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首页> 外文期刊>Cell cycle >Loss of p53 expression in cancer cells alters cell cycle response after inhibition o f exportin-1 but does not prevent cell death
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Loss of p53 expression in cancer cells alters cell cycle response after inhibition o f exportin-1 but does not prevent cell death

机译：癌细胞中P53表达的丧失改变细胞周期响应抑制of exportin-1后，但不能预防细胞死亡

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The tumor suppressor protein p53 is central to the cellular stress response and may be a predictive biomarker for cancer treatments. Upon stress, wildtype p53 accumulates in the nucleus where it enforces cellular responses, including cell cycle arrest and cell death. p53 is so dominant in its effects, that p53 enforcement - or - restoration therapy is being studied for anti-cancer therapy. Two mechanistically distinct small molecules that act via p53 are the selective inhibitor of nuclear export, selinexor, and MDM2 inhibitor, nutlin-3a. Here, individual cells are studied to define cell cycle response signatures, which captures the variability of responses and includes the impact of loss of p53 expression on cell fates. The individual responses are then used to build the population level response. Matched cell lines with and without p53 expression indicate that while loss-of-function results in altered cell cycle signatures to selinexor treatment, it does not diminish overall cell loss. On the contrary, response to single-agent nutlin-3a shows a strong p53-dependence. Upon treatment with both selinexor and nutlin-3a there are combination effects in at least some cell lines - even when p53 is absent. Collectively, the findings indicate that p53 does act downstream of selinexor and nutlin-3a, and that p53 expression is dispensable for selinexor to cause cell death, but nutlin-3a response is more p53-dependent. Thus, TP53 disruption and lack of expression may not predict poor cell response to selinexor, and selinexor's mechanism of action potentially provides for strong efficacy regardless of p53 function.
机译：肿瘤抑制蛋白P53是细胞应激反应的核心，并且可以是用于癌症治疗的预测生物标志物。在应力后，野生型P53积聚在核中，其中核心强制反应，包括细胞周期滞留和细胞死亡。 P53在其效果中如此占主导地位，正在研究抗癌治疗的P53执法或恢复治疗。通过P53起作用的两种机械主义不同的小分子是核出口，硒基和MDM2抑制剂，Nutlin-3a的选择性抑制剂。这里，研究各个细胞以限定细胞周期响应签名，其捕获响应的变化，并且包括损失P53表达对细胞命中的影响。然后使用各种反应来构建人口水平反应。匹配的细胞系具有和不具有P53表达，表明，虽然函数丧失导致改变的细胞周期符号对硒克洛匹克治疗，但它不会减少整体细胞损失。相反，对单孕铌-3a的反应显示出强的p53依赖性。在用苯胺克索和螺母-3A的处理后，在至少一些细胞系中存在组合效应 - 即使不存在P53。结果表明，P53确实在硒基和Nutlin-3a的下游作用，并且P53表达可分配硒氧，但果肉-3a反应更加p53依赖性。因此，TP53破坏和缺乏表达可能无法预测对Selinexor的差的细胞反应，并且塞里宁范围的作用机制可能提供了不管p53功能的强效力。

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