Knockdown of EphB1 receptor decreases medulloblastoma cell growth and migration and increases cellular radiosensitization

• Type of Material: Article
• Authors: Shilpa Bhatia, University of Colorado Denver; Nimrah A. Baig, Georgetown University; Olga Timofeeva, Georgetown University; Elena B. Pasquale, Sanford Burnham Medical Research Institute; Kellen Hirsch, University of Colorado Denver; Tobey MacDonald, Emory University; Anatoly Dritschilo, Georgetown University; Yi Chien Lee, Georgetown University; Mark Henkemeyer, University of Texas Southwestern Medical Center; Brian Rood, Children's National Medical Center; Mira Jung, Georgetown University; Xiao-Jing Wang, University of Colorado Denver; Marcel Kool, German Cancer Research Center; Olga Rodriguez, Georgetown University; Chris Albanese, Georgetown University; Sana D. Karam, University of Colorado Denver
• Language: English
• Date: 2015-04-20
• Publisher: Impact Journals
• Publication Version: Final Published Version
• Copyright Statement: © 2015 Bhatia et al.
• License: Creative Commons Attribution 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.18632/oncotarget.3369
• Title of Journal or Parent Work: Oncotarget
• ISSN: 1949-2553
• Volume: 6
• Issue: 11
• Start Page: 8929
• End Page: 8946
• Grant/Funding Information: This work was supported by the Paul Calabresi Career Development Award for Clinical Oncology (K12) and American Cancer Society Institutional Grant (SDK), NIH grant P01CA138390 (EBP), NIH P30 CA51008 (LW) and ABCC (CA and TM).
• Keywords: Eph; cell cycle; radiosensitization; ATAXIA-TELANGIECTASIA; EXPRESSION; SIGNALING PATHWAY; TYROSINE KINASE; CDK INHIBITOR; Life Sciences & Biomedicine; Oncology; PROLIFERATION; ATM; INVASION; GENETIC PROFILES; medulloblastoma; CANCER; Cell Biology; Science & Technology; ACTIVATION
• Research Categories: Health Sciences, Oncology; Health Sciences, General

Abstract

The expression of members of the Eph family of receptor tyrosine kinases and their ephrin ligands is frequently dysregulated in medulloblastomas. We assessed the expression and functional role of EphB1 in medulloblastoma cell lines and engineered mouse models. mRNA and protein expression profiling showed expression of EphB1 receptor in the human medulloblastoma cell lines DAOY and UW228. EphB1 downregulation reduced cell growth and viability, decreased the expression of important cell cycle regulators, and increased the percentage of cells in G1 phase of the cell cycle. It also modulated the expression of proliferation, and cell survival markers. In addition, EphB1 knockdown in DAOY cells resulted in significant decrease in migration, which correlated with decreased β1-integrin expression and levels of phosphorylated Src. Furthermore, EphB1 knockdown enhanced cellular radiosensitization of medulloblastoma cells in culture and in a genetically engineered mouse medulloblastoma model. Using genetically engineered mouse models, we established that genetic loss of EphB1 resulted in a significant delay in tumor recurrence following irradiation compared to EphB1-expressing control tumors. Taken together, our findings establish that EphB1 plays a key role in medulloblastoma cell growth, viability, migration, and radiation sensitivity, making EphB1 a promising therapeutic target.