The intrinsic radioresistance of glioblastoma-derived cell lines is associated with a failure of p53 to induce p21BAX expression
The intrinsic radioresistance of glioblastoma-derived cell lines is associated with a failure of p53 to induce p21BAX expression
复制标题
DOI：
10.1073/pnas.95.24.14453
复制
发表时间：
1998-11-24
影响因子：
11.1
通讯作者：
Israel, MA
中科院分区：
文献类型：
--
作者：
Shu, HKG;Kim, MM;Israel, MA
放射治疗是所有常见恶性脑肿瘤的主要治疗方式，包括髓母细胞瘤和胶质母细胞瘤。然而，这两种脑肿瘤对放射治疗的反应明显不同，髓母细胞瘤对放射治疗非常敏感，而胶质母细胞瘤对放射治疗高度耐受，髓母细胞瘤患者的长期生存率超过50%，而胶质母细胞瘤患者中很少有长期存活者。p53介导的细胞凋亡被认为是介导肿瘤对放疗的细胞毒性反应的重要机制。在这项研究中，我们比较了具有野生型p53的五种细胞系对辐射的反应：我们发现，髓母细胞瘤衍生的细胞系经历了广泛的辐射诱导的凋亡性细胞死亡，而胶质母细胞瘤衍生的细胞系没有表现出显著的辐射诱导的凋亡，p53介导的p21（BAX）诱导被认为是细胞暴露于细胞毒素后介导凋亡的途径的关键组分，并且编码p21（BAX）的mRNA的表达与经历辐射诱导的凋亡的这些细胞系相关，在胶质母细胞瘤衍生的细胞系中p53诱导p21（BAX）表达的失败可能具有生物学意义，因为在成神经管细胞瘤中抑制p21（BAX）诱导导致辐射诱导的凋亡的丧失，而在胶质母细胞瘤中p21（BAX）的强制表达足以诱导凋亡，在胶质母细胞瘤衍生的细胞系中，p53诱导p21（BAX）的失败提示了放射抗性的独特机制，并且可能代表了确定胶质母细胞瘤中对放射的治疗响应性的关键因素。
Radiation is the primary modality of therapy for all commonly occurring malignant brain tumors, including medulloblastoma and glioblastoma, These two brain tumors, however, have a distinctly different response to radiation therapy, Medulloblastoma is very sensitive to radiation therapy, whereas glioblastoma is highly resistant, and the long-term survival of medulloblastoma patients exceeds 50%, while there are few long-term survivors among glioblastoma patients. p53-mediated apoptosis is thought to be an important mechanism mediating the cytotoxic response of tumors to radiotherapy. In this study, we compared the response to radiation of five cell lines that have wild-type p53: three derived from glioblastoma and two derived from medulloblastoma, We found that the medulloblastoma-derived cell lines underwent extensive radiation-induced apoptotic cell death, while those from glioblastomas did not exhibit significant radiation-induced apoptosis, p53-mediated induction of p21(BAX) is thought to be a key component of the pathway mediating apoptosis after the exposure of cells to cytotoxins, and the expression of mRNA encoding p21(BAX) was correlated with these cell lines undergoing radiation-induced apoptosis, The failure of p53 to induce p21(BAX) expression in glioblastoma-derived cell lines is likely to be of biologic significance, since inhibition of p21(BAX) induction in medulloblastoma resulted in a loss of radiation-induced apoptosis, while forced expression of p21(BAX) in, glioblastoma was sufficient to induce apoptosis, The failure of p53 to induce p21(BAX) in, glioblastoma-derived cell lines suggests a distinct mechanism of radioresistance and may represent a critical factor in determining therapeutic responsiveness to radiation in glioblastomas.