对抗癌症药物标的系统识别揭示了核到线粒体的ROS感应通路
Junbing Zhang1, Claire M Simpson2, Jacqueline Berner1
1Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA.
Cell
|May 16, 2023
概括
抗癌药物增加活性氧物种 (ROS),但细胞如何感知ROS尚不清楚. 这项研究确定了一条涉及CHK1和SSBP1的核到线粒体通路,该通路可以消除ROS积累并调解对基药物的耐药性.
科学领域:
- 生物化学
- 分子生物学
- 癌症研究
背景情况:
- 抗癌药物可以通过增加细胞反应性氧物种 (ROS) 来诱导细胞死亡.
- 细胞感知ROS的确切机制,包括蛋白质修饰和对药物敏感性的作用,仍然在很大程度上是未知的.
- 了解这些途径对于开发更有效的癌症疗法至关重要.
研究的目的:
- 阐明抗癌药物通过ROS诱导细胞死亡的机制.
- 确定由ROS修饰的特定蛋白质及其在药物敏感性和耐药性中的作用.
- 调查一种新的核-至-线粒体ROS传感途径.
主要方法:
- 使用综合蛋白质基因学方法分析11种抗癌药物的效果.
- 通过ROS修改的已识别的蛋白质目标.
- 研究了CHK1作为核ROS传感器的作用及其与SSBP1的相互作用.
主要成果:
- 确定了许多独特的和共享的ROS蛋白标,包括核糖体成分,这表明了常见的药物诱导的转化调节机制.
- 发现CHK1作为核过氧化物 (H2O2) 传感器.
- 发现CHK1可化SSBP1,防止其线粒体局部化,从而减少核H2O2.
- 揭示了一种可用药物的核-至-线粒体通路,
结论:
- 一个涉及CHK1和SSBP1的新型核到线粒体ROS感应通路调节细胞ROS水平.
- 这一途径对于解决核H2O2积累至关重要,并在卵巢癌中调解抗抗癌剂的耐药性.
- 针对这种途径可以为卵巢癌治疗提供新的治疗策略.
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