Off-target response of a Wip1 chemical inhibitor in skin keratinocytes
Off-target response of a Wip1 chemical inhibitor in skin keratinocytes
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DOI：
10.1016/j.jdermsci.2013.09.003
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发表时间：
2014-02-01
影响因子：
4.6
通讯作者：
Cha, Hyuk-Jin
中科院分区：
文献类型：
--
作者：
Lee, Ji-Seon;Park, Jeong-Rak;Cha, Hyuk-Jin
背景资料：野生型p53诱导型磷酸酶（Wip1）不仅在调节各种环境应激的应激反应中起重要作用，而且当过表达时，它还损害了在许多癌症（包括皮肤癌）中经常发现的内在肿瘤监视网络。因此，使用Wip1的药理学抑制剂已被认为是一种新的化疗方法，以恢复各种癌症中的先天性肿瘤监视。目的：我们研究了紫外线（UV）应激条件下皮肤角质形成细胞中Wip1的药理学抑制剂的作用。将人角质形成细胞系或人表皮角质形成细胞暴露于UV，有或没有Wip1的唯一市售化学抑制剂CCT 007093;随后，我们确定了不同的应激反应，包括细胞凋亡和应激信号的激活。我们证明Wip1抑制剂出乎意料地减弱了皮肤角质形成细胞中UV介导的凋亡反应，这是由于减弱了JNK活化和减少了两者中的H2AX磷酸化，皮肤角质形成细胞和Wip1缺失细胞模型。另一方面，Wip1表达的丧失，无论是在小鼠或人角质形成细胞分别敲除或敲低，促进细胞凋亡和增强H2AX磷酸化后UV处理。值得注意的是，CCT 007093处理似乎促进异位表达Wip1的乳腺癌细胞和皮肤转化的角质形成细胞的凋亡，证明CCT 007093的作用基于Wip1表达水平而不同。因此，在本发明中，我们的研究表明，开发一种更有效和特异的Wip1抑制剂是必要的，以实现所需的化疗潜力，并避免关闭，目标效应。(C)2013年日本皮肤病研究学会。由Elsevier爱尔兰有限公司出版。保留所有权利。
Background: The wild type p53 inducible phosphatase (Wip1) plays an important role in modulating not only stress responses by various environmental stresses, but when overexpressed it also impairs the intrinsic tumor surveillance networks that are frequently found in a number of cancers including skin cancers. As a result, using a pharmacological inhibitor of Wip1 has been suggested to be a novel chemotherapeutic approach to recover the innate tumor surveillance in a variety of cancers.Objective: We studied the effect of a pharmacological inhibitor of Wip1 in skin keratinocytes, under a ultra-violet (UV) stress condition.Methods: A human keratinocyte cell line or human epidermal keratinocytes were exposed to UV, with or without the sole commercially available chemical inhibitor of Wip1, CCT007093; subsequently, we determined the diverse stress responses, including apoptosis and the activation of stress signaling.Results: We demonstrate that the Wip1 inhibitor unexpectedly attenuated the UV-mediated apoptotic response in skin keratinocytes, as a consequence of attenuated JNK activation and reduced H2AX phosphorylation in both, skin keratinocytes and a Wip1-null cell model. On the other hand, the loss of Wip1 expression, either by knockout or knockdown in mice or human keratinocytes respectively, promoted apoptosis and potentiated H2AX phosphorylation following UV treatment. Of note, CCT007093 treatment appeared to promote apoptosis in breast cancer cells and skin transformed keratinocytes that ectopically expressed Wip1, demonstrating that the effect of CCT007093 differs based on the level of Wip1 expression.Conclusion: Thus, our studies suggest that the development of a more potent and specific Wip1 inhibitor is necessary to achieve the desired chemotherapeutic potential and to avoid off-target effects. (C) 2013 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.