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

Yi Yong Baek, Dong Keon Lee, Joohwan Kim, Ji Hee 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

Research output: Contribution to journalArticle

6 Citations (Scopus)

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 VEGFA- 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.

Original languageEnglish
Pages (from-to)11763-11777
Number of pages15
JournalOncotarget
Volume8
Issue number7
DOIs
Publication statusPublished - 2017 Jan 1

Fingerprint

Vascular Endothelial Growth Factor Receptor
Capillary Permeability
Vascular Endothelial Growth Factor A
Neoplasms
irinotecan
Intercellular Signaling Peptides and Proteins
Vascular Endothelial Growth Factor B
Vascular Tissue Neoplasms
Neoplasm Metastasis
Adherens Junctions
arginyl-leucyl-tyrosyl-glutamic acid
Pericytes
Cytotoxins
Fibroblast Growth Factor 2
Growth
Multiple Myeloma
Blood Vessels
Endothelial Cells
Binding Sites
Apoptosis

All Science Journal Classification (ASJC) codes

  • Oncology

Cite this

Baek, Yi Yong ; Lee, Dong Keon ; Kim, Joohwan ; Kim, Ji Hee ; Park, Wonjin ; Kim, Taesam ; Han, Sanghwa ; Jeoung, Dooil ; You, Ji Chang ; Lee, Hansoo ; Won, Moo Ho ; Ha, Kwon Soo ; Kwon, Young-Guen ; Kim, Young Myeong. / Arg-Leu-Tyr-Glu tetrapeptide inhibits tumor progression by suppressing angiogenesis and vascular permeability via VEGF receptor-2 antagonism. In: Oncotarget. 2017 ; Vol. 8, No. 7. pp. 11763-11777.
@article{695839507baf48a1ae5cac75acfc7735,
title = "Arg-Leu-Tyr-Glu tetrapeptide inhibits tumor progression by suppressing angiogenesis and vascular permeability via VEGF receptor-2 antagonism",
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 VEGFA- 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.",
author = "Baek, {Yi Yong} and Lee, {Dong Keon} and Joohwan Kim and Kim, {Ji Hee} and Wonjin Park and Taesam Kim and Sanghwa Han and Dooil Jeoung and You, {Ji Chang} and Hansoo Lee and Won, {Moo Ho} and Ha, {Kwon Soo} and Young-Guen Kwon and Kim, {Young Myeong}",
year = "2017",
month = "1",
day = "1",
doi = "10.18632/oncotarget.14343",
language = "English",
volume = "8",
pages = "11763--11777",
journal = "Oncotarget",
issn = "1949-2553",
publisher = "Impact Journals",
number = "7",

}

Baek, YY, Lee, DK, Kim, J, Kim, JH, Park, W, Kim, T, Han, S, Jeoung, D, You, JC, Lee, H, Won, MH, Ha, KS, Kwon, Y-G & Kim, YM 2017, 'Arg-Leu-Tyr-Glu tetrapeptide inhibits tumor progression by suppressing angiogenesis and vascular permeability via VEGF receptor-2 antagonism', Oncotarget, vol. 8, no. 7, pp. 11763-11777. https://doi.org/10.18632/oncotarget.14343

Arg-Leu-Tyr-Glu tetrapeptide inhibits tumor progression by suppressing angiogenesis and vascular permeability via VEGF receptor-2 antagonism. / Baek, Yi Yong; Lee, Dong Keon; Kim, Joohwan; Kim, Ji Hee; Park, Wonjin; Kim, Taesam; Han, Sanghwa; Jeoung, Dooil; You, Ji Chang; Lee, Hansoo; Won, Moo Ho; Ha, Kwon Soo; Kwon, Young-Guen; Kim, Young Myeong.

In: Oncotarget, Vol. 8, No. 7, 01.01.2017, p. 11763-11777.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Arg-Leu-Tyr-Glu tetrapeptide inhibits tumor progression by suppressing angiogenesis and vascular permeability via VEGF receptor-2 antagonism

AU - Baek, Yi Yong

AU - Lee, Dong Keon

AU - Kim, Joohwan

AU - Kim, Ji Hee

AU - Park, Wonjin

AU - Kim, Taesam

AU - Han, Sanghwa

AU - Jeoung, Dooil

AU - You, Ji Chang

AU - Lee, Hansoo

AU - Won, Moo Ho

AU - Ha, Kwon Soo

AU - Kwon, Young-Guen

AU - Kim, Young Myeong

PY - 2017/1/1

Y1 - 2017/1/1

N2 - 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 VEGFA- 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.

AB - 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 VEGFA- 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.

UR - http://www.scopus.com/inward/record.url?scp=85012894123&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85012894123&partnerID=8YFLogxK

U2 - 10.18632/oncotarget.14343

DO - 10.18632/oncotarget.14343

M3 - Article

VL - 8

SP - 11763

EP - 11777

JO - Oncotarget

JF - Oncotarget

SN - 1949-2553

IS - 7

ER -