抗MAPK癌症治疗对DNA修复的代谢依赖的二次效应
Fabien Aubé1,2, Nicolas Fontrodona1,2, Laura Guiguettaz1
1Laboratoire de Biologie et Modélisation de la Cellule, Ecole Normale Supérieure de Lyon, CNRS, UMR 5239, Inserm, U1293, Université Claude Bernard Lyon 1, 46 allée d'Italie F-69364 Lyon, France.
NAR cancer
|May 1, 2024
概括
抗癌MAPK抑制剂减少黑色素瘤细胞中的阿斯巴酸和谷氨酸,导致mRNA翻译错误和降解. 这种代谢适应导致DNA修复缺陷和突变.
科学领域:
- 生物化学 生物化学
- 分子生物学分子生物学
- 癌症研究 癌症研究
背景情况:
- 氨基酸的可用性会影响mRNA的翻译在编码级.
- 黑色素瘤细胞容易受到影响蛋白质合成的代谢变化.
研究的目的:
- 为了研究MAPK抑制剂 (MAPKi) 对氨基酸代谢和黑色素瘤中mRNA转化的影响.
- 阐明这些代谢变化对DNA代谢和细胞完整性的下游影响.
主要方法:
- 用MAPKi治疗的黑色素瘤细胞中细胞内氨基酸度 (酸和谷氨酸) 的分析.
- 核糖体造型,以评估mRNA翻译效率,并识别核糖体停滞.
- 在对MAPKi治疗的反应中量化DNA损伤和突变率.
主要成果:
- 在黑色素瘤细胞中,MAPKi治疗减少了细胞内阿斯巴甜酸和谷氨酸的含量.
- 在阿斯巴甜酸和谷氨酸的编码体上观察到核糖体积累,导致mRNA降解.
- 幸存的细胞表现出代谢适应,降解氨基酸以获得能量,并降低与增殖相关的蛋白质的调节.
- 减少DNA修复蛋白的表达增加了DNA损伤和突变.
结论:
- MAPKi通过改变氨基酸的生物可用性来诱导代谢压力,影响mRNA翻译和蛋白质合成.
- 对MAPKi的代谢适应有助于DNA修复缺陷和黑色素瘤细胞中的基因组不稳定性.
- 这些发现强调了代谢重编程和癌症治疗中的DNA损伤反应之间的联系.
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