Simvastatin induces proliferation inhibition and apoptosis in C6 glioma cells via c-jun N-terminal kinase
Simvastatin induces proliferation inhibition and apoptosis in C6 glioma cells via c-jun N-terminal kinase
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DOI：
10.1016/j.neulet.2004.08.020
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发表时间：
2004-11-11
影响因子：
2.5
通讯作者：
Altiok, N
中科院分区：
文献类型：
--
作者：
Koyuturk, M;Ersoz, M;Altiok, N
降脂药物他汀类药物可诱导多种肿瘤细胞凋亡。在这里，我们研究了亲脂性他汀类药物辛伐他汀在 C6 胶质瘤细胞中的凋亡作用以及对细胞内信号转导的潜在影响。辛伐他汀治疗20小时后完全抑制细胞增殖，细胞核中增殖细胞核抗原表达减少表明。随后，辛伐他汀通过细胞质收缩、染色质浓缩和 DNA 断裂引起细胞凋亡。细胞凋亡的特征仅在处理 48 小时后才可见，这可能反映了细胞致力于生长停滞的要求。在免疫细胞化学和免疫印迹实验中，我们发现辛伐他汀在早期时间点显着增加了 C6 胶质瘤细胞核中 ATF-2 和 c-jun 的磷酸化，甚至在治疗后 24 小时仍保持这种磷酸化。相比之下，细胞存活途径中蛋白激酶 Erk1/2 和 AKT 的活性在整个治疗过程中保持不变。 JNK（而非 p38 激酶）的选择性抑制剂可减少辛伐他汀诱导的细胞死亡以及 ATF-2 和 c-jun 磷酸化，表明 JNK 依赖性的 ATF-2 和 c-jun 激活可能在辛伐他汀诱导的 C6 胶质瘤细胞增殖抑制和凋亡中发挥重要作用。这些观察结果表明，除了降胆固醇作用之外，他汀类药物在预防神经胶质瘤方面可能具有临床意义，并且 JNK 可能是使神经胶质瘤细胞对化疗药物敏感的合理靶标。 (C) 2004 Elsevier Ireland Ltd. 保留所有权利。
The lipid-lowering drugs, statins, induce apoptosis in a variety of tumor cells. Here we investigated the apoptotic effect of the lipophilic statin, simvastatin, in C6 glioma cells and the underlying effects on intracellular signal transduction. Simvastatin inhibited cell proliferation totally after 20 h of treatment as shown by the decrease in proliferating cell nuclear antigen expression in the nucleus. Subsequently, simvastatin caused apoptotic cell death by shrinkage of cytoplasm and condensation of chromatin, and DNA fragmentation. The features of apoptosis were visible only after 48 h of treatment, possibly reflecting a requirement for cell commitment to growth arrest. In immunocytochemical and immunoblotting experiments we have shown that simvastatin markedly increased the phosphorylation of ATF-2 and c-jun in the nucleus of the C6 glioma cells at early time points which was preserved even 24 h after treatment. In contrast, activities of protein kinases Erk1/2 and AKT in the cell survival pathway remained unchanged throughout the treatment. Selective inhibitor of JNK, but not p38 kinase, reduced simvastatin-induced cell death and ATF-2 and c-jun phosphorylation suggesting that JNK-dependent activation of ATF-2 and c-jun may play an important role in simvastatin-induced proliferation inhibition and apoptosis in C6 glioma cells. These observations suggest that statins may have clinical significance in the prevention of glial tumors beyond their cholesterol-lowering effect and JNK may be a rational target for sensitizing glioma cells to chemotherapeutic agents. (C) 2004 Elsevier Ireland Ltd. All rights reserved.