Radiation responses of 2D and 3D glioblastoma cells : a novel, 3D-specific radioprotective role of VEGF/Akt signaling through functional activation of NHEJ
Gomez-Roman, Natividad and Chong, Ming Y. and Chahal, Sandeep K. and Caragher, Seamus P. and Jackson, Mark R. and Stevenson, Katrina H. and Dongre, Sidhartha A. and Chalmers, Anthony J. (2020) Radiation responses of 2D and 3D glioblastoma cells : a novel, 3D-specific radioprotective role of VEGF/Akt signaling through functional activation of NHEJ. Molecular Cancer Therapeutics, 19 (2). pp. 575-589. ISSN 1535-7163 (https://doi.org/10.1158/1535-7163.MCT-18-1320)
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Abstract
Glioblastoma is resistant to conventional treatments and has dismal prognosis. Despite promising in vitro data, molecular targeted agents have failed to improve outcomes in patients, indicating that conventional two-dimensional (2D) in vitro models of GBM do not recapitulate the clinical scenario. Responses of primary glioblastoma stem-like cells (GSC) to radiation in combination with EGFR, VEGF, and Akt inhibition were investigated in conventional 2D cultures and a three-dimensional (3D) in vitro model of GBM that recapitulates key GBM clinical features. VEGF deprivation had no effect on radiation responses of 2D GSCs, but enhanced radiosensitivity of GSC cultures in 3D. The opposite effects were observed for EGFR inhibition. Detailed analysis of VEGF and EGF signaling demonstrated a radioprotective role of Akt that correlates with VEGF in 3D and with EGFR in 2D. In all cases, positive correlations were observed between increased radiosensitivity, markers of unrepaired DNA damage and persistent phospho-DNA-PK nuclear foci. Conversely, increased numbers of Rad51 foci were observed in radioresistant populations, indicating a novel role for VEGF/Akt signaling in influencing radiosensitivity by regulating the balance between nonhomologous end-joining and homologous recombination–mediated DNA repair. Differential activation of tyrosine kinase receptors in 2D and 3D models of GBM explains the well documented discrepancy between preclinical and clinical effects of EGFR inhibitors. Data obtained from our 3D model identify novel determinants and mechanisms of DNA repair and radiosensitivity in GBM, and confirm Akt as a promising therapeutic target in this cancer of unmet need.
ORCID iDs
Gomez-Roman, Natividad ORCID: https://orcid.org/0000-0002-2325-7517, Chong, Ming Y., Chahal, Sandeep K., Caragher, Seamus P., Jackson, Mark R., Stevenson, Katrina H., Dongre, Sidhartha A. and Chalmers, Anthony J.;-
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Item type: Article ID code: 74953 Dates: DateEvent29 February 2020Published31 October 2019Published Online24 October 2019AcceptedSubjects: Medicine > Internal medicine > Neoplasms. Tumors. Oncology (including Cancer) Department: Faculty of Science > Strathclyde Institute of Pharmacy and Biomedical Sciences Depositing user: Pure Administrator Date deposited: 17 Dec 2020 16:53 Last modified: 23 Nov 2024 01:15 Related URLs: URI: https://strathprints.strath.ac.uk/id/eprint/74953