Antiproliferative effects of tocopherols (vitamin E) on murine glioma C6 cells: Homologue-specific control of PKC/ERK and cyclin signaling
Antiproliferative effects of tocopherols (vitamin E) on murine glioma C6 cells: Homologue-specific control of PKC/ERK and cyclin signaling
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DOI：
10.1016/j.freeradbiomed.2006.04.012
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发表时间：
2006-08-01
影响因子：
7.4
通讯作者：
Galli, Francesco
中科院分区：
文献类型：
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作者：
Betti, Michele;Minelli, Andrea;Galli, Francesco
脑肿瘤（特别是神经胶质瘤）的化学预防策略很少，令人惊讶的是研究不足。我们研究了生育酚（TOCs;维生素E）对小鼠胶质瘤C6细胞增殖和死亡过程的影响。这些维生素显示出不同的细胞摄取以及对细胞生长的浓度和时间依赖性抑制作用，这些抑制作用在最低测试浓度（1-10 μ M）下是显著的。然而，TOC的抑制效力似乎至少部分反映了稳态时的实际细胞浓度，其数量级为γ-TOC>= α-TOC> δ-TOC与β-TOC一致。此外，对于细胞外浓度>= 10 μ M，TOC也显示出显著的细胞毒性效应，主要是由于坏死，而凋亡可以忽略不计。γ-TOC（显示优先细胞摄取和最低非特异性细胞毒性的形式）是细胞周期进展（停滞在G 0/G1期）的最有效抑制剂，导致细胞周期蛋白E和细胞周期蛋白依赖性激酶2和4的表达降低以及p27（进入S期的特异性抑制剂）的过表达。根据这些信号，上游活化的ERK 1/2和PKC以及下游Rb磷酸化被降低。总之，在TOC中，γ形式对C6细胞中的细胞周期进程发挥最有效和特异性的控制作用（细胞生长抑制作用）。这表明这种形式的维生素E在神经胶质瘤中具有化学预防作用。(c)2006年爱思唯尔公司All rights reserved.
Chemoprevention strategies for brain tumors (specifically gliomas) are few and surprisingly poorly investigated. We have studied the effects of tocopherols (TOCs; vitamin E) on proliferation and death processes of murine glioma C6 cells. These vitamers showed different cell uptake and concentration- and time-dependent inhibitory effects on cell growth that were significant at the lowest concentrations tested (1-10 mu M). However, the inhibitory potency of TOCs seemed to reflect at least in part their actual cell concentrations at steady state, with the order of magnitude gamma-TOC >= alpha-TOC > delta-TOC congruent to beta-TOC. Moreover, for extracellular concentrations >= 10 mu M, TOCs also showed a significant cytotoxic effects due mainly to necrosis, while apoptosis was negligible. gamma-TOC (the form showing preferential cell uptake and lowest unspecific cytotoxicity) was the most effective inhibitor of cell cycle progression (arrest in G0/G1 phase) leading to lowered expression of cyclin E and cyclin-dependent kinases 2 and 4 and overexpression of p27 (specific inhibitor of S-phase entering). According to these signals, activated ERK1/2 and PKC upstream and Rb phosphorylation downstream were decreased. In conclusion, within TOCs the gamma form exerts the most potent and specific control of cell cycle progression in C6 cells (cytostatic effect). This suggests a chemopreventive role of this form of vitamin E in gliomas. (c) 2006 Elsevier Inc. All rights reserved.