通过稳定ATF4促进器G-四重复的克服癌症持续细胞
Chengmei Xiao1, Yipu Li1, Yushuang Liu1
1State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Bioactive Natural Product Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
Advanced science (Weinheim, Baden-Wurttemberg, Germany)
|July 12, 2024
概括
通过激活GCN2-ATF4-ASCT2轴,氨酸的限制会产生耐治疗的持续性细胞. 天然化合物科普提辛向ATF4-G4结构,降低ATF4水平并杀死癌细胞.
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:
- 持久细胞 (PS) 有助于治疗耐药的癌症.
- 氨酸限制通过激活综合应激反应和GCN2-ATF4-ASCT2轴来诱导PS.
- 由于其结构,准ATF4蛋白具有挑战性.
研究的目的:
- 调查ATF4促进体G-四重复 (ATF4-G4) 在PS中的作用.
- 识别可以准ATF4-G4.4.的小分子.
- 探索治疗策略,对抗氨酸受限制的持久性癌细胞.
主要方法:
- 识别和结构解决ATF4-G4结构.
- 选与ATF4-G4.4结合的自然化合物.
- 确定提辛-ATF4-G4复合物的高分辨率结构.
- 评估复合物对ATF4水平和癌细胞活力的影响.
主要成果:
- 天然化合物素 (COP) 稳定了ATF4-G4结构.
- 复杂的COP-ATF4-G4形成破坏了TFAP2A和ATF4-G4.4之间的相互作用.
- 这种干扰导致细胞内ATF4水平降低和癌细胞死亡.
- 向ATF4-G4的科普提辛显示出对PS的治疗潜力.
结论:
- ATF4-G4结构是对抗持久性癌细胞的可用药物标.
- 科普蒂辛代表了一种有前途的治疗剂,用于向氨酸受限制的持久细胞.
- 这项研究提供了一种克服恶性瘤治疗耐药性的新策略.
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