| 张馨丹,赵正刚,张文轩,李芳红,周素瑾,赵子建.甲硫氨酸限制对骨肉瘤细胞增殖、凋亡及铁死亡的影响[J].,2024,(9):1608-1613 |
| 甲硫氨酸限制对骨肉瘤细胞增殖、凋亡及铁死亡的影响 |
| Effects of Methionine Restriction on the Proliferation, Apoptosis, and Ferroptosis of Osteosarcoma Cells |
| 投稿时间：2023-11-23 修订日期：2023-12-18 |
| DOI：10.13241/j.cnki.pmb.2024.09.002 |
| 中文关键词: 甲硫氨酸限制 骨肉瘤 增殖 铁死亡 |
| 英文关键词: Methionine restriction Osteosarcoma Proliferation Ferroptosis |
| 基金项目:国家重点计划研究发展项目（2018YFA0800603）；广东省"珠江人才计划"项目（2016ZT06Y432）；广东省重点领域研发计划项目（2019B020201015）；广东省基础与应用基础研究联合基金（2023A1515110036） |
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| 中文摘要: |
| 摘要 目的：探讨甲硫氨酸限制对骨肉瘤细胞增殖，凋亡和铁死亡的影响。方法：使用细胞计数检测剥夺甲硫氨酸对三株不同的骨肉瘤细胞系增殖的影响；高通量测序（RNA-seq）分析甲硫氨酸限制后骨肉瘤细胞的转录组学变化；流式细胞术检测细胞周期，凋亡以及ROS，脂质ROS水平；Western blot检测铁死亡关键蛋白谷胱甘肽过氧化物GPX4以及铁死亡标志蛋白前列腺素内过氧化物合成Cox-2的表达。结果：甲硫氨酸限制显著抑制骨肉瘤细胞的增殖（P<0.001）；RNA-seq分析筛选出1719个差异表达基因，基因富集分析发现甲硫氨酸限制可显著激活铁死亡通路并显著抑制细胞周期通路；细胞实验证实甲硫氨酸限制将骨肉瘤细胞阻滞在G2M期，显著诱导凋亡细胞比例增加；同时，细胞内Cox-2的表达增加，GPX4的活性降低，活性氧和脂质活性氧积累，最终导致细胞死亡，且这种作用可以被铁死亡抑制剂Fer-1部分挽救。结论：本研究的结果为甲硫氨酸限制治疗骨肉瘤提供了一定的科学依据。 |
| 英文摘要: |
| ABSTRACT Objective: To investigate the effects of methionine restriction on the proliferation, apoptosis, and ferroptosis of osteosarcoma cells. Methods: Three human osteosarcoma cell lines, MNNG-HOS, U2OS and Saos-2, were treated with normal or methionine-restricted medium, and the effects of methionine restriction on cell growth were assessed by cell counting; High-throughput sequencing (RNA-seq) was employed to analyze the molecular changes in osteosarcoma cells following methionine restriction; Flow cytometry was used to evaluate the cell cycle, cell apoptosis, reactive oxygen species (ROS), and lipid ROS levels; Western blot analysis was conducted to determine the protein expression of key ferroptosis biomarkers GPX4 and COX2. Results: Methionine restriction significantly inhibited the proliferation of osteosarcoma cells (P<0.001); RNA-seq analysis identified 1719 differentially expressed genes. The enrichment analysis indicated that the Ferroptosis pathway was significantly activate, and cell cycle pathway were significantly inhibited (P<0.001); Cytological experiments showed that methionine restriction induced G2/M Cell Cycle arrest and apoptosis in osteosarcoma cells; Besides, methionine restriction could induce ROS, lipid ROS level, and decrease GPX4 protein expression, upregulate COX2 protein expression in osteosarcoma cells. Moreover, methionine restriction Induced ferroptosis could be partially rescued by ferrostatin-1. Conclusion: Our findings provide potential novel therapeutic approaches or combination therapies for treating osteosarcoma while offering a theoretical basis for utilizing methionine restriction therapy against osteosarcoma. |
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