PTEN status switches cell fate between premature senescence and apoptosis in glioma exposed to ionizing radiation
PTEN status switches cell fate between premature senescence and apoptosis in glioma exposed to ionizing radiation
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DOI：
10.1038/cdd.2010.139
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发表时间：
2011-04-01
影响因子：
12.4
通讯作者：
Lee, J-S
中科院分区：
文献类型：
--
作者：
Lee, J-J;Kim, B. C.;Lee, J-S
在人类神经胶质瘤中经常观察到肿瘤抑制性磷酸酶和张力蛋白同源物（PTEN）的缺失，其赋予AKT活化和对电离辐射（IR）和药物治疗的抗性。最近的报道表明，PTEN丢失或AKT激活诱导过早衰老，但关于这种影响的许多细节仍然不清楚。在这项研究中，我们测试了是否PTEN的状态确定的命运的细胞通过检查PTEN缺陷U87，U251，和U373，和PTEN熟练的LN 18和LN 428胶质瘤细胞暴露于IR后。这些细胞表现出不同的细胞反应，衰老或凋亡，这取决于PTEN的状态。我们进一步观察到，具有高水平AKT活化和细胞内活性氧（ROS）的PTEN缺陷的U87细胞经历衰老，而PTEN熟练的LN 18细胞进入凋亡。活性氧是必不可少的诱导衰老的PTEN缺陷的细胞，但不是凋亡的PTEN-熟练的细胞。此外，转染野生型（wt）PTEN或AKT小干扰RNA诱导的变化，从早衰细胞凋亡和p53或p21的耗竭防止IR诱导的U87细胞的早衰。我们的数据表明，在IR暴露的胶质瘤细胞中，PTEN作为细胞命运的关键决定因素，关于衰老和凋亡。我们的结论是，过早衰老可能有一个补偿作用的细胞凋亡的情况下，肿瘤抑制基因PTEN通过AKT/ROS/p53/p21信号通路。Cell Death and Differentiation（2011）18，666-677; doi：10.1038/cdd.2010.139; 2010年11月12日在线发表
Loss of the tumor suppressor phosphatase and tensin homolog (PTEN) has frequently been observed in human gliomas, conferring AKT activation and resistance to ionizing radiation (IR) and drug treatments. Recent reports have shown that PTEN loss or AKT activation induces premature senescence, but many details regarding this effect remain obscure. In this study, we tested whether the status of PTEN determined fate of the cell by examining PTEN-deficient U87, U251, and U373, and PTEN-proficient LN18 and LN428 glioma cells after exposure to IR. These cells exhibited different cellular responses, senescence or apoptosis, depending on the PTEN status. We further observed that PTEN-deficient U87 cells with high levels of both AKT activation and intracellular reactive oxygen species (ROS) underwent senescence, whereas PTEN-proficient LN18 cells entered apoptosis. ROS were indispensable for inducing senescence in PTEN-deficient cells, but not for apoptosis in PTEN-proficient cells. Furthermore, transfection with wild-type (wt) PTEN or AKT small interfering RNA induced a change from premature senescence to apoptosis and depletion of p53 or p21 prevented IR-induced premature senescence in U87 cells. Our data indicate that PTEN acts as a pivotal determinant of cell fate, regarding senescence and apoptosis in IR-exposed glioma cells. We conclude that premature senescence could have a compensatory role for apoptosis in the absence of the tumor suppressor PTEN through the AKT/ROS/p53/p21 signaling pathway. Cell Death and Differentiation (2011) 18, 666-677; doi:10.1038/cdd.2010.139; published online 12 November 2010