主转录因子重编程释放选择性翻译 促进致命前列腺癌中的割抵抗和免疫逃避
Sandra Santasusagna1,2, Shijia Zhu3,4, Vijayakumar Jawalagatti1,2
1Department of Urology, Mayo Comprehensive Cancer Center, Rochester, Minnesota.
Cancer discovery
|September 7, 2023
概括
在致命的前列腺癌中,降低的微转录因子 (MITF) 允许eIF3B重编程翻译,驱动对雄激素剥夺疗法 (ADT) 和免疫规避的抗性. 准这种途径使瘤对ADT和免疫疗法敏感.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 癌症研究 癌症研究
背景情况:
- 瘤细胞重新连接信号通路以生存治疗.
- 致命的前列腺癌表现出对雄激素剥夺疗法 (ADT) 和免疫逃避的抵抗力.
研究的目的:
- 调查微转录因子 (MITF) 在前列腺癌治疗耐药性的作用.
- 阐明eIF3B介导的翻译重编程在赋予抗性和免疫逃避中的机制.
主要方法:
- 直接促进剂结合试验用于研究MITF-eIF3B相互作用.
- 全基因组的eIF3B增强了交叉链接免疫沉降测序 (eCLIP-seq) 以确定结合位点.
- 临床前模型测试eIF3B依赖转化药理学向.
主要成果:
- MITF的下调释放了关键mRNAs的eIF3B-依赖翻译.
- eIF3B在5'未翻译区域与UC丰富的基因结合,调节雄激素受体和MHC-I.的翻译.
- 对eIF3B的药理定位使前列腺癌对ADT和抗PD-1疗法产生敏感性.
结论:
- MITF-eIF3B轴代表了在治疗耐药前列腺癌中转录和翻译控制之间的关键联系.
- 针对eIF3B依赖的翻译提供了一种可用药物的策略,以克服ADT耐药性并提高免疫疗法的有效性.
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