A dominant role for p53-dependent cellular senescence in radiosensitization of human prostate cancer cells
A dominant role for p53-dependent cellular senescence in radiosensitization of human prostate cancer cells
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DOI：
10.4161/cc.6.5.3901
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发表时间：
2007-03-01
期刊：
影响因子：
4.3
通讯作者：
Terrian, David M.
中科院分区：
文献类型：
--
作者：
Lehmann, Brian D.;McCubrey, James A.;Terrian, David M.
由于p53失活可能限制放射治疗局限性前列腺癌的有效性，重要的是要了解该基因如何调节暴露于电离辐射后的克隆生存。在这里，我们表明，过早的细胞衰老是细胞死亡的主要模式占人前列腺癌细胞系保留p53功能的放射敏感性。由这种肿瘤抑制因子控制的替代应激反应途径，包括细胞周期阻滞、DNA损伤修复、有丝分裂灾难和细胞凋亡，对辐射诱导的克隆性死亡的贡献显著较小。使用一个显性负性的p53的C-末端片段，我们提出的第一个证据表明，内源性p53功能的完全丧失足以限制辐射诱导的衰老和前列腺癌细胞的克隆性死亡。相反，缺乏该基因的功能等位基因（即，DU 145）通过p53依赖性细胞衰老和凋亡途径显著增加克隆性死亡。我们的数据提供的证据表明，即使是一个p53等位基因的突变可能足以改变其克隆的命运。此外，他们支持p53通路可用作增强前列腺癌细胞放射敏感性的特异性靶点的想法。通过药物nutlin-3激活p53被证明是保留p53的功能等位基因的前列腺癌细胞的有效放射增敏剂，并且这种效果完全归因于p53依赖性细胞衰老的诱导增加。
Because p53 inactivation may limit the effectiveness of radiation therapy for localized prostate cancer, it is important to understand how this gene regulates clonogenic survival after an exposure to ionizing radiation. Here, we show that premature cellular senescence is the principal mode of cell death accounting for the radiosensitivity of human prostate cancer cell lines retaining p53 function. Alternative stress response pathways controlled by this tumor suppressor, including cell cycle arrest, DNA damage repair, mitotic catastrophe and apoptosis, contributed significantly less to radiation-induced clonogenic death. Using a dominant negative C-terminal fragment of p53, we present the first evidence that a complete loss of endogenous p53 function is sufficient to limit the irradiation-induced senescence and clonogenic death of prostate cancer cells. Conversely, inheritance of wild-type p53 by prostate cancer cells lacking a functional allele of this gene (i.e., DU145) significantly increases clonogenic death through p53-dependent cellular senescence and apoptotic pathways. Our data provide evidence that mutations of even one p53 allele may be sufficient to alter their clonogenic fate. In addition, they support the idea that the p53 pathway can be used as a specific target for enhancing the radiosensitivity of prostate cancer cells. Activation of p53 by the drug nutlin-3 is shown to be an effective radiosensitizer of prostate cancer cells retaining functional alleles of p53 and this effect was entirely attributable to an increased induction of p53-dependent cellular senescence.