Radiation-induced caspase-8 mediates p53-independent apoptosis in glioma cells
Radiation-induced caspase-8 mediates p53-independent apoptosis in glioma cells
复制标题
DOI：
10.1158/0008-5472.can-05-1283
复制
发表时间：
2006-04-15
期刊：
影响因子：
11.2
通讯作者：
Haas-Kogan, DA
中科院分区：
文献类型：
--
作者：
Afshar, G;Jelluma, N;Haas-Kogan, DA
恶性胶质瘤几乎无一例外是致命的，且对放疗具有极强的抗性。缺乏野生型（WT）p53功能的胶质瘤细胞比表达野生型p53的同基因细胞更易发生放疗诱导的凋亡。我们探究了这种凋亡的机制，发现在缺乏野生型p53的情况下，放疗会增加半胱天冬酶 - 8的表达和活性。使用半胱天冬酶 - 8反义寡核苷酸或小干扰RNA（siRNA）抑制半胱天冬酶 - 8的表达，可部分阻断放疗诱导的凋亡。相反，通过表达Bcl - 2抑制线粒体死亡途径，对放疗诱导的半胱天冬酶 - 8活性或凋亡没有影响。我们的数据表明，与普遍接受的p53依赖性放疗诱导凋亡模型不同，在我们的细胞系统中，放疗依赖半胱天冬酶 - 8的活性来帮助介导不依赖p53的细胞死亡。在一个可诱导E2F1活性的系统中，E2F1激活半胱天冬酶 - 8，相应地降低细胞活力，而这些效应可被半胱天冬酶 - 8的siRNA消除。在该模型中，在缺乏野生型p53的情况下，p21（Cipl）不被诱导，E2F1活性得以维持，并允许半胱天冬酶 - 8的转录和激活。该模型或许可以解释为什么成人胶质瘤中的p53突变与生存率提高和对放疗的反应增强呈矛盾性相关。
Malignant gliomas are almost uniformly fatal and display exquisite radiation resistance. Glioma cells lacking wild-type (WT) p53 function are more susceptible to radiation-induced apoptosis than their isogenic counterparts expressing WT p53. We explored the mechanisms of such apoptosis and found that, in the absence of WT p53, radiation increases caspase-8 expression and activity. Inhibition of caspase-8 expression using caspase-8 antisense or small interfering RNA (siRNA) oligonucleotides partially blocks radiation-induced apoptosis. In contrast, inhibition of the mitochondrial death pathway by expression of Bcl-2 has no effect on radiation-induced caspase-8 activity or apoptosis. Our data indicate that, in contrast to commonly accepted models of p53-dependent radiation-induced apoptosis, in our cell system, radiation relies on caspase-8 activity to help mediate p53-independent cell death. in a system of inducible E2F1 activity, E2F1 activated caspase-8 and, accordingly, decreased cellular viability, effects that were abolished by caspase-8 siRNA. In this model, in the absence of WT p53, p21(Cipl) is not induced, and E2F1 activity is sustained and allows transcription and activation of caspase-8. This model may explain why p53 mutations in adult gliomas paradoxically correlate with improved survival and enhanced response to radiation.