在MEK抑制剂诱导的加工体溶解后,KRAS和NRAS的翻译增加
Olivia Vidal-Cruchez1,2, Victoria J Nicolini1,2, Tifenn Rete1,2
1Université Côte d'Azur, Institute of Research on Cancer and Aging of Nice (IRCAN), CNRS, INSERM, Centre Antoine Lacassagne, 28, Avenue de Valombrose, 06107 Nice, France.
Cancers
|June 28, 2023
概括
线素激活蛋白激酶 (MAPK) 途径抑制剂通过溶解处理体 (P-body) 生物凝聚物来增加RAS基因转换,从而导致癌症药物耐药性. 这揭示了MAPK信号传输中的新反循环.
科学领域:
- 分子生物学分子生物学
- 癌症生物学 癌症生物学
- 细胞生物学 细胞生物学
背景情况:
- 甲基因激活蛋白激酶 (MAPK) 路径过度激活驱动了许多人类癌症.
- 癌症药物耐药性源于针对该途径的疗法,通常与补偿性RAS过度表达有关.
- RAS过度表达和随后的耐药性背后的机制尚不清楚.
研究的目的:
- 研究MEK抑制剂 (MEKi) 导致癌症耐药性的机制.
- 阐明RAS瘤基因翻译在MAPK通路信号和抵抗中的作用.
- 确定调节RAS蛋白表达和MAPK通路活性的新型反循环.
主要方法:
- 在不同细胞类型中利用细胞培养模型.
- 服用MEK抑制剂 (MEKi) 并监测KRAS和NRAS瘤基因翻译.
- 研究了加工体 (P-body) 生物凝聚物及其支架蛋白的作用.
- 评估了MEKi移除和ERK重新激活时P体和RAS信号的动态变化.
主要成果:
- MEK 抑制剂 (MEKi) 通过P体生物凝聚物溶解来增加KRAS和NRAS的代体翻译.
- 这种效应是动态的,在MEKi退出后,P体的改革和RAS信号减少.
- 较低水平的P体支架蛋白与增加的RAS表达相关.
- 确定了一种涉及RAS转化调节和MAPK信号中的P体的新型反循环.
结论:
- P体生物凝聚物的溶解是驱动RAS过度表达和随后癌症抗药性的关键机制.
- 针对这种P体介导的转化控制提供了一种潜在的策略,以克服对MAPK向疗法的耐药性.
- 这项研究揭示了RAS-MAPK信号的新调节层,这对癌症治疗有意义.
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