Lovastatin inhibits G1/S transition of normal human B-lymphocytes independent of apoptosis
Lovastatin inhibits G1/S transition of normal human B-lymphocytes independent of apoptosis
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DOI：
10.1006/excr.1999.4608
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发表时间：
1999-10-10
影响因子：
3.7
通讯作者：
Blomhoff, HK
中科院分区：
文献类型：
--
作者：
Naderi, S;Blomhoff, R;Blomhoff, HK
洛伐他汀是一种有效的蛋白质异戊二烯化抑制剂，据报道，它具有多效性细胞效应。在本研究中，我们阐明了洛伐他汀对正常人B淋巴细胞的细胞周期进程和凋亡的影响。当加入到抗免疫球蛋白（抗mu）和SAG刺激的E淋巴细胞中时，洛伐他汀（20 μ M）抑制细胞处于细胞周期的晚期G1期。因此，没有早期激活参数，如钙离子流量或MYC诱导受洛伐他汀的影响，而进展的细胞进入第二个细胞周期，以及DNA合成显着减少。因此，我们研究了洛伐他汀对负责调节G1/S转换的细胞周期机制组分的影响。我们证明，pRB磷酸化，cdk 2的活性需要这种磷酸化，和细胞周期蛋白A，D和E的水平受到抑制后，24小时的洛伐他汀治疗，而p27（Kip 1）的水平升高。对p21（Cip 1）、细胞周期蛋白D2、cdk 4和cdk 6无影响。这些数据与洛伐他汀在24至32 h之间抑制细胞进入GI一致。在GI晚期向刺激的B细胞中添加洛伐他汀仍能抑制60%的DNA合成，但此时仅观察到对细胞周期机制的轻微影响。因此，我们寻找诱导的细胞凋亡作为细胞进入S期减少的解释。然而，尽管有能力提高未刺激的B细胞的凋亡从48%至61%的TUNEL法判断，洛伐他汀只有轻微影响细胞凋亡时，刺激的B细胞。因此，似乎加速的细胞凋亡不能解释洛伐他汀对细胞周期进程的影响。(C)北京：科学出版社.
Lovastatin is a potent inhibitor of protein prenylation, and it has been reported to have pleiotropic cellular effects. In the present study we have elucidated the effects of lovastatin on cell cycle progression and apoptosis of normal human B-lymphocytes, When added to E-lymphocytes stimulated with anti-immunoglobulin (anti-mu) and SAG, lovastatin (20 mu M) inhibited the cells in the late G1 phase of the cell cycle. Thus, no early activation parameters such as Ca2+ flux or MYC induction were affected by lovastatin, whereas progression of cells into the second cell cycle as well as DNA synthesis was markedly reduced. We therefore examined the effects of lovastatin on components of the cell cycle machinery responsible for regulating the G1/S transition. We demonstrated that pRB phosphorylation, cdk2 activity needed for this phosphorylation, and the levels of cyclin A, D, and E were inhibited after 24 h of lovastatin treatment, while the levels of p27(Kip1) were elevated. There was no:effect on p21(Cip1), cyclin D2, cdk4, and cdk6. These data are consistent with the cells being inhibited by lovastatin between 24 and 32 h into GI. Lovastatin added to stimulated B-cells in late GI still inhibited the DNA synthesis by 60%, but at this point only minor effects were noted on the cell cycle machinery. We therefore looked for induced apoptosis as an explanation for reduced S-phase entry of the cells. However, despite the ability to enhance the apoptosis of unstimulated B-cells from 48 to 61% as judged by the TUNEL method, lovastatin only marginally affected apoptosis when administered to stimulated B-cells. Thus, it appears that accelerated apoptosis cannot account for the effect of lovastatin on cell cycle progression. (C) 1999 Academic Press.