Journal article
Gallium Uncouples Iron Metabolism to Enhance Glioblastoma Radiosensitivity
International journal of molecular sciences, Vol.25(18), 10047
09/18/2024
DOI: 10.3390/ijms251810047
PMCID: PMC11432413
PMID: 39337531
Abstract
Gallium-based therapy has been considered a potentially effective cancer therapy for decades and has recently re-emerged as a novel therapeutic strategy for the management of glioblastoma tumors. Gallium targets the iron-dependent phenotype associated with aggressive tumors by mimicking iron in circulation and gaining intracellular access through transferrin-receptor-mediated endocytosis. Mechanistically, it is believed that gallium inhibits critical iron-dependent enzymes like ribonucleotide reductase and NADH dehydrogenase (electron transport chain complex I) by replacing iron and removing the ability to transfer electrons through the protein secondary structure. However, information regarding the effects of gallium on cellular iron metabolism is limited. As mitochondrial iron metabolism serves as a central hub of the iron metabolic network, the goal of this study was to investigate the effects of gallium on mitochondrial iron metabolism in glioblastoma cells. Here, it has been discovered that gallium nitrate can induce mitochondrial iron depletion, which is associated with the induction of DNA damage. Moreover, the generation of gallium-resistant cell lines reveals a highly unstable phenotype characterized by impaired colony formation associated with a significant decrease in mitochondrial iron content and loss of the mitochondrial iron uptake transporter, mitoferrin-1. Moreover, gallium-resistant cell lines are significantly more sensitive to radiation and have an impaired ability to repair any sublethal damage and to survive potentially lethal radiation damage when left for 24 h following radiation. These results support the hypothesis that gallium can disrupt mitochondrial iron metabolism and serve as a potential radiosensitizer.
Details
- Title: Subtitle
- Gallium Uncouples Iron Metabolism to Enhance Glioblastoma Radiosensitivity
- Creators
- Stephenson B. Owusu - University of IowaAmira Zaher - University of IowaStephen Ahenkorah - University of Iowa, RadiologyDarpah N. PandyaThaddeus J. Wadas - University of IowaMichael S. Petronek - University of Iowa
- Resource Type
- Journal article
- Publication Details
- International journal of molecular sciences, Vol.25(18), 10047
- Publisher
- MDPI; BASEL
- DOI
- 10.3390/ijms251810047
- PMID
- 39337531
- PMCID
- PMC11432413
- ISSN
- 1422-0067
- eISSN
- 1422-0067
- Grant note
- NIH: R21 CA270742 Carver College of Medicine: P30 CA086862
This work was supported by the Radiation Research Foundation (L998500-G) and NIH grant R21 CA270742. The core facilities were supported in part by the Carver College of Medicine and the Holden Comprehensive Cancer Center, NIH P30 CA086862.
- Language
- English
- Date published
- 09/18/2024
- Academic Unit
- Radiology; Iowa Neuroscience Institute; Radiation Oncology; Radiation Research Laboratory; Internal Medicine
- Record Identifier
- 9984719272302771
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