title: Motif mimetic of epsin perturbs tumor growth and metastasis.
abstract: Tumor angiogenesis is critical for cancer progression. In multiple murine models, endothelium-specific epsin deficiency abrogates tumor progression by shifting the balance of VEGFR2 signaling toward uncontrolled tumor angiogenesis, resulting in dysfunctional tumor vasculature. Here, we designed a tumor endothelium-targeting chimeric peptide (UPI) for the purpose of inhibiting endogenous tumor endothelial epsins by competitively binding activated VEGFR2. We determined that the UPI peptide specifically targets tumor endothelial VEGFR2 through an unconventional binding mechanism that is driven by unique residues present only in the epsin ubiquitin-interacting motif (UIM) and the VEGFR2 kinase domain. In murine models of neoangiogenesis, UPI peptide increased VEGF-driven angiogenesis and neovascularization but spared quiescent vascular beds. Further, in tumor-bearing mice, UPI peptide markedly impaired functional tumor angiogenesis, tumor growth, and metastasis, resulting in a notable increase in survival. Coadministration of UPI peptide with cytotoxic chemotherapeutics further sustained tumor inhibition. Equipped with localized tumor endothelium-specific targeting, our UPI peptide provides potential for an effective and alternative cancer therapy.
authors.forename: Yunzhou
authors.initials: Y
authors.lastname: Dong
authors.forename: Hao
authors.initials: H
authors.lastname: Wu
authors.forename: H N Ashiqur
authors.initials: HN
authors.lastname: Rahman
authors.forename: Yanjun
authors.initials: Y
authors.lastname: Liu
authors.forename: Satish
authors.initials: S
authors.lastname: Pasula
authors.forename: Kandice L
authors.initials: KL
authors.lastname: Tessneer
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Cai
authors.forename: Xiaolei
authors.initials: X
authors.lastname: Liu
authors.forename: Baojun
authors.initials: B
authors.lastname: Chang
authors.forename: John
authors.initials: J
authors.lastname: McManus
authors.forename: Scott
authors.initials: S
authors.lastname: Hahn
authors.forename: Jiali
authors.initials: J
authors.lastname: Dong
authors.forename: Megan L
authors.initials: ML
authors.lastname: Brophy
authors.forename: Lili
authors.initials: L
authors.lastname: Yu
authors.forename: Kai
authors.initials: K
authors.lastname: Song
authors.forename: Robert
authors.initials: R
authors.lastname: Silasi-Mansat
authors.forename: Debra
authors.initials: D
authors.lastname: Saunders
authors.forename: Charity
authors.initials: C
authors.lastname: Njoku
authors.forename: Hoogeun
authors.initials: H
authors.lastname: Song
authors.forename: Padmaja
authors.initials: P
authors.lastname: Mehta-D'Souza
authors.forename: Rheal
authors.initials: R
authors.lastname: Towner
authors.forename: Florea
authors.initials: F
authors.lastname: Lupu
authors.forename: Rodger P
authors.initials: RP
authors.lastname: McEver
authors.forename: Lijun
authors.initials: L
authors.lastname: Xia
authors.forename: Derek
authors.initials: D
authors.lastname: Boerboom
authors.forename: R Sathish
authors.initials: RS
authors.lastname: Srinivasan
authors.forename: Hong
authors.initials: H
authors.lastname: Chen
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D020816:Amino Acid Motifs; D000818:Animals; D051379:Mice; D018345:Mice, Knockout; D009362:Neoplasm Metastasis; D009374:Neoplasms, Experimental / Q000098:blood supply* / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010455:Peptides / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D010455:Peptides; C114154:epsin; C000592875:Kdr protein, mouse; D040301:Vascular Endothelial Growth Factor Receptor-2