Cell survival following direct executioner-caspase activation.
Cell survival following direct executioner-caspase activation.
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直接刽子手半胱天冬酶激活后的细胞存活。
DOI：
10.1073/pnas.2216531120
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发表时间：
2023-01-24
影响因子：
11.1
通讯作者：
Montell, Denise J.
中科院分区：
文献类型：
--
作者：
Nano, Maddalena;Mondo, James A.;Harwood, Jacob;Balasanyan, Varuzhan;Montell, Denise J.
最近在各种细胞和生物体中的研究表明，细胞可以从细胞死亡的边缘恢复过来。这种特性增强了损伤后的组织修复，但也被癌细胞吸收以在化疗和放疗中存活。通过结合先进的工具，直接在活细胞中提供和测量精确剂量的caspase-3活性，我们解决了两个关键问题，从凋亡诱导恢复。细胞能否从执行者-半胱天冬酶的直接激活中恢复，或者存活是药物诱导的应激反应与死亡信号一起发生的结果？caspase信号水平和/或动力学在多大程度上决定细胞命运？在这里，我们报告的程度和限制，半胱天冬酶活性在决定细胞的命运。在细胞凋亡过程中，Executer-caspase的激活被认为是一个不归路。然而，许多研究报告了药物或放射治疗后半胱天冬酶激活的存活率。一个悬而未决的问题是，细胞是否可以从直接的半胱天冬酶激活中恢复，而不需要药物诱导的促生存应激反应。为了解决这个问题，我们设计了一个HeLa细胞系，诱导表达caspase-3，并将其与定量caspase活性报告相结合。虽然高半胱天冬酶活性水平杀死所有细胞，非常低的水平允许所有细胞存活，但足以杀死15%至30%细胞的半胱天冬酶活性剂量仍然允许70%至85%存活。在这些剂量下，半胱天冬酶活性的速率、峰值水平和总量都不能准确预测细胞死亡与存活。因此，细胞可以在直接的执行者-胱天蛋白酶激活中存活，并且细胞状态的变化改变了潜在致命的胱天蛋白酶活性的结果。这种异质性可能是响应于诱导肿瘤坏死的癌症治疗而不完全杀死肿瘤细胞的基础。
Recent work in a variety of cells and organisms shows that cells can recover from the brink of cell death. This property enhances tissue repair after injury but is also co-opted by cancer cells to survive chemo- and radiation therapies. By combining sophisticated tools to deliver and measure precise doses of caspase-3 activity directly in living cells, we address two key questions regarding recovery from apoptotic induction. Can cells recover from direct activation of executioner-caspase, or is survival a consequence of drug-induced stress responses that occur together with death signaling? And, to what extent do caspase signaling levels and/or dynamics determine cell fate? Here, we report the extent and limitations of caspase activity in determining cell fate. Executioner-caspase activation has been considered a point-of-no-return in apoptosis. However, numerous studies report survival from caspase activation after treatment with drugs or radiation. An open question is whether cells can recover from direct caspase activation without pro-survival stress responses induced by drugs. To address this question, we engineered a HeLa cell line to express caspase-3 inducibly and combined it with a quantitative caspase activity reporter. While high caspase activity levels killed all cells and very low levels allowed all cells to live, doses of caspase activity sufficient to kill 15 to 30% of cells nevertheless allowed 70 to 85% to survive. At these doses, neither the rate, nor the peak level, nor the total amount of caspase activity could accurately predict cell death versus survival. Thus, cells can survive direct executioner-caspase activation, and variations in cellular state modify the outcome of potentially lethal caspase activity. Such heterogeneities may underlie incomplete tumor cell killing in response to apoptosis-inducing cancer treatments.
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影响因子：
11.8
作者：
Arama, E;Agapite, J;Steller, H
通讯作者：
Steller, H
影响因子：
7.7
作者：
Ding, Austin Xun;Sun, Gongping;Montell, Denise J.
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Montell, Denise J.
影响因子：
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Fernando, P;Brunette, S;Megeney, LA
通讯作者：
Megeney, LA
影响因子：
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