Arsenic trioxide exerts antimyeloma effects by inhibiting activity in the cytoplasmic substrates of histone deacetylase 6.
Arsenic trioxide exerts antimyeloma effects by inhibiting activity in the cytoplasmic substrates of histone deacetylase 6.
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三氧化二砷通过抑制组蛋白脱乙酰酶 6 细胞质底物的活性来发挥抗骨髓瘤作用。
DOI：
10.1371/journal.pone.0032215
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Hou J
中科院分区：
文献类型：
--
作者：
Qu X;Du J;Zhang C;Fu W;Xi H;Zou J;Hou J
三氧化二砷（As 2 O3）治疗多发性骨髓瘤（MM）有显著疗效。组蛋白去乙酰化酶（HDAC）在基因表达调控中起重要作用，其失调与骨髓瘤有关。特别是，HDAC 6，一个独特的细胞质成员的II类，主要功能作为α-微管蛋白脱乙酰酶和热休克蛋白90脱乙酰酶，已成为药物开发的目标，以治疗癌症，由于其在致癌细胞转化的主要贡献。然而，As 2 O3的作用机制尚未确定。本研究观察了As_2O_3对人骨髓瘤细胞系和原代骨髓瘤细胞增殖和凋亡的影响，并通过Western blot和免疫沉淀法研究了As_2O_3通过抑制α-微管蛋白和Hsp 90的活性而发挥抗骨髓瘤作用。我们发现As 2 O3在相对较低的浓度（0.5 ~ 2.5 µM）下直接作用于MM细胞，影响MM细胞的生存和凋亡。而As 2 O3在较高浓度（大于4 μM）时抑制HDAC活性，且呈剂量依赖性。随后，我们发现As 2 O3以剂量和时间依赖的方式显著增加乙酰化α-微管蛋白和乙酰化Hsp 90的水平，抑制IKKα活性的伴侣蛋白结合，并增加IKKα的降解。重要的是，IKKα相关的Hsp 90的丢失发生在IKKα水平的任何可检测的丢失之前，表明As 2 O3通过Hsp 90伴侣功能下调HDAC 6以使IKKα蛋白不稳定的新途径。此外，我们观察到As 2 O3对TNF-α诱导的NF-κB信号通路的影响是显著降低NF-κB p65上Ser-536的磷酸化。因此，我们的研究为深入了解As 2 O3在HDAC 6-Hsp 90-IKKα-NFκB信号转导轴中抗骨髓瘤活性的分子机制提供了重要的线索，并且As 2 O3的理论基础可以很容易地扩展到所有HDAC相关疾病。
Arsenic trioxide (As2O3) has shown remarkable efficacy for the treatment of multiple myeloma (MM). Histone deacetylases (HDAC) play an important role in the control of gene expression, and their dysregulation has been linked to myeloma. Especially, HDAC6, a unique cytoplasmic member of class II, which mainly functions as α-tubulin deacetylase and Hsp90 deacetylase, has become a target for drug development to treat cancer due to its major contribution in oncogenic cell transformation. However, the mechanisms of action for As2O3 have not yet been defined. In this study, we investigated the effect of As2O3 on proliferation and apoptosis in human myeloma cell line and primary myeloma cells, and then we studied that As2O3 exerts antimyeloma effects by inhibiting activity in the α-tubulin and Hsp90 through western blot analysis and immunoprecipitation. We found that As2O3 acts directly on MM cells at relatively low concentrations of 0.5∼2.5 µM, which effects survival and apoptosis of MM cells. However, As2O3 inhibited HDAC activity at the relatively high concentration and dose-dependent manner (great than 4 µM). Subsequently, we found that As2O3 treatment in a dose- and time-dependent fashion markedly increased the level of acetylated α-tubulin and acetylated Hsp90, and inhibited the chaperone association with IKKα activities and increased degradation of IKKα. Importantly, the loss of IKKα-associated Hsp90 occurred prior to any detectable loss in the levels of IKKα, indicating a novel pathway by which As2O3 down-regulates HDAC6 to destabilize IKKα protein via Hsp90 chaperone function. Furthermore, we observed the effect of As2O3 on TNF-α-induced NF-κB signaling pathway was to significantly reduced phosphorylation of Ser-536 on NF-κB p65. Therefore, our studies provide an important insight into the molecular mechanism of anti-myeloma activity of As2O3 in HDAC6-Hsp90-IKKα-NFκB signaling axis and the rationale for As2O3 can be extended readily using all the HDAC associated diseases.
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通讯作者：
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影响因子：
64.8
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