Lehmann Brian D, McCubrey James A, Jefferson Holly S, Paine Matthew S, Chappell William H, Terrian David M
Department of Anatomy and Cell Biology, Brody School of Medicine, East Carolina University, Greenville, North Carolina, USA.
Cell Cycle. 2007 Mar 1;6(5):595-605. doi: 10.4161/cc.6.5.3901. Epub 2007 Mar 18.
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.
由于p53失活可能会限制局部前列腺癌放射治疗的效果，因此了解该基因如何调节暴露于电离辐射后的克隆形成存活至关重要。在此，我们表明过早的细胞衰老 是导致保留p53功能的人前列腺癌细胞系放射敏感性的主要细胞死亡模式。由该肿瘤抑制因子控制的其他应激反应途径，包括细胞周期停滞、DNA损伤修复、有丝分裂灾难和凋亡，对辐射诱导的克隆形成死亡的贡献要小得多。使用p53的显性负性C末端片段，我们首次证明内源性p53功能的完全丧失足以限制前列腺癌细胞的辐射诱导衰老和克隆形成死亡。相反，缺乏该基因功能等位基因的前列腺癌细胞（即DU145）继承野生型p53会通过p53依赖的细胞衰老和凋亡途径显著增加克隆形成死亡。我们的数据提供了证据，表明即使一个p53等位基因突变也可能足以改变其克隆形成命运。此外，它们支持p53途径可作为增强前列腺癌细胞放射敏感性的特定靶点这一观点。药物nutlin-3激活p53被证明是保留p53功能等位基因的前列腺癌细胞的有效放射增敏剂，并且这种作用完全归因于p53依赖的细胞衰老诱导增加。
