TY - JOUR
T1 - Targeting Forward and Reverse EphB4/EFNB2 Signaling by a Peptide with Dual Functions
AU - Xiong, Chiyi
AU - Wen, Yunfei
AU - Zhao, Jun
AU - Yin, Dengke
AU - Xu, Lingyun
AU - Chelariu-Raicu, Anca
AU - Yao, Cody
AU - Leng, Xiaohong
AU - Liu, Jinsong
AU - Chaudhari, Rajan R.
AU - Zhang, Shuxing
AU - Sood, Anil K.
AU - Li, Chun
N1 - Funding Information:
This work was supported in part by the John S. Dunn Foundation (CL), the Center for RNAi and Non-Coding RNA at The University of Texas MD Anderson Cancer Center (CL & AKS), the Marsha Rivkin Center (YW), the National Comprehensive Cancer Network (YW), the U.S. National Institutes of Health (P50 CA217685, UH3 TR000943, R35 CA209904) (AKS and YW), and the American Cancer Society Research Professor Award (AKS). The Research Animal Support Facility and RPPA core facility are supported by a Cancer Center Support Grant from the U.S. National Institutes of Health (P30CA016672). We thank Lucia Le Roux for help with confocal fluorescence image study, and Kathryn Hale, Scientific Publications Services, Research Medical Library, MD Anderson Cancer Center for her editorial contribution.
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85077940774&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85077940774&partnerID=8YFLogxK
U2 - 10.1038/s41598-020-57477-x
DO - 10.1038/s41598-020-57477-x
M3 - Article
C2 - 31949258
AN - SCOPUS:85077940774
SN - 2045-2322
VL - 10
JO - Scientific reports
JF - Scientific reports
IS - 1
M1 - 520
ER -