利醇通过破坏KEAP1-NRF2相互作用来抑制MYC驱动的ANLN表达和肝癌进展
Minh Tuan Nguyen1, Gi Jeong Lee1, Boram Kim1
1BK21 FOUR Team and Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University, Seoul 04620, Republic of Korea.
Pharmacological research
|December 6, 2024
概括
抗精神病药物penfluridol通过向MYC/NRF2/KEAP1通路,有效地抑制肝癌细胞中的阿尼林 (ANLN). 这种新型的ANLN阻断剂显示出治疗肝细胞癌 (HCC) 的潜力.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 药理学 药理学是指药理学的学科.
背景情况:
- 肝细胞癌 (HCC) 的预后不好,特别是在晚期.
- 素 (ANLN) 对于细胞生长和细胞运动至关重要,其过度表达与HCC发育和患者生存率低下有关.
- 目前,已知没有药物可以抑制ANLN.
研究的目的:
- 为了确定潜在的治疗药物,抑制ANLN表达在HCC.
- 阐明夫醇影响ANLN表达和HCC进展的机制.
- 评估penfluridol在临床前HCC模型中的疗效.
主要方法:
- 对ANLN表达和患者预后的癌症基因组图谱 (TCGA) 数据的分析.
- 选连接地图数据库以识别影响ANLN的化合物.
- 实验室内研究涉及肝癌细胞系,以评估ANLN淘汰效应和penfluridol对增殖,细胞循环和殖民地形成的影响.
- 研究涉及MYC,NRF2和KEAP1.1的分子机制.
- 在体内研究,使用肝癌的合成基因小鼠模型.
主要成果:
- 高ANLN表达与HCC患者的预后不佳相关.
- 利醇在mRNA和蛋白质水平上显著降低ANLN的调节,诱导G2/M细胞周期的停止并减少殖民地形成.
- 佛醇通过上调NRF2来抑制MYC与ANLN促进体的结合,NRF2将MYC隔离.
- 佛醇通过破坏NRF2-KEAP1相互作用来增强NRF2活动.
- 在体内,penfluridol抑制了瘤生长,增加了NRF2,并降低了MYC和ANLN水平.
结论:
- 利醇是第一个被确定的ANLN抑制剂,在HCC中具有潜在的治疗应用.
- 佛醇调节MYC/NRF2/KEAP1轴,为肝癌提供了一种新的治疗策略.
- 针对ANLN是一种有前途的方法,可以改善HCC治疗结果.
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