Cell Cycle and Senescence Suppression of Ser / Thr Phosphatase 4 ( PP 4 C / PPP 4 C ) Mimics a Novel Post-Mitotic Action of Fostriecin , Producing Mitotic Slippage Followed by Tetraploid Cell Death
Cell Cycle and Senescence Suppression of Ser / Thr Phosphatase 4 ( PP 4 C / PPP 4 C ) Mimics a Novel Post-Mitotic Action of Fostriecin , Producing Mitotic Slippage Followed by Tetraploid Cell Death
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发表时间：
2013
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通讯作者：
Benjamin Theobald;Kathy Bonness;A. Musiyenko;J. Andrews;G. Urban;Xizhong A. Huang;N. Dean;R. Honkanen
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作者：
Benjamin Theobald;Kathy Bonness;A. Musiyenko;J. Andrews;G. Urban;Xizhong A. Huang;N. Dean;R. Honkanen
Fostriecin是从Sterptomyces提取物中提纯的天然产物，具有足够的抗肿瘤活性，足以进行人体临床试验。不幸的是，与供应和稳定的药物配方有关的困难阻碍了进一步的发展。在分子水平上，Fostriecin被认为是四个PPP家族磷酸酶的催化抑制剂，描述这一类分子设计的报告表明，针对Fostriecin敏感亚家族中的酶的衍生物可能是成功的。然而，目前还不清楚Fostriecin的肿瘤选择性细胞毒性是由于抑制了特定的磷酸酶、多种磷酸酶还是有限的Fostriecin敏感的磷酸酶。敏感的磷酸酶抑制如何促进肿瘤选择性细胞毒性也不清楚。在这里，活细胞的高含量延时成像揭示了对Fostriecin的细胞行为的新见解，表明Fostriecin诱导的细胞凋亡不是在持续的有丝分裂停止后简单地诱导的。相反，当四倍体细胞经历有丝分裂滑移时，细胞凋亡发生在明显的第二间期。对Fostriecin和针对人Fostriecin敏感磷酸酶的反义寡核苷酸的作用进行了比较，发现仅抑制PP4C就足以模拟Fostriecin的许多作用。重要的是，靶向抑制PP4C诱导了细胞凋亡，在有丝分裂滑移后的四倍体细胞中发生死亡。在抑制PP1C、PP2Ac或PP5C后，没有观察到这种影响。这些数据阐明了PP4C是一种对蛋白质不敏感的磷酸酶，并表明PP4C的抑制触发了有丝分裂的滑移/凋亡。提示：福斯特里菌素类抑制剂的未来发展应考虑将PP4C作为潜在的重要靶点。摩尔癌症资源；11(8)；845-55。2013年度AACR。
Fostriecin is a natural product purified from Sterptomyces extracts with antitumor activity sufficient to warrant human clinical trials. Unfortunately, difficulties associated with supply and stable drug formulation stalled further development. At a molecular level, fostriecin is known to act as a catalytic inhibitor of four PPPfamily phosphatases, and reports describing the design of molecules in this class suggest derivatives targeting enzymes within the fostriecin-sensitive subfamily can be successful. However, it is not clear if the tumorselective cytotoxicity of fostriecin results from the inhibition of a specific phosphatase, multiple phosphatases, or a limited subset of fostriecin sensitive phosphatases. How the inhibition of sensitive phosphatases contributes to tumor-selective cytotoxicity is also not clear. Here, high-content time-lapse imaging of live cells revealed novel insight into the cellular actions of fostriecin, showing that fostriecin-induced apoptosis is not simply induced following a sustained mitotic arrest. Rather, apoptosis occurred in an apparent second interphase produced when tetraploid cells undergo mitotic slippage. Comparison of the actions of fostriecin and antisense-oligonucleotides specifically targeting human fostriecin-sensitive phosphatases revealed that the suppression PP4C alone is sufficient to mimic many actions of fostriecin. Importantly, targeted suppression of PP4C induced apoptosis, with death occurring in tetraploid cells following mitotic slippage. This effect was not observed following the suppression of PP1C, PP2AC, or PP5C. These data clarify PP4C as a fostriecinsensitive phosphatase and demonstrate that the suppression of PP4C triggers mitotic slippage/apoptosis. Implications: Future development of fostriecin class inhibitors should consider PP4C as a potentially important target. Mol Cancer Res; 11(8); 845–55. 2013 AACR.