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

Abstract

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.

Nrf2 Activation and Its Coordination with the Protective Defense Systems in Response to Electrophilic Stress

“…However, a higher dose of xenobiotic electrophiles causes nonspecific protein modification, disrupting these signals, leading to cell death. Our previous studies confirmed such a dose-dependent transition, focusing on some sensor proteins that mediate cellular redox signaling pathways during exposure to xenobiotic electrophiles; phosphatase and tensin homologue (PTEN) modification by MeHg [11] and 1,4-NQ [75] as well as heat shock protein 90 (HSP90) by 1,4-NQ [12] and cadmium [77]. The fact that these xenobiotic electrophile-mediated redox signaling pathways and cellular toxicity are negatively regulated by RSS through the formation of their sulfur adducts, indicate that RSS act as the initial defense system for xenobiotic electrophile exposure [12,75,77] (Figure 3).…”

“…This indicates that RSS are involved in the repression of electrophile-mediated toxicity by the formation of inactive metabolites of electrophiles. Consistent with this notion, the toxicity of MeHg, Cd and 1,4-NQ was effectively blocked by treatment with the model polysulfide Na 2 S 4 [75,77,80].…”

“…As noted above, electrophiles can be captured by RSS, leading to the formation of their sulfur adducts. For example, we previously reported that MeHg, Cd, 1,4-NQ and NAPQI, which is the toxic metabolite of acetaminophen, can react with RSS, such as H 2 S, CysSSH, GSSH, GSSSG or the model polysulfide Na 2 S 4 , leading to the formation of bismethylmercury sulfide [(MeHg) 2 S], cadmium sulfide (CdS), CdS 2 O 3 , 1,4-NQ-SH, 1,4-NQ-S-1,4-NQ, 1,4-NQ-S-1,4-NQ-OH, NAPQIH 2 -SSSCys, NAPQIH 2 -SSCys and NAPQIH 2 -SSG [5,12,[75][76][77][78]. Additionally, (MeHg) 2 S and NAPQIH 2 -SSSCys were identified as novel metabolites of MeHg and acetaminophen from the liver and urine of mice treated with these compounds [78,79].…”

“…Additionally, (MeHg) 2 S and NAPQIH 2 -SSSCys were identified as novel metabolites of MeHg and acetaminophen from the liver and urine of mice treated with these compounds [78,79]. Remarkably, sulfur adduct electrophiles such as (MeHg) 2 S, CdS and 1,4-NQ-S-1,4-NQ-OH are less electrophilic and toxic than their parent compounds; thus, they are defined as detoxified metabolites [75][76][77]. This indicates that RSS are involved in the repression of electrophile-mediated toxicity by the formation of inactive metabolites of electrophiles.…”

Influence of Titanium Species on the Ordered Mesoporous Structure of V‐Zr Catalysts for Naphthalene Oxidation with Hydrogen Peroxide

“…In particular, mesoporous metal oxides prepared by a modified EISA method were easily obtained, where some cationic active species can be uniformly incorporated into the framework to form the specific catalysts . The product 1,4‐naphthoquinone, which was widely used in various fields such as medicine, biology, and perfumery, can be obtained by selective oxidation of naphthalene with hydrogen peroxide over various mesoporous metal oxides. However, since liquid‐phase oxidation of naphthalene was a continuous reaction, 1,4‐naphthoquinone as an intermediate product was easily further oxidized, where some chemicals with low values would be formed .…”