一种非酶性依赖因诺醇需要的酶1控制癌细胞循环的进展和瘤生长
Iratxe Zuazo-Gaztelu1, David Lawrence1, Ioanna Oikonomidi1
1Department of Research Oncology, Genentech, Inc., South San Francisco, California, United States of America.
癌细胞利用需要内醇的酶1α (IRE1) 进行生长,但并不总是通过其已知的酶功能. 这一发现揭示了针对癌症治疗中IRE1的新型治疗策略.
科学领域:
- 分子生物学分子生物学
- 癌症生物学 癌症生物学
- 细胞平衡是细胞的平衡.
背景情况:
- 需要内醇的酶1α (IRE1) 存在于内质网膜中,对癌症中的蛋白质稳态至关重要.
- 已知的IRE1的功能包括转录因子XBP1s的酶激活和调节的RNA衰变.
- 癌细胞的生存和增殖往往取决于IRE1的活性.
研究的目的:
- 为了研究IRE1在癌症中的作用,除了其酶活性之外.
- 为了确定癌细胞是否可以依赖IRE1.1的非酶功能.
- 探索与癌症中的IRE1相关的新型治疗点.
主要方法:
- IRE1在癌症细胞系中进行了淘汰实验.
- 酶性IRE1抑制和XBP1破坏试验.
- 细胞周期进展和瘤生长评估.
- 分析DNA损伤,染色体不稳定性和表观遗传修饰 (异染色素,DNA/基因素甲基化).
- 免疫电子显微镜用于定位IRE1蛋白.
主要成果:
- 一些癌症细胞系需要IRE1,但不需要其酶活性,才能生存.
- 降低IRE1,但不是酶抑制,显著损害细胞循环进展和瘤生长.
- IRE1沉默激活TP53和CDKN1A/p21,增加了DNA损伤和染色体不稳定.
- IRE1 枯竭减少了异色染色素和DNA / 基因组H3K9me3甲基化.
- 在核外中检测到内源性IRE1蛋白.
结论:
- 癌细胞通过酶和非酶机制利用IRE1.
- IRE1的非酶功能,可能涉及核定位,对于癌细胞增殖至关重要.
- 这些发现对开发针对癌症IRE1的新治疗策略具有重要意义.
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