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Iron Mediates Radiation-Induced Glioblastoma Cell Diffusion
Journal article   Open access   Peer reviewed

Iron Mediates Radiation-Induced Glioblastoma Cell Diffusion

Stephenson Boakye Owusu, Akalanka B. Ekanayake, Alexei V. Tivanski and Michael S. Petronek
International journal of molecular sciences, Vol.26(10), 4755
05/16/2025
DOI: 10.3390/ijms26104755
PMCID: PMC12112530
PMID: 40429897
url
https://doi.org/10.3390/ijms26104755View
Published (Version of record) Open Access

Abstract

Radiation therapy is a standard of care treatment for patients with glioblastoma. However, patients’ survival rate is dismal, with nearly all patients experiencing disease progression after treatment. Enriched iron content associated with increased transferrin receptor (TfR) expression is an indicator of poor glioblastoma patient outcomes; however, the underlying contributions to tumor progression remain elusive. The goal of this present study is to understand how iron metabolism in glioma contributes to radiation-induced glioblastoma cell motility. U251 and a doxycycline-inducible ferritin heavy chain overexpressing U251 (U251 FtH+) cell line were used. For in vitro studies, cells were irradiated with 2 Gy using a 37Cs source, and after 72 h, atomic force microscopy (AFM) nanoindentation was employed to assess changes in cell stiffness following irradiation. Cell motility was studied using temporal confocal microscopy. For in vivo studies, U251 cells were grown in the rear flanks of female nude athymic mice, and the tumor was irradiated with five fractions of 2 Gy (10 Gy). The tumors were then imaged using a GE 7T small animal MRI to assess changes in T2* MRI, and colorimetric analysis of labile iron was performed using ferrozine. Following irradiation, a biomechanical shift characterized by decreased cell stiffness along with increased cell motility occurred in U251 cells, which corresponded to increased TfR expression. FtH overexpression completely reversed the enhanced cell motility following irradiation. Irradiation of U251 tumors induced the same iron metabolic shift. Interestingly, the change in labile iron in U251 tumors corresponded with an increase in T2* relaxation times, suggesting that T2* mapping may serve as a surrogate marker for assessing radiation-induced changes in iron metabolism.
 glioblastoma ionizing radiation iron ferritin overexpression tumor migration

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