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Arg-Leu-Tyr-Glu tetrapeptide inhibits tumor progression by suppressing angiogenesis and vascular permeability via VEGF receptor-2 antagonism

2016; Impact Journals LLC; Volume: 8; Issue: 7 Linguagem: Inglês

10.18632/oncotarget.14343

1949-2553

Yi-Yong Baek, Dong-Keon Lee, Joo‐Hwan Kim, Jihee Kim, Wonjin Park, Taesam Kim, Sanghwa Han, Dooil Jeoung, Ji Chang You, Hansoo Lee, Moo‐Ho Won, Kwon‐Soo Ha, Young‐Guen Kwon, Young-Myeong Kim,

Peptidase Inhibition and Analysis

// Yi-Yong Baek 1, * , Dong-Keon Lee 1, * , Joohwan Kim 1 , Ji-Hee Kim 1 , Wonjin Park 1 , Taesam Kim 1 , Sanghwa Han 2 , Dooil Jeoung 2 , Ji Chang You 3 , Hansoo Lee 4 , Moo-Ho Won 5 , Kwon-Soo Ha 1 , Young-Guen Kwon 6 , Young-Myeong Kim 1 1 Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University, Chuncheon, Gangwon-do, 200-702, South Korea 2 Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon, Gangwon-do, 200-702, South Korea 3 Department of Pathology, School of Medicine, The Catholic University of Korea, Seoul 137-701, Korea 4 Department of and Life Sciences, College of Natural Sciences, Kangwon National University, Chuncheon, Gangwon-do, 200-702, South Korea 5 Department of Neurobiology, School of Medicine, Kangwon National University, Chuncheon, Gangwon-do, 200-702, South Korea 6 Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, 120-752, South Korea * These authors have contributed equally to this work Correspondence to: Young-Myeong Kim, email: ymkim@kangwon.ac.kr Keywords: antiangiogenic peptide, tumor growth and metastasis, VEGFR-2, VEGF-A Received: December 21, 2015 Accepted: December 03, 2016 Published: December 28, 2016 ABSTRACT The tetrapeptide Arg-Leu-Tyr-Glu (RLYE) is known to inhibit vascular endothelial growth factor-A (VEGF-A)-induced angiogenesis in vitro . Herein, we examined its underlying mechanism and antitumor activity associated with vascular remodeling. RLYE inhibited VEGF-A-induced angiogenesis in a mouse model and suppressed VEGF-A-induced angiogenic signal cascades in human endothelial cells. However, RLYE showed no inhibitory effect on VEGF-A-induced proliferation and migration of multiple myeloma cells expressing VEGF receptor (VEGFR)-1, but not VEGFR-2. In addition, RLYE showed no inhibitory effect on angiogenic activities induced by VEGF-B, basic fibroblast growth factor, epithermal growth factor, sphingosine-1-phosphate, and placental growth factor. RLYE bound specifically to VEGFR-2 at the VEGF-A binding site, thereby blocking VEGF-A-VEGFR-2 binding and VEGF-A-induced VEGFR-2 internalization. The RLYE peptide inhibited tumor growth and metastasis via suppression of tumor angiogenesis in tumor-bearing mice. Moreover, RLYE showed a synergistic effect of the cytotoxic agent irinotecan on tumor cell apoptosis and tumor progression via tumor vessel normalization due to stabilization of VE-cadherin-mediated adherens junction, improvement of pericyte coverage, and inhibition of vascular leakage in tumors. Our results suggest that RLYE can be used as an antiangiogenic and tumor blood vessel remodeling agent for inhibition of tumor growth and metastasis by antagonizing VEGFR-2, with the synergistic anti-cancer effect via enhancement of drug delivery and therapeutic efficacy.