蛋白质体抑制增强了溶酶体介导的向蛋白质降解
bioRxiv : the preprint server for biology
|February 20, 2025
概括
癌细胞在对蛋白酶体抑制剂的反应中激活自适应性自. 这项研究利用这种反应,使用向自的嵌合体 (AUTAC) 来降解Mcl1,增强蛋白酶体抑制剂的有效性并促进癌细胞死亡.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 细胞应激反应的应激反应
背景情况:
- 蛋白质酶抑制剂用于多发性骨髓瘤和地幔细胞淋巴瘤,但癌细胞会产生耐药性.
- 癌细胞激活核因子红色素2相关因子1 (NRF1) 升调蛋白质体和自基因,抵消蛋白质体抑制.
- 通过NRF1介导的自适应性自减少了蛋白质毒性压力,减少了蛋白质酶体抑制剂的有效性.
研究的目的:
- 研究利用,而不是抑制适应性自反应对蛋白酶体抑制的治疗策略.
- 设计和评估一种针对自细胞的嵌合体 (AUTAC),用于选择性降解抗亡蛋白Mcl1.
- 为了确定与Mcl1 AUTAC结合蛋白酶体抑制是否增强癌细胞死亡.
主要方法:
- 开发一种针对自细胞的仿真体 (AUTAC) 化合物,用于Mcl1.cl的溶酶体降解.
- 用一种蛋白酶体抑制剂 (carfilzomib) 和Mcl1 AUTAC的组合治疗癌细胞.
- 评估NRF1依赖机制和对野生类型和耐药癌症细胞系中细胞死亡的协同作用.
主要成果:
- 通过AUTAC通过溶酶体介导的Mcl1降解在存在蛋白质酶体抑制时显著放大.
- 这种放大取决于转录因子NRF1.1.
- 卡菲尔佐米布和Mcl1 AUTAC的组合在多发性骨髓瘤和肺癌细胞中协同诱导细胞死亡,包括耐药表型.
结论:
- 将蛋白质酶抑制剂与Mcl1 AUTAC结合起来,代表了一种通过利用自适应性自来增强癌症治疗的新策略.
- 这种方法建立了一个扩大溶酶体介导的向蛋白质降解以获得治疗益处的框架.
- 这些发现在癌症治疗和其他涉及蛋白质平衡的疾病中具有广泛的潜在应用.
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