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p53-Independent ceramide formation in human glioma cells during gamma-radiation-induced apoptosis.

γ 辐射诱导的细胞凋亡过程中人神经胶质瘤细胞中 p53 独立的神经酰胺形成。

基本信息

批准号：
14370429
负责人：
IWAMA Toru
金额：
$ 7.1万
依托单位：
GIFU UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2003
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14370429/
关键词：
apoptosis p53 glima radiation セラミドヒト悪性膠腫 caspase-3

项目摘要

Although the p53 tumor-suppressor gene product plays a critical role in apoptotic cell death induced by DNA-damaging chemotherapeutic agents, human glioma cells with functional p53 were more resistant to gamma-radiation than those with mutant p53. U-87 MG cells with wild-type p53 were resistant to gamma-radiation. U87-W E6 cells that lost functional p53, by the expression of type 16 human papillomavirus E6 oncoprotein, became susceptible to radiation-induced apoptosis. The formation of ceramide by acid sphingomyelinase (A-SMase), but not by neutral sphingomyelinase, was associated with p53-independent apoptosis SR33557 (2-isopropyl-1-(4-[3-N-methyl-N-(3,4-dimethoxybphenethyl) amino]propyloxy)benzene-sulfonyl) indolizine, an inhibitor of A-SMase, suppressed radiation-induced apoptotic cell death. In contrast, radiation-induced A-Smase activation was blocked in glioma cells with endogenous functional p53. The expression of acid ceramidase was induced by gamma-radiation, and was more evident in cells with functional p53. N-oleoylethanolamine, which is known to inhibit ceramidase activity, unexpectedly downregulated acid ceramidase and accelerated radiation-induced apoptosis in U87-W E6 cells. Moreover, cells with functional p53 could be sensitized to gamma-radiation by N-oleoylethanolamine, which suppressed radiation-induced acid ceramidase expression and then enhanced ceramide formation. Sensitization to gamma-radiation was also observed in U87-MG cells depleted of functional p53 by retroviral expression of small interfering RNA. These results indicate that ceramide may function as a mediator of p53.-independent apoptosis in human glioma cells in response to gamma-radiation, and suggest that p53-dependent expression of acid ceramidase and blockage of A-SMase activation play pivotal roles in protection from gamma-radiation of cells with endogenous functional p53.

尽管 p53 肿瘤抑制基因产物在 DNA 损伤性化疗药物诱导的细胞凋亡中发挥着关键作用，但具有功能性 p53 的人神经胶质瘤细胞比具有突变 p53 的细胞对伽马辐射具有更强的抵抗力。具有野生型 p53 的 U-87 MG 细胞对伽马辐射具有抵抗力。由于表达 16 型人乳头瘤病毒 E6 癌蛋白，失去功能性 p53 的 U87-W E6 细胞变得对辐射诱导的细胞凋亡敏感。酸性鞘磷脂酶 (A-SMase) 而非中性鞘磷脂酶形成的神经酰胺与 p53 依赖性细胞凋亡相关 SR33557（2-异丙基-1-(4-[3-N-甲基-N-(3,4-二甲氧基苯乙基)氨基]丙氧基）苯磺酰基中氮茚，一种 A-SMase，抑制辐射诱导的细胞凋亡。相比之下，放射诱导的 A-Smase 激活在神经胶质瘤细胞中被内源性功能性 p53 阻断。酸性神经酰胺酶的表达是由γ辐射诱导的，并且在具有功能性p53的细胞中更为明显。 N-油酰乙醇胺已知可抑制神经酰胺酶活性，意外地下调酸性神经酰胺酶并加速 U87-W E6 细胞中辐射诱导的细胞凋亡。此外，具有功能性p53的细胞可以通过N-油酰乙醇胺对γ辐射敏感，从而抑制辐射诱导的酸性神经酰胺酶的表达，然后增强神经酰胺的形成。在通过逆转录病毒表达小干扰RNA而耗尽功能性p53的U87-MG细胞中也观察到对γ辐射的敏感性。这些结果表明，神经酰胺可能作为人神经胶质瘤细胞响应伽玛辐射的p53独立细胞凋亡的介导物，并表明酸性神经酰胺酶的p53依赖性表达和A-SMase激活的阻断在保护具有内源功能性p53的细胞免受伽玛辐射中发挥着关键作用。