Targeting Forward and Reverse EphB4/EFNB2 Signaling by a Peptide with Dual Functions.

Abstract

The tyrosine kinase receptor EphB4 is frequently overexpressed in ovarian and other solid tumors and is involved in interactions between tumor cells and the tumor microenvironment, contributing to metastasis. Trans-interaction between EphB4 and its membrane-bound ligand ephrin B2 (EFNB2) mediates bi-directional signaling: forward EFNB2-to-EphB4 signaling suppresses tumor cell proliferation, while reverse EphB4-to-EFNB2 signaling stimulates the invasive and angiogenic properties of endothelial cells. Currently, no small molecule-based, dual-function, EphB4-binding peptides are available. Here, we report our discovery of a bi-directional ephrin agonist peptide, BIDEN-AP which, when selectively internalized via receptor-mediated endocytosis, suppressed invasion and epithelial-mesenchymal transition of ovarian cancer cells. BIDEN-AP also inhibited endothelial migration and tube formation. In vivo, BIDEN-AP and its nanoconjugate CCPM-BIDEN-AP significantly reduced growth of orthotopic ovarian tumors, with CCPM-BIDEN-AP displaying greater antitumor potency than BIDEN-AP. Both BIDEN-AP and CCPM-BIDEN-AP compromised angiogenesis by downregulating epithelial-mesenchymal transition and angiogenic pathways. Thus, we report a novel EphB4-based therapeutic approach against ovarian cancer.

• Authors: Chiyi Xiong, Yunfei Wen, Jun Zhao, Dengke Yin, Lingyun Xu, Anca Chelariu-Raicu, Cody Yao, Xiaohong Leng, Jinsong Liu, Rajan R Chaudhari, Shuxing Zhang, Anil K Sood, Chun Li
• Journal: Scientific reports (Sci Rep) Vol. 10 Issue 1 Pg. 520 (01 16 2020) ISSN: 2045-2322 [Electronic] England
• PMID: 31949258 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• EFNB2 protein, human
• EPHB4 protein, human
• Ephrin-B2
• Ephrins
• Micelles
• Peptides
• Receptor, EphB4

Topics

• Animals
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Ephrin-B2 (metabolism)
• Ephrins (agonists)
• Epithelial-Mesenchymal Transition (drug effects)
• Female
• Humans
• Mice
• Micelles
• Ovarian Neoplasms (drug therapy, metabolism)
• Peptides (administration & dosage, genetics, pharmacology)
• Phosphorylation
• Protein Binding (drug effects)
• Receptor, EphB4 (metabolism)
• Signal Transduction (drug effects)
• Tumor Microenvironment (drug effects)
• Xenograft Model Antitumor Assays