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

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.

Endocytic Adaptor Proteins in Health and Disease: Lessons from Model Organisms and Human Mutations

“…To be able to selectively modify the trafficking of disease-relevant surface proteins will for example open up new avenues for targeted cancer therapies. A prominent example is the use of peptides blocking the Epsin-VEGFR2 interaction to impair tumor angiogenesis which inhibits tumor growth and metastasis in mouse models [332][333][334]. The selective inhibition of endocytosis could also prove useful in combination with cancer therapies, which exploit the antibody-based recognition of surface-localized tumor markers such as EGFR for the delivery of cytotoxic drugs.…”

Endocytic Adaptors in Cardiovascular Disease

“…As discussed above, epsins are multi-functional proteins that act as endocytic adapters and sort ubiquitinated cargoes. Several studies show that epsins sort ubiquitinated proteins, such as vascular endothelial growth factor receptor-2 (VEGFR2) (Pasula et al, 2012;Dong et al, 2015Dong et al, , 2017, the linear ubiquitin chain assembly complex (LUBAC) (Song et al, 2020), the receptor tyrosine-protein kinase ErbB3 (Szymanska et al, 2016), Notch ligands (Tian et al, 2004;Wang and Struhl, 2004;Chen et al, 2009;Xie et al, 2012;Langridge and Struhl, 2017), and low-density lipoprotein receptor-related protein 1 (LRP1) (Brophy et al, 2019), in addition to playing a role in establishing cell polarity (Li L.et al, 2016). Because epsins are involved in the Notch signaling pathway, which is essential for normal embryonic development, the deficiency of both epsins 1 and 2 results in embryonic lethality.…”

Specialised endocytic proteins regulate diverse internalisation mechanisms and signalling outputs in physiology and cancer

“…EPN1 and EPN2 alterations have been shown to play a major role in tumour angiogenesis in line with their function in the VEGF pathway; lack of EPN1 and EPN2 in mouse models of lung carcinoma and melanoma resulted in vascular defects and markedly retarded tumour growth [Pasula et al., 2012]. In recent years, much effort has been made to develop a therapeutic strategy to inhibit the EPN1 and EPN2 interaction with the VEGFR2, with preliminary but promising results in glioma treatment through the application of a chemically synthesised chimeric peptide that caused impaired angiogenesis, retarded tumour growth and increased survival rates in several tumour models [Dong et al., 2018; Dong et al., 2017; Dong et al., 2015].…”