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.

Keywords

UPI peptide / epsin / cancer therapy / glioma / tumor angiogenesis

References

[1] Folkman J.Tumor angiogenesis: therapeutic implications..N Engl J Med1971;285:1182-6

[2] Cao Y.A review of Judah Folkman's remarkable achievements in biomedicine..Proc Natl Acad Sci U S A2008;105:13203-5 PMCID:PMC2533169

[3] Gaur P,Samuel S.Targeting tumor angiogenesis..Semin Oncol2009;36:S12-9

[4] Blázquez C,Planas A,Villanueva C,Aragonés J,Jorcano JL.Inhibition of tumor angiogenesis by cannabinoids..FASEB J2003;17:529-31

[5] Ferrara N.Angiogenesis as a therapeutic target..Nature2005;438:967-74

[6] Carmeliet P.Angiogenesis in health and disease..Nat Med2003;9:653-60

[7] Adams RH.Molecular regulation of angiogenesis and lymphangiogenesis..Nat Rev Mol Cell Biol2007;8:464-78

[8] Carmeliet P.Molecular mechanisms and clinical applications of angiogenesis..Nature2011;473:298-307 PMCID:PMC4049445

[9] Jain RK,Clark JW.Lessons from phase III clinical trials on anti-VEGF therapy for cancer..Nat Clin Pract Oncol2006;3:24-40

[10] Carmeliet P.Angiogenesis in cancer and other diseases..Nature2000;407:249-57

[11] Noguera-Troise I,Papadopoulos NJ,Boland P,Lin HC,Thurston G.Blockade of Dll4 inhibits tumour growth by promoting non-productive angiogenesis..Nature2006;444:1032-7

[12] Ridgway J,Wu Y,Liang WC,Kowalski J,Callahan C,Singh M,Tan C,de Sauvage F,Yan M.Inhibition of Dll4 signalling inhibits tumour growth by deregulating angiogenesis..Nature2006;444:1083-7

[13] Niethammer AG,Becker JC,Pertl U,Eliceiri BP.A DNA vaccine against VEGF receptor 2 prevents effective angiogenesis and inhibits tumor growth..Nat Med2002;8:1369-75

[14] Chen H,Slepnev VI,Takei K,Di Fiore PP.Epsin is an EH-domain-binding protein implicated in clathrin-mediated endocytosis..Nature1998;394:793-7

[15] Tessneer KL,Pasula S,Liu X,McManus J,Yu L.Epsin family of endocytic adaptor proteins as oncogenic regulators of cancer progression..J Can Res Updates2013;2:144-50

[16] Chen H,Zatti A,Liu L,Perucco E,Min W,De Camilli P.Embryonic arrest at midgestation and disruption of Notch signaling produced by the absence of both epsin 1 and epsin 2 in mice..Proc Natl Acad Sci U S A2009;106:13838-43 PMCID:PMC2728981

[17] Rahman HN,Dong Y,Wen A,Brophy ML,Cai X,Chang B,Rahman NS,Fernandes C,Xia L,Srinivasan RS.Selective targeting of a novel epsin-VEGFR2 interaction promotes VEGF-mediated angiogenesis..Circ Res2016;118:957-69 PMCID:PMC4798882

[18] Liu X,Song H,Dong Y,Yago T,Chang B,Wu H,Ichise H,Wren JD,Xia L,Chen H.Temporal and spatial regulation of epsin abundance and VEGFR3 signaling are required for lymphatic valve formation and function..Sci Signal2014;7:ra97 PMCID:PMC4226761

[19] Dong Y,Rahman HN,Pasula S,Cai X,Chang B,Hahn S,Brophy ML,Song K,Saunders D,Song H,Towner R,McEver RP,Boerboom D,Chen H.Motif mimetic of epsin perturbs tumor growth and metastasis..J Clin Invest2015;125:4349-64 PMCID:PMC4665789

[20] Pasula S,Dong Y,McManus J,Liu X,Mansat RS,Hahn S,Saunders D,Knight J,Luscinskas F,Towner R,Xia L,De Camilli P,Chen H.Endothelial epsin deficiency decreases tumor growth by enhancing VEGF signaling..J Clin Invest2012;122:4424-38 PMCID:PMC3533553

[21] Chang B,McManus J,Hahn S,Wu H,Chen Y,Dong Y,Rahman R,Xia L.Epsin is required for Dishevelled stability and Wnt signalling activation in colon cancer development..Nat Commun2015;6:6380 PMCID:PMC4397653

[22] Tessneer KL,Cai X,McManus J,Yu L,Chang B,Griffin C,Adams RH.Genetic reduction of vascular endothelial growth factor receptor 2 rescues aberrant angiogenesis caused by epsin deficiency..Arterioscler Thromb Vasc Biol2014;34:331-7 PMCID:PMC3920663

[23] Sugahara KN,Karmali PP,Agemy L,Hanahan D,Ruoslahti E.Tissue-penetrating delivery of compounds and nanoparticles into tumors..Cancer Cell2009;16:510-20 PMCID:PMC2791543

[24] Sugahara KN,Karmali PP,Agemy L,Ruoslahti E.Coadministration of a tumor-penetrating peptide enhances the efficacy of cancer drugs..Science2010;328:1031-5 PMCID:PMC2881692

[25] Weis SM.αV integrins in angiogenesis and cancer..Cold Spring Harb Perspect Med2011;1:a006478 PMCID:PMC3234453

[26] Kovárová M,Arudchandran R,Rivera J.Structure-function analysis of Lyn kinase association with lipid rafts and initiation of early signaling events after Fcepsilon receptor I aggregation..Mol Cell Biol2001;21:8318-28 PMCID:PMC99996

[27] Chen H.The association of epsin with ubiquitinated cargo along the endocytic pathway is negatively regulated by its interaction with clathrin..Proc Natl Acad Sci U S A2005;102:2766-71 PMCID:PMC549477

[28] Kurosaki T.Regulation of B-cell signal transduction by adaptor proteins..Nat Rev Immunol2002;2:354-63

[29] Solution structure of Vps27 UIM-ubiquitin complex important for endosomal sorting and receptor downregulation..EMBO J2003;22:4597-606 PMCID:PMC212737

[30] Bogdanowich-Knipp SJ,Siahaan TJ.The effect of conformation on the solution stability of linear vs. cyclic RGD peptides..J Pept Res1999;53:523-9

[31] Liu S.Radiolabeled cyclic RGD peptides as integrin alpha(v)beta(3)-targeted radiotracers: maximizing binding affinity via bivalency..Bioconjug Chem2009;20:2199-213 PMCID:PMC2795072

[32] á Roxin.Flexible or fixed: a comparative review of linear and cyclic cancer-targeting peptides..Future Med Chem2012;4:1601-18

[33] Hofmann K.A ubiquitin-interacting motif conserved in components of the proteasomal and lysosomal protein degradation systems..Trends Biochem Sci2001;26:347-50

[34] Dahlman JE,Khan OF,Jhunjunwala S,Xing Y,Sahay G,Bader A,Yin H,Dong Y,Seedorf D,Singh Sandhu K,Novobrantseva T,Lytton-Jean AK,Kalish B,Perez M,Dutta P,Charisse K,Fitzgerald K,Danino D,von Andrian UH,Panigrahy D,Koteliansky V,Anderson DG.In vivo endothelial siRNA delivery using polymeric nanoparticles with low molecular weight..Nat Nanotechnol2014;9:648-55 PMCID:PMC4207430

[35] Guo P,Jia D,Auguste DT.ICAM-1-targeted, Lcn2 siRNA-encapsulating liposomes are potent anti-angiogenic agents for triple negative breast cancer..Theranostics2016;6:1-13 PMCID:PMC4679350

[36] Guo P,Yang J,Moses MA.Inhibiting metastatic breast cancer cell migration via the synergy of targeted, pH-triggered siRNA delivery and chemokine axis blockade..Mol Pharm2014;11:755-65 PMCID:PMC3993942

[37] Cong L.Genome engineering using CRISPR-Cas9 system..Methods Mol Biol2015;1239:197-217

[38] Heckl D.Toward whole-transcriptome editing with CRISPR-Cas9..Mol Cell2015;58:560-2

[39] Sternberg SH.Expanding the biologist's toolkit with CRISPR-Cas9..Mol Cell2015;58:568-74