Therapeutic Efficacy of a Synthetic Epsin Mimetic Peptide in Glioma Tumor Model: Uncovering Multiple Mechanisms Beyond the VEGF-associated Tumor Angiogenesis

Overview

Journal J Neurooncol

Publisher Springer

Date 2018 Jan 23

PMID 29357089

Citations 4

Authors

Jerry Dong

Debra Saunders

Robert Silasi-Mansat

Lili Yu

Hua Zhu

Florea Lupu

Rheal Towner

Yunzhou Dong

Hong Chen

Affiliations

Soon will be listed here.

Abstract

Binding of epsin ubiquitin-interacting motif (UIM) with ubiquitylated VEGFR2 is a critical mechanism for epsin-dependent VEGFR2 endocytosis and physiological angiogenesis. Deletion of epsins in vessel endothelium produces uncontrolled tumor angiogenesis and retards tumor growth in animal models. The aim of this study is to test the therapeutic efficacy and targeting specificity of a chemically-synthesized peptide, UPI, which compete for epsin binding sites in VEGFR2 and potentially inhibits Epsin-VEGFR2 interaction in vivo, in an attempt to reproduce an epsin-deficient phenotype in tumor angiogenesis. Our data show that UPI treatment significantly inhibits and shrinks tumor growth in GL261 glioma tumor model. UPI peptide specifically targets VEGFR2 signaling pathway revealed by genetic and biochemical approaches. Furthermore, we demonstrated that UPI peptide treatment caused serious thrombosis in tumor vessels and damages tumor cells after a long-term UPI peptide administration. Besides, we revealed that UPI peptides were unexpectedly targeted cancer cells and induced apoptosis. We conclude that UPI peptide is a potent inhibitor to glioma tumor growth through specific targeting of VEGFR2 signaling in the tumor vasculature and cancer cells, which may offer a potentially novel treatment for cancer patients who are resistant to current anti-VEGF therapies.

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