Glycerol restores heat-induced p53-dependent apoptosis of human glioblastoma cells bearing mutant p53
Glycerol restores heat-induced p53-dependent apoptosis of human glioblastoma cells bearing mutant p53
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甘油可恢复热诱导的 p53 突变型人胶质母细胞瘤细胞的 p53 依赖性细胞凋亡
作者：
T. Ohnishi;K. Ohnishi;A. Takahashi
背景我们之前曾报道过，甘油作为化学伴侣可以恢复一些携带突变p53的人类癌细胞系中WAF 1的表达。由于WAF 1的表达被激活的野生型p53上调，甘油似乎恢复了wtp 53的功能。本研究的目的是检测甘油在转染携带突变型p53基因的载体的人胶质母细胞瘤细胞（A-172）中对热诱导的p53依赖性凋亡的恢复（A-172/mp53细胞）或neo对照载体结果与A-172/neo细胞相比，A-172/mp53细胞表现出耐热性，但在热处理前用甘油预处理，A-172/mp53细胞反而变得对热敏感。Bax在A-172/mp53细胞中的积累是通过加热甘油预处理诱导的，但没有它，而在A-172/neo细胞中的积累在两种情况下都是诱导的。此外，从加热细胞中提取的mp53在加热结合甘油预处理后与序列特异性区域结合。磷酸化的mp53在丝氨酸15被抑制的磷脂酰肌醇3-激酶（PI 3-K）family.ConclusionThese结果表明，甘油是有效的诱导构象变化的磷酸化p53和恢复mp53 wtp 53的功能，导致通过诱导细胞凋亡增强热敏感性。这种用于增强携带mp53的癌细胞的热敏感性的新工具可能适用于p53靶向热疗，因为在大约50%的人类癌症中观察到p53的突变或失活。
BackgroundWe have previously reported that glycerol acts as a chemical chaperone to restore the expression of WAF1 in some human cancer cell lines bearing mutant p53. Since the expression of WAF1 is up-regulated by activated wildtype p53, glycerol appears to restore wtp53 function. The aim of the present study is to examine the restoration of heat-induced p53-dependent apoptosis by glycerol in human glioblastoma cells (A-172) transfected with a vector carrying a mutant p53 gene (A-172/mp53 cells) or neo control vector (A-172/neo cells).ResultsA-172/mp53 cells showed heat resistance compared with A-172/neo cells but A-172/mp53 cells in turn became heat sensitive when pre-treated with glycerol before heat treatment. The accumulation of Bax in the A-172/mp53 cells was induced by heating with glycerol pre-treatment, but not without it, whereas the accumulation in the A-172/neo cells was induced in both cases. Furthermore, mp53 extracted from heated cells came to bind to the sequence specific region after heating combined with glycerol pre-treatment. The phosphorylation of mp53 at serine15 was suppressed by an inhibitor of the phosphatidylinositol 3-kinase (PI3-K) family.ConclusionThese results suggest that glycerol is effective in inducing conformational change of phosphorylated p53 and restoring mp53 to wtp53 function, leading to enhanced heat sensitivity through the induction of apoptosis. This novel tool for enhancement of heat sensitivity in cancer cells bearing mp53 may be applicable for p53-targeted hyperthermia, because mutation or inactivation of p53 is observed in approximately 50% of human cancers.
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