PPIA决定了NRF2的稳定性,以促进肺癌的进展
Weiqiang Lu1,2, Jiayan Cui3, Wanyan Wang3
1Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China. wqlu@bio.ecnu.edu.cn.
Nature communications
|June 3, 2024
概括
核因素红色素2相关因子2 (NRF2) 驱动癌症的生长. 通过使用像环素A这样的药物来向其稳定性通过peptidylprolyl isomerase A (PPIA) 降解,为非小细胞肺癌 (NSCLC) 提供了一个新的治疗策略.
科学领域:
- 分子瘤学分子瘤学
- 癌症治疗方法 癌症治疗方法
背景情况:
- 核因素红色素2相关因子2 (NRF2) 过度活化是非小细胞肺癌 (NSCLC) 的致癌驱动因素.
- 目前的治疗方法缺乏针对NRF2过度激活的具体点.
研究的目的:
- 确定NRF2-过活化的NSCLC的新疗法标.
- 为了研究基基异构酶A (PPIA) 在NRF2蛋白稳定性和NSCLC生长中的作用.
主要方法:
- 使用生物化学测定和X射线共晶结构研究了PPIA和NRF2之间的相互作用.
- 评估了PPIA切除和环素A (CsA) 对NRF2蛋白降解和NSCLC细胞生长的影响.
- 在NSCLC患者衍生异种移植 (PDX) 模型中评估了CsA和一种谷氨酸酶抑制剂的联合治疗.
主要成果:
- PPIA通过阻断KEAP1的无处不在和降解来稳定NRF2.
- 切除PPIA或治疗CSA促进NRF2降解,并抑制NRF2驱动的NSCLC生长.
- CsA破坏了NRF2/KLF5/SLC1A5介导的谷氨酸代谢,与谷氨酸酶抑制剂的联合治疗在NSCLC PDX模型中延缓了瘤进展.
结论:
- 针对NRF2蛋白稳定性是NRF2-过活化的NSCLC的可行治疗策略.
- PPIA是NRF2稳定性的关键调节者,其被CsA抑制提供了一个潜在的治疗途径.
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