Page 20 - Y. Vascular biology

[Y. Vascular biology-11]

Arg-Leu-Tyr-Glu inhibits tumor progression by suppressing

angiogenesis via VEGF receptor-2 antagonism

Wonjin Park¹, Suji Kim¹, Minsik Park¹, Taesam Kim¹, Young-Guen Kwon³, Young-Myeong Kim¹˙²*

¹Molecular and cellular biochemistry, Kangwon national university, Chuncheon 24341, Republic of korea,

²Kangwon institute of inclusive technology, Kangwon national university, Chuncheon 24341, Republic of korea,
³Biochemistry, Yonsei university, Seoul 120-752, Republic of korea

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. 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.