Oxidation and inactivation of low molecular weight protein tyrosine phosphatase by the anticancer drug Aplidin
Oxidation and inactivation of low molecular weight protein tyrosine phosphatase by the anticancer drug Aplidin
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DOI：
10.1002/ijc.21602
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发表时间：
2006-04-15
影响因子：
6.4
通讯作者：
Raugei, G
中科院分区：
文献类型：
--
作者：
Taddei, ML;Chiarugi, P;Raugei, G
海洋plitidepsin Aplidin来源于地中海被囊动物Aplidium albicans，是一种强凋亡诱导剂，具有很好的抗肿瘤活性。然而，人们对该分子的作用机制知之甚少。在这篇文章中，我们报告，Aplidin是细胞毒性的NIH 3 T3细胞，其作用是通过产生活性氧（ROS）。鱼藤酮，而不是其他选择性抑制剂的活性氧产生，阻断诱导的活性氧，这表明线粒体呼吸链的参与Aplidin行动。由Aplidin引起的细胞内氧化还原电位的升高使几种分子靶标失活。在这些靶点中，我们将注意力集中在蛋白酪氨酸磷酸酶（PTPs）上。与ROS介导的PTP氧化的良好表征的效果一致，由于在其催化位点中存在半胱氨酸残基，我们发现Aplidin诱导PTP活性的强烈降低。特别是，由于低分子量-PTP（LMW-PTP）的表达与肿瘤的发生和进展密切相关，我们研究了Aplidin对这种酶的影响。我们的数据表明，LMW-PTP在Aplidin处理过程中被氧化和失活，从而导致其底物β-连环蛋白的过度磷酸化。这些发现表明，至少部分，Aplidin的抗肿瘤活性可能是由于直接抑制LMW-PTP及其相关的致癌潜力。(c)2005 Wiley-Liss，Inc.
The marine plitidepsin Aplidin derived from the Mediterranean tunicate Aplidium albicans is a strong apoptotic inducer with promising antitumor activity. However, little is known about the mechanism of action of the molecule. In this article, we report that Aplidin is cytotoxic for NIH3T3 cells and that its action is exerted through the production of reactive oxygen species (ROS). Rotenone, but not other selective inhibitors of ROS production, blocks the induction of ROS, suggesting the involvement of the mitochondrial respiratory chain in Aplidin action. The intracellular rise of redox potential caused by Aplidin inactivates several molecular targets. Among these targets, we focused our attention on protein tyrosine phosphatases (PTPs). In agreement with the well-characterized effect of ROS-mediated PTP oxidation, due to the presence of a cysteine residue in their catalytic site, we found that Aplidin induces a strong decrease in PTP activity. In particular, since the expression of low molecular weight-PTP (LMW-PTP) is strongly associated with tumor onset and progression, we investigated the effect of Aplidin on this enzyme. Our data show that LMW-PTP is oxidized and inactivated during Aplidin treatment, thus causing a hyper-phosphorylation of its substrate beta-catenin. These findings demonstrate that, at least in part, the antitumoral activity of Aplidin could be due to the direct inhibition of LMW-PTP and its related oncogenic potential. (c) 2005 Wiley-Liss, Inc.