Motif mimetic of epsin perturbs tumor growth and metastasis

Yunzhou Dong*, Hao Wu, H. N. Ashiqur Rahman, Yanjun Liu, Satish Pasula, Kandice L. Tessneer, Xiaofeng Cai, Xiaolei Liu, Baojun Chang, John McManus, Scott Hahn, Jiali Dong, Megan L. Brophy, Lili Yu, Kai Song, Robert Silasi-Mansat, Debra Saunders, Charity Njoku, Hoogeun Song, Padmaja Mehta-D'SouzaRheal Towner, Florea Lupu, Rodger P. McEver, Lijun Xia, Derek Boerboom, R. Sathish Srinivasan, Hong Chen

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)4349-4364
Number of pages16
JournalJournal of Clinical Investigation
Volume125
Issue number12
DOIs
StatePublished - Dec 2015

ASJC Scopus subject areas

  • Medicine(all)

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