB-1 expression in CD31-positive angiogenic endothelial cells, but not in cancer cells, in the tumors. With regard to the mechanism of its antiangiogenic effects, YB-1 ASOA downregulated both Bcl-xL/VEGFR2 and Bcl-xL/Tie signal axes, which are key regulators of angiogenesis, and induced apoptosis in vascular endothelial cells. In the xenograft tumor model that had low sensitivity to anti-VEGF antibody, YB-1 ASOA significantly suppressed tumor growth; not only VEGFR2 but also Tie2 expression was decreased in tumor vessels. In conclusion, YB-1/Bcl-xL/VEGFR2 and YB-1/Bcl-xL/Tie signal axes play pivotal roles in tumor angiogenesis, and YB-1 ASOA may be feasible as an antiangiogenic therapy for solid tumors.
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U2 - 10.1016/j.omtn.2017.09.004
DO - 10.1016/j.omtn.2017.09.004
M3 - Article
AN - SCOPUS:85041844501
VL - 9
SP - 170
EP - 181
JO - Molecular Therapy - Nucleic Acids
JF - Molecular Therapy - Nucleic Acids
SN - 2162-2531
ER -