Journal
JOURNAL OF NEURO-ONCOLOGY
Volume 138, Issue 1, Pages 17-27Publisher
SPRINGER
DOI: 10.1007/s11060-018-2766-z
Keywords
Epsin; Tumor angiogenesis; VEGFR2 signaling; Glioma tumor therapy; Mimetic peptide; UPI
Categories
Funding
- NIH [R01HL-093242, R01HL118676, R01HL-130845, R01HL133216, R01HL137229, P20 RR018758]
- AHA Established Investigator Award
- Department of Defense, Established Investigator Award [W81XWH-11-1-00226]
- National Scientific Development Grant (SDG) from the American Heart Association (AHA) [0835544N]
- AHA-SDG grant [12SDG8760002]
- OCAST grants [AR11-043, HR14-056]
- Fleming Scholar Program in Oklahoma Medical Research Foundation
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Binding of epsin ubiquitin-interacting motif (UIM) with ubiquitylated VEGFR2 is a critical mechanism for epsin-dependent VEGFR2 endocytosis and physiological angiogenesis. Deletion of epsins in vessel endothelium produces uncontrolled tumor angiogenesis and retards tumor growth in animal models. The aim of this study is to test the therapeutic efficacy and targeting specificity of a chemically-synthesized peptide, UPI, which compete for epsin binding sites in VEGFR2 and potentially inhibits Epsin-VEGFR2 interaction in vivo, in an attempt to reproduce an epsin-deficient phenotype in tumor angiogenesis. Our data show that UPI treatment significantly inhibits and shrinks tumor growth in GL261 glioma tumor model. UPI peptide specifically targets VEGFR2 signaling pathway revealed by genetic and biochemical approaches. Furthermore, we demonstrated that UPI peptide treatment caused serious thrombosis in tumor vessels and damages tumor cells after a long-term UPI peptide administration. Besides, we revealed that UPI peptides were unexpectedly targeted cancer cells and induced apoptosis. We conclude that UPI peptide is a potent inhibitor to glioma tumor growth through specific targeting of VEGFR2 signaling in the tumor vasculature and cancer cells, which may offer a potentially novel treatment for cancer patients who are resistant to current anti-VEGF therapies.
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