Polysulfide Na2S4 regulates the activation of PTEN/Akt/CREB signaling and cytotoxicity mediated by 1,4-naphthoquinone through formation of sulfur adducts

• 安孫子, ユミ

• 新開, 泰弘

• 鵜木, 隆光

• Hirose, Reiko

• Uehara, Takashi

• 熊谷, 嘉人

抄録

Electrophiles can activate redox signal transduction pathways, through actions of effector molecules ( e.g ., kinases and transcription factors) and sensor proteins with low p K a 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 Na 2 S 4 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 Na 2 S 4 . 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 Na 2 S 4 . Incubation of 1,4-NQ with Na 2 S 4 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 Na 2 S 4 , can increase the threshold of 1,4-NQ for activating PTEN–Akt signaling and cytotoxicity by capturing this electrophile to form its sulfur adducts.

収録刊行物

• Scientific Reports

  Scientific Reports 7 4814-, 2017-07

  Nature Publishing Group

キーワード

• Multidisciplinary

詳細情報

• CRID: 1050001202548545408
• NII論文ID: 120007128910
• DOI: 10.1038/s41598-017-04590-z
• ISSN: 20452322
• HANDLE: 2241/00146885
• Web Site: https://tsukuba.repo.nii.ac.jp/records/41949
• Web Site: https://www.nature.com/articles/s41598-017-04590-z.pdf
• Web Site: https://www.nature.com/articles/s41598-017-04590-z
• 本文言語コード: en
• 資料種別: journal article
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