Targeting Forward and Reverse EphB4/EFNB2 Signaling by a Peptide with Dual Functions.
Sci Rep
; 10(1): 520, 2020 01 16.
Article
em En
| MEDLINE
| ID: mdl-31949258
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Neoplasias Ovarianas
/
Peptídeos
/
Receptor EphB4
/
Efrinas
/
Efrina-B2
Limite:
Animals
/
Female
/
Humans
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article