Varlamova Elena G, Gudkov Sergey V, Turovsky Egor A
Institute of Cell Biophysics of the Russian Academy of Sciences, Federal Research Center "Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences", 142290, Pushchino, Russia.
Prokhorov General Physics Institute of the Russian Academy of Sciences, 38 Vavilove st., 119991, Moscow, Russia.
Arch Biochem Biophys. 2025 Feb;764:110261. doi: 10.1016/j.abb.2024.110261. Epub 2024 Dec 5.
The present study aims to understand the molecular mechanism underlying the therapeutic effect of cerium nanoparticles (CeNPs) in oncology. Cancer cells were treated with different concentrations of pure nanocerium of different sizes synthesized by laser ablation. Due to the not insignificant influence of surface defects and oxygen species on the ROS-modulating properties of cerium nanoparticles, the nanoparticles were not coated with surfactants or organic molecules during synthesis, which could potentially inhibit a number of pro-oxidative effects. Reactive oxygen species (ROS) production, expression of genes encoding redox-status proteins, selenoproteins and proteins regulating cell death and endoplasmic reticulum stress (ER-stress) were investigated as indicators of the molecular mechanism of cancer cell death. Studies were conducted on the effects of cerium nanoparticles on the Ca signaling system of cancer cells of different origins. Mouse fibroblasts (L-929 cell line) were used as non-cancerous ("normal") cells for which a whole series of experiments were performed, and a comparative analysis of the effects of nanoceria. It was found that 75 nm-sized cerium nanoparticles did not affect the redox-status and ROS production of cancer cells. In fibroblast cells, however, this nanoparticle diameter led to a deterioration of the cellular redox status and ROS production in a wide range of nanoparticle concentrations. Larger nanoparticles (100 nm-sized and 160 nm-sized), on the other hand, showed a different effect on cancer cells of different origins. In mouse fibroblast L-929 cells, however, 100 nm-sized or 160 nm-sized CeNPs acted in a high concentration range to disrupt mitochondrial membrane potential and activate early apoptosis. High concentrations of CeNPs were required to increase ROS production, reduce redox-status and induce apoptosis in human A-172 glioblastoma cells compared to the hepatocellular carcinoma cell line HepG2 and the breast cancer cell line MCF-7. In the A-172 glioblastoma cells, ER-stress was also not activated and their Ca signaling system was activated by a significantly higher concentration of CeNPs, which could also contribute to the formation of tolerance of this cancer cell line to nanoceria. The Ca signaling system of mouse fibroblasts was found to be highly sensitive to activation by nanoceria and the cells produced Ca2+ signals with higher amplitude compared to A-172 and MCF-7 cells.
本研究旨在了解铈纳米颗粒（CeNPs）在肿瘤学中治疗作用的分子机制。用激光烧蚀合成的不同尺寸的纯纳米铈对癌细胞进行不同浓度处理。由于表面缺陷和氧物种对铈纳米颗粒的ROS调节特性有不可忽视的影响，因此在合成过程中纳米颗粒未用表面活性剂或有机分子包覆，因为这可能会抑制许多促氧化作用。研究了活性氧（ROS）的产生、编码氧化还原状态蛋白、硒蛋白以及调节细胞死亡和内质网应激（ER应激）的蛋白的基因表达，以此作为癌细胞死亡分子机制的指标。研究了铈纳米颗粒对不同来源癌细胞的钙信号系统的影响。小鼠成纤维细胞（L-929细胞系）用作非癌细胞（“正常”细胞），对其进行了一系列实验，并对纳米氧化铈的作用进行了比较分析。结果发现，75纳米大小的铈纳米颗粒不影响癌细胞的氧化还原状态和ROS产生。然而，在成纤维细胞中，这种纳米颗粒直径在广泛的纳米颗粒浓度范围内导致细胞氧化还原状态恶化和ROS产生。另一方面，较大的纳米颗粒（100纳米大小和160纳米大小）对不同来源的癌细胞表现出不同的作用。然而，在小鼠成纤维细胞L-929中，100纳米大小或160纳米大小的CeNPs在高浓度范围内起作用，破坏线粒体膜电位并激活早期凋亡。与肝癌细胞系HepG2和乳腺癌细胞系MCF-7相比，人A-172胶质母细胞瘤细胞需要高浓度的CeNPs才能增加ROS产生、降低氧化还原状态并诱导凋亡。在A-172胶质母细胞瘤细胞中，ER应激也未被激活，并且其钙信号系统被显著更高浓度的CeNPs激活，这也可能导致该癌细胞系对纳米氧化铈产生耐受性。发现小鼠成纤维细胞的钙信号系统对纳米氧化铈的激活高度敏感，并且与A-172和MCF-7细胞相比，细胞产生的Ca2+信号幅度更高。
