Evaluation of zinc (II) chelators for inhibiting p53-mediated apoptosis.
Evaluation of zinc (II) chelators for inhibiting p53-mediated apoptosis.
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DOI：
10.18632/oncotarget.1535
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发表时间：
2013-12
期刊：
影响因子：
--
通讯作者：
Hosoi Y
中科院分区：
文献类型：
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作者：
Morita A;Ariyasu S;Ohya S;Takahashi I;Wang B;Tanaka K;Uchida T;Okazaki H;Hanaya K;Enomoto A;Nenoi M;Ikekita M;Aoki S;Hosoi Y
在之前的一项研究中，我们报道了原钒酸钠（钒酸盐）是第一个已知的抑制剂，它能够通过阻断转录依赖性和转录非依赖性 p53 凋亡途径来保护小鼠免于死于辐射诱导的胃肠道综合征。在本文中，我们报道相对于其他已知的辐射防护 p53 抑制剂 Pifithrin-α (PFTα) 和 Pifithrin-μ (PFTμ)，钒酸盐具有诱导 p53 变性的独特活性。钒酸盐的这种强大的辐射防护作用促使我们对能够诱导 p53 变性的 p53 抑制剂进行更广泛的研究。基于作为p53结构因子的锌离子解离可诱导p53变性，我们筛选了一些锌(II)螯合剂，用于抑制体外p53的DNA结合活性和抑制MOLT-4细胞中辐射诱导的p53依赖性细胞凋亡。研究结果表明，五种锌 (II) 螯合剂中的两种也能抑制细胞凋亡。在所测试的抑制剂中，Bispicen (N,N'-双(2-吡啶甲基)-1,2-乙二胺)具有最高的抑制活性。使用具有不同 p53 状态或功能的细胞（即 p53 敲低 MOLT-4 转化体及其回复体、p53 突变细胞、p53 无效细胞）和 p53 独立细胞凋亡刺激进行的机制研究表明，Bispicen 对细胞凋亡的抑制作用是通过 p53 特异性介导的。此外，Bispicen 与钒酸盐类似，可诱导 p53 变性以及阻断转录依赖性和非依赖性细胞凋亡途径。我们的研究结果表明，使用锌 (II) 螯合剂代表了一种通过抑制 p53 依赖性细胞凋亡途径来防止辐射诱导的 p53 依赖性细胞凋亡的新方法。
In a previous study, we reported that sodium orthovanadate (vanadate) is the first known inhibitor that is capable of protecting mice from death from the radiation-induced gastrointestinal syndrome via its ability to block both transcription-dependent and transcription-independent p53 apoptotic pathways. In this paper, we report that vanadate has a unique activity for inducing the denaturation of p53 relative to other known radioprotective p53 inhibitors, pifithrin-α (PFTα) and pifithrin-µ (PFTµ). This potent radioprotective effect of vanadate prompted us to undertake a more extensive search for p53 inhibitors that can induce p53 denaturation. Based on the fact that p53 denaturation can be induced by the dissociation of a zinc ion, which is used as a structural factor of p53, we screened some zinc (II) chelators for the suppression of the DNA binding activity of p53 in vitro and the inhibition of radiation-induced p53-dependent apoptosis in MOLT-4 cells. The findings indicate that two of five zinc (II) chelators also suppressed apoptosis. Among the inhibitors tested, Bispicen (N,N'-Bis(2-pyridylmethyl)-1,2-ethanediamine) had the highest inhibition activity. A mechanistic study using cells bearing different p53 status or functions (i.e., p53-knockdown MOLT-4 transformant and its revertants, p53 mutant cells, p53-null cells), and p53-independent apoptotic stimuli revealed that the suppressive effect of Bispicen on apoptosis is specifically mediated through p53. Moreover, Bispicen, similar to vanadate, induces the denaturation of p53 as well as the blocking of both transcription-dependent and -independent apoptotic pathways. Our findings indicate that the use of zinc (II) chelators represent a new approach for protecting against radiation-induced p53-dependent apoptosis through the inhibition of p53-dependent apoptotic pathways.