蛋白质稳定网络是急性髓性白血病的治疗目标
bioRxiv : the preprint server for biology
|October 10, 2024
概括
急性髓性白血病 (AML) 细胞通过激活蛋白质稳定路径 (如HSF1和自) 来抵抗蛋白质酶抑制剂. 针对这些途径为AML提供了一个有希望的治疗策略.
科学领域:
- 癌症生物学 癌症生物学
- 分子瘤学分子瘤学
- 蛋白质稳定网络 蛋白质稳定网络
背景情况:
- 蛋白质稳定路径对于癌细胞生存至关重要,但具有挑战性的治疗点.
- 蛋白质酶抑制剂在多发性骨髓瘤中有效,但不是急性骨髓性白血病 (AML).
- 蛋白酶体抑制剂在各种癌症中的有效性差异的原因尚不清楚.
研究的目的:
- 调查为什么蛋白酶体抑制剂在AML中无效.
- 确定关键的蛋白质稳定机制,使AML细胞在蛋白质酶抑制下存活.
- 探索针对AML中的蛋白质稳定性的新型治疗策略.
主要方法:
- 在AML细胞系和患者样本中研究了蛋白酶体抑制剂的疗效.
- 评估了热冲击因子1 (HSF1) 和自在AML细胞对蛋白酶体抑制的反应中的作用.
- 利用HSF1的遗传失活化和联合药物治疗 (自和蛋白酶体抑制剂).
- 对蛋白质合成,细胞增殖,细胞亡和综合应激反应 (ISR) 途径的评估影响.
- 使用AML模型在体内评估治疗疗效.
主要成果:
- AML细胞激活HSF1和自,以维持蛋白质稳定,防止蛋白质酶抑制.
- 无活化HSF1使AML细胞对蛋白酶体抑制剂敏感,导致蛋白质积累的扩展,蛋白质合成的减少和生存能力受损.
- 自和蛋白酶组合抑制协同杀死AML细胞,减少瘤负担,并延长体内生存时间.
- 联合治疗优先影响AML干细胞/原始细胞,而不是正常的造血干细胞/原始细胞.
- 结合疗法以PKR依赖的方式激活了综合应激反应.
结论:
- AML细胞选择蛋白质稳定路径 (HSF1,自) 进行生长,进展和耐药性.
- 通过同时准蛋白质体和自细胞来破坏蛋白质稳定网络是AML的一种有前途的治疗策略.
- 这种方法证明了AML细胞的优先向,包括干细胞/原始细胞种群,具有改善临床结果的潜力.
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