Department of Radiation Oncology, Division of Free Radical and Radiation Biology, The University of Iowa, Iowa City, IA 52242, USA.
Department of Radiology, The University of Iowa, Iowa City, IA 52242, USA.
Int J Mol Sci. 2024 Sep 18;25(18):10047. doi: 10.3390/ijms251810047.
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.
基于镓的治疗方法已被认为是一种潜在有效的癌症治疗方法已有数十年的历史，并最近重新作为一种新的治疗策略出现，用于管理神经胶质瘤肿瘤。镓通过模拟循环中的铁并通过转铁蛋白受体介导的内吞作用获得细胞内进入，从而针对与侵袭性肿瘤相关的铁依赖性表型。从机制上讲，人们认为镓通过取代铁并通过蛋白质二级结构去除传递电子的能力来抑制像核糖核苷酸还原酶和 NADH 脱氢酶（电子传递链复合物 I）等关键的铁依赖性酶。然而，关于镓对细胞内铁代谢的影响的信息是有限的。由于线粒体铁代谢是铁代谢网络的中心枢纽，因此本研究的目的是研究镓对神经胶质瘤细胞中线粒体铁代谢的影响。在这里，已经发现硝酸镓可以诱导线粒体铁耗竭，这与 DNA 损伤的诱导有关。此外，镓抗性细胞系的产生揭示了一种高度不稳定的表型，其特征是与线粒体铁含量显著减少和线粒体铁摄取转运蛋白 mitoferrin-1 丧失相关的集落形成受损。此外，镓抗性细胞系对辐射更敏感，并且在辐射后 24 小时内修复任何亚致死性损伤和生存潜在致死性辐射损伤的能力受损。这些结果支持了这样的假设，即镓可以破坏线粒体铁代谢并作为潜在的放射增敏剂。
