Lithium increases expression of p21WAF/Cip1 and survivin in human glioblastoma cells
Lithium increases expression of p21WAF/Cip1 and survivin in human glioblastoma cells
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DOI：
10.1007/s10565-006-0126-9
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发表时间：
2007-03-01
影响因子：
6.1
通讯作者：
Osmak, M.
中科院分区：
文献类型：
--
作者：
Karlovic, D.;Jakopec, S.;Osmak, M.
锂是最广泛使用的情绪稳定剂，但其治疗功能背后的精确分子机制尚未完全阐明。最近的临床前和临床证据表明其具有神经保护和神经营养作用。由于最近发现神经胶质细胞和神经元之间的中枢神经系统功能和代谢紧密耦合，因此锂对神经胶质细胞的作用也可能参与该药物的总体有益作用。本研究的目的是分析锂处理诱导人胶质母细胞瘤A1235细胞的分子机制，特别是其对凋亡相关基因表达的影响。较低水平的锂（0.5 mmol/L 和 2 mmol/L）不会引起任何细胞毒性或孵育 72 小时后细胞周期时相分布的变化。然而，较高剂量（20 mmol/L）对胶质母细胞瘤细胞具有细胞抑制作用，并导致细胞积聚在细胞周期的G(2)/M期。锂处理不会改变 Bcl-2 或 procaspase-3 的水平，也不会裂解 PARP，但会增加 p21(WAF/Cip1) 和生存素的水平。因此，p21(WAF/Cip1)（一种具有抗凋亡功能的蛋白质）和生存素（一种通过抑制细胞凋亡和促进细胞增殖来支持细胞生长的蛋白质）表达增加可能是细胞对锂的长期反应的早期事件，与该药物的有益作用有关。
Lithium is the most widely prescribed mood stabilizer, but the precise molecular mechanisms underlying its therapeutic function are not yet fully elucidated. Recent preclinical and clinical evidence indicates its neuroprotective and neurotrophic effects. As a tight coupling of function and metabolism in the central nervous system between glial cells and neurons has recently been detected, lithium's effect on glial cells may participate also in the total beneficial effects of this drug. The aim of the present study was to analyze molecular mechanisms induced in human glioblastoma A1235 cells by the treatment with lithium, especially its influence on the expression of apoptosis-related genes. Lower levels of lithium (0.5 mmol/L and 2 mmol/L) did not cause any cytotoxicity or changes in the cell cycle phase distribution following 72 h incubation. However, a higher dose (20 mmol/L) was cytostatic for glioblastoma cells, and caused accumulation of cells in G(2)/M phase of the cell cycle. The treatment with lithium did not alter the levels of Bcl-2 or procaspase-3 and did not cleave PARP, but increased the levels of p21(WAF/Cip1) and survivin. Thus, increased expression of p21(WAF/Cip1) (a protein with antiapoptotic function), and survivin (a protein that supports the growth of cells by suppression of apoptosis and promotion of cell proliferation) may be the early events in the long-term cell response to lithium that are involved in the beneficial effects of this drug.