Geldanamycin inhibits trichostatin A-induced cell death and histone H4 hyperacetylation in COS-7 cells
Geldanamycin inhibits trichostatin A-induced cell death and histone H4 hyperacetylation in COS-7 cells
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DOI：
10.1016/s0024-3205(01)01558-2
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发表时间：
2002-03-01
期刊：
影响因子：
6.1
通讯作者：
Lee, WC
中科院分区：
文献类型：
--
作者：
Huang, HC;Liu, YC;Lee, WC
人们普遍认为，用组蛋白脱乙酰酶抑制剂曲古抑菌素 A (TSA) 处理细胞会导致组蛋白 H4 过度乙酰化和细胞周期停滞。该化合物经常在细胞周期、增殖和分化研究中与其他潜在的抗癌药物进行比较。此外，格尔德霉素 (GA) 是一种 90 kDa 热休克蛋白 (HSP90) 特异性抑制剂，是一种众所周知的潜在抗癌药物。本研究探讨 GA 是否可以影响 TSA 诱导的细胞功能。当使用TSA处理时，虽然引起COS-7细胞死亡，但0.5μg/ml GA预处理30分钟并添加50ng/ml TSA(GA+TSA)显然避免了细胞死亡。我们的结果表明，单独使用 50 ng/ml TSA (TSA) 进行长时间处理 24 小时时，细胞存活率仅为 20% 左右。相比之下，用GA+TSA处理时，细胞存活率提高了两倍。此外，DNA 片段化分析显示，单独使用 TSA 长时间处理后 8 小时产生片段化 DNA。 16小时内，TSA处理的细胞的凋亡百分比在15-25%之间。相比之下，其他处理均不超过6%。此外，GA 还能抑制 TSA 诱导的组蛋白 H4 过度乙酰化。 Western blotting 分析进一步表明，TSA 处理的细胞中 HSP70 水平没有显着增加。然而，在GA-和GA+TSA处理的细胞中，积累的70-kDa热休克蛋白(HSP70)在8小时时显着增加2至3倍，并且在20小时时最大量增加至5至7倍。相反，HSP90 在所有处理中均没有显着增加。根据本研究的结果，我们认为 GA 诱导的热休克蛋白（特别是 HSP70）的增加可以预防 TSA 诱导的细胞凋亡。 (C) 2002 Elsevier Science Inc. 保留所有权利。
As widely believed treating cells with trichostatin A (TSA), an inhibitor of histone deacetylase, results in histone H4 hyperacetylation and cell cycle arrest. This compound is often compared with other potential anticancer drugs in cell cycle, proliferation and differentiation research. Furthermore, geldanamycin (GA), a 90-kDa heat shock protein (HSP90) specific inhibitor, is a well-known potential anticancer agent. This study examines whether GA can affect the cellular functions induced by TSA. When using TSA treatment, although caused COS-7 cell death, pretreatment of 0.5 mug/ml GA for 30 min and an addition of 50 ng/ml TSA (GA+TSA) apparently averted cell death. Our results indicated that the cell survival rate was only approximately 20% when prolonged treatment was undertaken with 50 ng/ml TSA (TSA) alone for 24 h. In contrast, the cell survival rate was enhanced by two folds when treating with GA+TSA. Furthermore, DNA fragmentation assay revealed that fragmented DNA was produced 8 h after prolonged treatment with TSA alone. Within 16 h, the apoptotic percentages of TSA-treated cells were between 15-25%. In contrast, the other treatments did not exceed 6%. Furthermore, GA inhibited TSA-induced histone H4 hyperacetylation. Western blotting analysis further demonstrated that the HSP70 levels did not significantly increase in TSA-treated cells. However, the accumulated 70-kDa heat shock protein (HSP70) markedly increased up to 2 to 3 folds at 8 h in GA- and GA + TSA-treated cells, and the maximum amount up to 5 to 7 folds at 20 h. Conversely, HSP90 did not markedly increase in all treatments. Based on the results in this study, we suggest that apoptosis induced by TSA can be prevented by GA-induced increment of heat shock proteins, particularly HSP70. (C) 2002 Elsevier Science Inc. All rights reserved.