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.
Highlights
Robust tumor growth results in hypoxia, which promotes the stabilization of the oxygen-sensitive transcription factor hypoxia-inducible factor-1alpha (HIF-1α) that induces the expression of multiple genes implicated in angiogenesis, metabolism, and cell survival [1, 2]
Since recently demonstrated that ArgLeu-Tyr-Glu (RLYE) inhibits in vitro angiogenic behaviors, such as proliferation, migration, and tube-like structure formation, of Human umbilical vein endothelial cells (HUVECs) treated with vascular endothelial growth factor-A (VEGF-A) [19], we hypothesize that RLYE can inhibit tumor growth and metastasis via inhibition of tumor angiogenesis
Treatment with RLYE effectively blocked vascular www.impactjournals.com/oncotarget endothelial growth factor (VEGF)-A-induced increases in the angiogenic characteristics of capillary sprouting and neovessel formation (Figure 1C). These results indicate that RLYE is capable of inhibiting VEGF-A-induced neovessel formation in vivo
Summary
Robust tumor growth results in hypoxia, which promotes the stabilization of the oxygen-sensitive transcription factor hypoxia-inducible factor-1alpha (HIF-1α) that induces the expression of multiple genes implicated in angiogenesis, metabolism, and cell survival [1, 2]. Angiogenesis inhibitors including neutralizing VEGF antibodies and receptor-tyrosine kinase inhibitors, such as bevacizumab, ramucirumab, sunitinib, and axitinib, have been developed and used clinically to treat several solid tumors including colorectal cancer and renal cell carcinoma [8]. They reduce tumor blood vessel abnormalities (that are, vascular junction destabilization, pericyte loss, and vascular permeability and leakage) and improve delivery of anticancer drugs to tumor, thereby potentiating efficacy of their antitumor activity [9, 10]. Small chemical drugs that inhibit VEGF receptor tyrosine kinase can suppress several other tyrosine kinase activities due to low specificity, resulting in unwanted side effects, such as hypertension or proteinuria [12, 13]
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