Sodium Orthovanadate Inhibits p53-Mediated Apoptosis
Sodium Orthovanadate Inhibits p53-Mediated Apoptosis
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DOI：
10.1158/0008-5472.can-08-3771
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发表时间：
2010-01-01
期刊：
影响因子：
11.2
通讯作者：
Ikekita, Masahiko
中科院分区：
文献类型：
--
作者：
Morita, Akinori;Yamamoto, Shinichi;Ikekita, Masahiko
原钒酸钠(钒酸)抑制P53的DNA结合活性，但其对P53功能的确切影响尚未被检测到。在这里，我们表明，钒酸通过转录依赖和转录非依赖的机制，相对于其他P53抑制剂，包括匹非菊酯(PFT)α，发挥了强大的抗细胞凋亡活性。我们比较了钒酸盐对PFTα和PFTβMU的影响，PFTβMU是一种通过P53抑制转录非依赖性细胞凋亡的药物。钒酸盐可抑制线粒体膜电位降低、Bax和Bak的构象改变、P53的线粒体易位以及P53与Bcl2的相互作用等与P53相关的凋亡事件。同样，在稳定的SAOS-2细胞中，钒酸盐抑制了线粒体靶向的温度敏感的p53的凋亡诱导活性。在依赖于P53的放射防护试验中，钒酸盐完全保护小鼠免受8Gy亚致死剂量和12Gy部分致死剂量的伤害。综上所述，我们的研究结果表明，钒酸通过转录依赖和转录非依赖两种途径有效地抑制P53介导的细胞凋亡，并提示必须同时抑制这两种途径才能完全阻断P53介导的细胞凋亡。癌症资源；70(1)；257-65。(C)2010年AACR。
Sodium orthovanadate (vanadate) inhibits the DNA-binding activity of p53, but its precise effects on p53 function have not been examined. Here, we show that vanadate exerts a potent antiapoptotic activity through both transcription-dependent and transcription-independent mechanisms relative to other p53 inhibitors, including pifithrin (PFT) alpha. We compared the effects of vanadate to PFT alpha and PFT beta mu, an inhibitor of transcription-independent apoptosis by p53. Vanadate suppressed p53-associated apoptotic events at the mitochondria, including the loss of mitochondrial membrane potential, the conformational change of Bax and Bak, the mitochondrial translocation of p53, and the interaction of p53 with Bcl-2. Similarly, vanadate suppressed the apoptosis-inducing activity of a mitochondrially targeted temperature-sensitive p53 in stable transfectants of SaOS-2 cells. In radioprotection assays, which rely on p53, vanadate completely protected mice from a sublethal dose of 8 Gy and partially from a lethal dose of 12 Gy. Together, our findings indicated that vanadate effectively suppresses p53-mediated apoptosis by both transcription-dependent and transcription-independent pathways, and suggested that both pathways must be inhibited to completely block p53-mediated apoptosis. Cancer Res; 70(1); 257-65. (C) 2010 AACR.