Research Papers:
Arg-Leu-Tyr-Glu tetrapeptide inhibits tumor progression by suppressing angiogenesis and vascular permeability via VEGF receptor-2 antagonism
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Abstract
Yi-Yong Baek1,*, Dong-Keon Lee1,*, Joohwan Kim1, Ji-Hee Kim1, Wonjin Park1, Taesam Kim1, Sanghwa Han2, Dooil Jeoung2, Ji Chang You3, Hansoo Lee4, Moo-Ho Won5, Kwon-Soo Ha1, Young-Guen Kwon6, Young-Myeong Kim1
1Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University, Chuncheon, Gangwon-do, 200-702, South Korea
2Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon, Gangwon-do, 200-702, South Korea
3Department of Pathology, School of Medicine, The Catholic University of Korea, Seoul 137-701, Korea
4Department of and Life Sciences, College of Natural Sciences, Kangwon National University, Chuncheon, Gangwon-do, 200-702, South Korea
5Department of Neurobiology, School of Medicine, Kangwon National University, Chuncheon, Gangwon-do, 200-702, South Korea
6Department 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: [email protected]
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.
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