Polysulfide Na(2)S(4) regulates the activation of PTEN/Akt/CREB signaling and cytotoxicity mediated by 1,4-naphthoquinone through formation of sulfur adducts.
Polysulfide Na(2)S(4) regulates the activation of PTEN/Akt/CREB signaling and cytotoxicity mediated by 1,4-naphthoquinone through formation of sulfur adducts.
复制标题
DOI：
10.1038/s41598-017-04590-z
复制
发表时间：
2017-07-06
影响因子：
4.6
通讯作者：
Kumagai Y
中科院分区：
文献类型：
--
作者：
Abiko Y;Shinkai Y;Unoki T;Hirose R;Uehara T;Kumagai Y
亲电体可以通过效应分子（例如，激酶和转录因子）和具有共价修饰的低pKa硫醇的传感器蛋白。在这项研究中，我们研究了1，4-萘醌（1，4-NQ）是否可以影响磷酸酶和张力蛋白同源物（PTEN）-Akt信号通路和过硫化物/多硫化物可以调节这种适应性反应。原代小鼠肝细胞同时暴露于Na 2S 4和1，4-NQ显著降低1，4-NQ介导的细胞死亡和细胞蛋白的S-芳基化。在Na 2S 4存在下，暴露于1，4-NQ期间细胞PTEN的修饰也被阻断。1，4-NQ，在高达10 µM时，增加Akt和cAMP反应元件结合蛋白（CREB）的磷酸化。然而，在较高浓度下，1，4-NQ抑制这两种蛋白质的磷酸化。Akt和CREB激活的这些钟形剂量曲线在用1，4-NQ和Na 2S 4处理的细胞中右移。将1，4-NQ与Na 2S 4孵育导致形成1，4-NQ-S-1，4-NQ-OH。与1，4-NQ不同，真正的1，4-NQ-S-1，4-NQ-OH加合物没有细胞毒性、共价结合能力，也没有激活细胞中PTEN-Akt信号传导的能力。我们的研究结果表明，多硫化物，如Na 2S 4，可以通过捕获这种亲电体形成其硫加合物来增加1，4-NQ激活PTEN-Akt信号传导和细胞毒性的阈值。
Electrophiles can activate redox signal transduction pathways, through actions of effector molecules (e.g., kinases and transcription factors) and sensor proteins with low pKa thiols that are covalently modified. In this study, we investigated whether 1,4-naphthoquinone (1,4-NQ) could affect the phosphatase and tensin homolog (PTEN)–Akt signaling pathway and persulfides/polysulfides could modulate this adaptive response. Simultaneous exposure of primary mouse hepatocytes to Na2S4 and 1,4-NQ markedly decreased 1,4-NQ-mediated cell death and S-arylation of cellular proteins. Modification of cellular PTEN during exposure to 1,4-NQ was also blocked in the presence of Na2S4. 1,4-NQ, at up to 10 µM, increased phosphorylation of Akt and cAMP response element binding protein (CREB). However, at higher concentrations, 1,4-NQ inhibited phosphorylation of both proteins. These bell-shaped dose curves for Akt and CREB activation were right-shifted in cells treated with both 1,4-NQ and Na2S4. Incubation of 1,4-NQ with Na2S4 resulted in formation of 1,4-NQ–S–1,4-NQ-OH. Unlike 1,4-NQ, authentic 1,4-NQ-S-1,4-NQ-OH adduct had no cytotoxicity, covalent binding capability nor ability to activate PTEN-Akt signaling in cells. Our results suggested that polysulfides, such as Na2S4, can increase the threshold of 1,4-NQ for activating PTEN–Akt signaling and cytotoxicity by capturing this electrophile to form its sulfur adducts.
登录
查看更多内容
影响因子：
2.4
作者：
Nishida M;Kumagai Y;Ihara H;Fujii S;Motohashi H;Akaike T
通讯作者：
Akaike T
影响因子：
15
作者：
Fang X;Fu Y;Long MJ;Haegele JA;Ge EJ;Parvez S;Aye Y
通讯作者：
Aye Y
影响因子：
5.3
作者：
Kobayashi, Makoto;Li, Li;Yamamoto, Masayuki
通讯作者：
Yamamoto, Masayuki
影响因子：
10.5
作者：
Itoh, K;Wakabayashi, N;Yamamoto, M
通讯作者：
Yamamoto, M
影响因子：
4.8
作者：
Lee, SR;Yang, KS;Rhee, SG
通讯作者：
Rhee, SG