ROS-driven Akt dephosphorylation at Ser-473 is involved in 4-HPR-mediated apoptosis in NB4 cells
ROS-driven Akt dephosphorylation at Ser-473 is involved in 4-HPR-mediated apoptosis in NB4 cells
复制标题
ROS 驱动的 Akt Ser-473 去磷酸化参与 NB4 细胞中 4-HPR 介导的细胞凋亡
DOI：
10.1016/j.freeradbiomed.2009.05.024
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发表时间：
2009-09-01
影响因子：
7.4
通讯作者：
Yang, Bo
中科院分区：
文献类型：
--
作者：
Cao, Ji;Xu, Danqing;Yang, Bo
N-（4-羟基苯基）视黄酰胺（4-HPR）作为一种合成类维生素A，已被证明可以抑制多种癌症的致癌作用。大量研究表明，ROS参与4-HPR介导的细胞凋亡。在此，我们提供了进一步的证据，Akt信号通路参与4-HPR介导的细胞凋亡。值得注意的是，PI 3 K（p110）的表达没有明显变化，LY 294002和胰岛素均不影响4-HPR诱导的细胞凋亡。这些观察结果暗示Akt和ROS之间的直接相互作用。我们的数据还表明，4-HPR介导的ROS引起Akt构象的变化，形成分子内二硫键：N-乙酰半胱氨酸和谷胱甘肽，作为巯基抗氧化剂，显着减少ROS的产生在4-HPR暴露的细胞。进一步的实验表明，Akt的构象变化不仅破坏了Akt-Hsp 90的结合，而且增强了Akt-PP 2A的相互作用。所有这些结果共同表明，4-HPR诱导的细胞凋亡与ROS介导的Akt构象变化有关，因此，这种变化通过调节Akt-Hsp 90或Akt-PP 2A复合物的形成介导Akt的去磷酸化。(C)2009爱思唯尔公司All rights reserved.
N-(4-hydroxyphenyl) retinamide (4-HPR), as a synthetic retinoid, has been shown to inhibit carcinogenesis in a variety of cancers. Extensive studies have indicated that ROS are involved in 4-HPR-mediated apoptosis. Herein, we provide further evidence that the Akt signaling pathway is involved in 4-HPR-mediated apoptosis. Of note is the fact that the expression of PI3K (p110) does not change obviously, and neither LY294002 nor insulin could influence the apoptosis induced by 4-HPR. These observations implicate the direct interaction between Akt and ROS. Our data also reveal that 4-HPR-mediated ROS evoke Akt conformational change by forming an intramolecular disulfide bond: N-acetylcysteine and glutathione, as thiol antioxidants, significantly abate the ROS generation in 4-HPR-exposed cells. Further experiments indicate that the conformational change in Akt not only disrupts Akt-Hsp90 binding, but also enhances Akt-PP2A interaction. All these results collectively suggest that 4-HPR-induced apoptosis is associated with a ROS-mediated conformational change in Akt, and this change, as a consequence, mediates dephosphorylation of Akt via regulating Akt-Hsp90 or Akt-PP2A complex formation. (C) 2009 Elsevier Inc. All rights reserved.