Mimetic peptide of ubiquitin-interacting motif of epsin as a cancer therapeutic-perspective in brain tumor therapy through regulating VEGFR2 signaling.

Yunzhou Dong,Rheal Towner,Jerry Dong,Hong Chen,Hao Wu,Kai Song,Habibunnabi Ashiqur Rahman

doi:10.20517/2574-1209.2016.01

Abstract

Epsins, endocytic adaptor proteins required for internalization of ubiquitylated receptors, are generally upregulated in human cancers. It has been characterized that mice deficient of epsins in the endothelium inhibit tumor growth by dysregulating vascular endothelial growth factor receptor-2 (VEGFR2) signaling and non-productive tumor angiogenesis. Binding of the epsin ubiquitin (Ub)-interacting motif (UIM) with ubiquitylated VEGFR2 is a critical mechanism for epsin-dependent VEGFR2 endocytosis and degradation, indicative of epsin UIM as a potential therapeutic target. A Computer Assisted Drug Design approach was utilized to create the UIM mimetic peptides for the functional competition of epsin binding sites in ubiquitylated VEGFR2 in vivo. Specifically targeting VEGFR2 in the tumor vasculature, the chemically synthesized chimeric UIM peptide, UPI, causes non-functional tumor angiogenesis, retards tumor growth, and increases survival rates in several tumor models. The authors showed that UPI binds ubiquitylated VEGFR2 to form a supercomplex in an Ub-dependent fashion. Collectively, the UPI targeting strategy offers a potentially novel treatment for cancer patients who are resistant to current anti-angiogenic therapies. In this review, the authors outline the main points of this research specifically as a potential application for glioma tumor therapy.

Highlights

Angiogenesis is essential for embryogenesis and postnatal tissue repair
Because the therapeutic efficacy of Bevacizumab is mild in clinical applications where patients could develop resistance to the drug during the course of the treatment, it was imperative to develop alternative compounds to modulate tumor angiogenesis and complement the efficacy of Bevacizumab for those who are resistant to anti-angiogenic therapies
We previously reported that the UIM-dependent binding of epsins with vascular endothelial growth factor receptor-2 (VEGFR2) is required for VEGFR2

Summary

INTRODUCTION

Angiogenesis is essential for embryogenesis and postnatal tissue repair. Deadly cancers, can emerge from tumor angiogenesis, a physiological process involving the production of functional vessels for cancer cell embedment, colonization, growth, and metastasis. Epsins were originally isolated as adaptor proteins in the clatherin-mediated endocytosis of ubiquitylated cell surface receptors.[14,15] Using molecular, cellular, genetic, and mutant mouse models, we have identified that epsins modulate embryogenesis,[16] angiogenesis vasculature,[17] lymph angiogenesis,[18] tumor angiogenesis,[19,20] and cancer progression.[21] Mechanistic studies have demonstrated that epsins target the Notch[16] or ubiquitylated receptor VEGFR2,[17,19,20,22] VEGFR3 or Wnt signaling pathway,[21] and modulate angiogenesis or epithelial cell proliferation. Specific targeting We hypothesize that if a synthetic UIM-containing peptide can be targeted to tumor vessels, it could competitively bind to the ubiquitylated VEGFR2 receptor and block the epsin-VEGFR2 interaction, which could photocopy the knockout of epsins in tumor endothelial cells (TECs). The interaction surfaces of UIM-Ub or UPI-Ub and UIM-VEGFR2 or UPI-VEGFR2 are clearly complementary in terms of charges from

CONCLUSION