抑制蛋白质损伤反应以克服癌症治疗中的多药性耐药性
Fangyuan Shao1,2,3, Zongjie Li1,2, Hao Xiao4
1Cancer Center, Faculty of Health Sciences, University of Macau, Macau SAR, China.
Cell discovery
|September 30, 2025
概括
抗癌药物会破坏蛋白质,引发细胞反应. 向蛋白酶活性可以在癌症治疗中克服多药性耐药性.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 生物化学 生化学
背景情况:
- 多药耐药性 (MDR) 是癌症治疗的一个主要挑战.
- 人们还没有完全理解MDR背后的监管机制.
- 抗癌药物可能会导致非目标蛋白损伤,导致细胞毒性.
研究的目的:
- 研究抗癌药物诱导的蛋白质损伤的机制.
- 为了确定细胞对蛋白质损伤的反应,称为蛋白质损伤反应 (PDR).
- 探索蛋白酶活性在MDR中的作用,并制定克服它的策略.
主要方法:
- 药物诱导的蛋白质结合和随后的细胞损伤的分析.
- 蛋白损伤反应 (PDR) 途径的表征,包括无处化和蛋白酶体降解.
- 开发一套检测患者样本中的蛋白酶水平的工具.
- 在3D瘤切片培养和临床试验中验证蛋白质酶体抑制剂.
主要成果:
- 抗癌药物与新合成的蛋白质结合,造成损伤,特别是线粒体蛋白质.
- 这种初始损伤触发了涉及活性氧物种的积极反循环,并导致PDR.
- 在耐药转移性乳腺癌和结肠癌中观察到蛋白酶活性升高.
- 一个蛋白质酶检测套件识别了具有高蛋白质酶活性的患者.
- 蛋白质酶抑制剂在具有高蛋白质酶活性的患者中逆转了MDR.
结论:
- 药物诱导的蛋白质损伤和随后的PDR是癌症治疗耐药性的关键机制.
- 蛋白酶活性是MDR的预测生物标志物.
- 用抑制剂向蛋白酶体活性提供了一个有希望的策略,以克服MDR在特定的癌症患者群体.
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