Ceramide triggers caspase activation during gamma-radiation-induced apoptosis of human glioma cells lacking functional p53.
Ceramide triggers caspase activation during gamma-radiation-induced apoptosis of human glioma cells lacking functional p53.
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DOI：
10.3892/or.12.1.119
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发表时间：
2004-07
期刊：
影响因子：
4.2
通讯作者：
S. Hara;S. Nakashima;T. Kiyono;M. Sawada;S. Yoshimura;T. Iwama;N. Sakai
中科院分区：
文献类型：
--
作者：
S. Hara;S. Nakashima;T. Kiyono;M. Sawada;S. Yoshimura;T. Iwama;N. Sakai
我们以前已经表明，治疗表达野生型p53的人胶质瘤U87-MG细胞与DNA拓扑异构酶II抑制剂，依托泊苷导致神经酰胺依赖性凋亡细胞死亡。然而，U87-W E6细胞由于表达人乳头瘤病毒16型（HPV-16）E6癌蛋白而缺乏功能性p53，对依托泊苷耐药。为了深入了解p53和神经酰胺在γ辐射诱导的胶质瘤细胞死亡中的作用，我们使用U87-WE 6和载体感染的U87-LXSN细胞。表达野生型p53的U87-LXSN胶质瘤细胞对γ射线具有相对抗性。失去功能性p53的U87-W E6细胞变得对辐射诱导的凋亡敏感。caspase-3的激活和酸性鞘磷脂酶而非中性鞘磷脂酶的神经酰胺形成与p53非依赖性细胞凋亡相关。影响神经酰胺代谢的药物可改变辐射诱导的U87-W E6细胞caspase激活和凋亡。SR 33557是一种酸性鞘磷脂酶抑制剂，可抑制辐射诱导的半胱天冬酶激活，然后抑制凋亡细胞死亡。与此相反，N-油酰乙醇胺（OE）和D-苏型-1-苯基-2-癸酰氨基-3-吗啉代-1-丙醇（PAPK），分别抑制神经酰胺酶和UDP-葡萄糖：神经酰胺葡萄糖基转移酶-1，然后增加神经酰胺的形成，增强辐射诱导的半胱天冬酶激活。这些结果表明，功能性p53的胶质瘤细胞对γ-辐射具有相对抗性，并且神经酰胺可能在γ-辐射诱导的缺乏功能性p53的胶质瘤细胞凋亡过程中的caspase激活中起重要作用。
We have previously shown that treatment of human glioma U87-MG cells expressing wild-type p53 with a DNA topoisomerase II inhibitor, etoposide resulted in ceramide-dependent apoptotic cell death. However, U87-W E6 cells lacking functional p53 due to the expression of human papilloma virus type 16 (HPV-16) E6 oncoprotein were resistant to etoposide. In order to gain insight into the roles of p53 and ceramide in gamma-radiation-induced glioma cell death, we used U87-W E6 and vector-infected U87-LXSN cells. U87-LXSN glioma cells expressing wild-type p53 were relatively resistant to gamma-radiation. U87-W E6 cells, which lost functional p53, became susceptible to radiation-induced apoptosis. Activation of caspase-3, and formation of ceramide by acid sphingomyelinase, but not by neutral sphingomyelinase, were associated with p53-independent apoptosis. Radiation-induced caspase activation and apoptotic death in U87-W E6 cells were modified by the agents which affected ceramide metabolism. SR33557, an inhibitor of acid sphingomyelinase, suppressed radiation-induced caspase activation and then apoptotic cell death. In contrast, N-oleoylethanolamine (OE) and D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP), which inhibit ceramidase and UDP-glucose:ceramide glucosyltransferase-1, respectively, and then augment ceramide formation, enhanced radiation-induced caspase activation. These results indicate that glioma cells with functional p53 were relatively resistant to gamma-radiation, and that ceramide may play an important role in caspase activation during gamma-radiation-induced apoptosis of glioma cells lacking functional p53.