天然化合物Alternol激活了多个内质网膜应激反应通路,导致细胞死亡
Wang Liu1, Chenchen He2, Changlin Li3
1Department of Urology, The University of Kansas Medical Center, Kansas City, KS, United States.
Frontiers in pharmacology
|June 4, 2024
概括
阿尔特诺尔触发了内质网膜 (ER) 应激反应,激活了导致前列腺癌细胞免疫细胞死亡的特定信号通路. 这个过程涉及到未折叠的蛋白质反应和细胞外ATP的释放.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 免疫学 免疫学 免疫学
背景情况:
- 阿尔特诺,一种来自Taxus brevifolia真菌的化合物,之前已经表明可以诱导依赖活性氧物种 (ROS) 的免疫细胞死亡.
- 用前列腺癌细胞系 (PC-3,C4-2,22RV1) 来研究Alternol的机制.
研究的目的:
- 综合探索阿尔特诺尔诱导的免疫细胞死亡背后的机制.
- 阐明阿尔特诺与细胞蛋白的相互作用及其对内质网膜 (ER) 应激通路的影响.
主要方法:
- 细胞热转移试验 (CETSA) 来评估Alternol-chaperone蛋白相互作用.
- 针对ER应激蛋白和ATP释放试验的西部斑分析.
- 研究了ER压力信号通路,包括PERK,IRE1α和PKR级联.
主要成果:
- 阿尔特诺与诸如HYOU1,HSP90AB1和HSPA8之类的陪伴蛋白相互作用并增加其表达,可能导致未折叠蛋白反应 (UPR).
- 阿尔特诺尔通过PERK和IRE1α通路诱导ROS依赖的ER压力,激活ATF-3/ATF-4,CHOP和XBP1拼接.
- 抑制ER应激通路减少了Alternol诱导的细胞外ATP释放,这是免疫细胞死亡的标志.
结论:
- 阿尔特诺尔治疗激活了多个ER压力信号级联.
- 这些ER应激反应的高潮是免疫细胞死亡,其特征是细胞外ATP释放.
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