Diallyl tetrasulfane activates both the eIF2α and Nrf2/HO-1 pathways

• Published in: Biochimica et biophysica acta Vol. 1830; no. 1; pp. 2214 - 2225
• Main Authors: Saidu, Nathaniel Edward Bennett, Touma, Rania, Asali, Imad Abu, Jacob, Claus, Montenarh, Mathias
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.01.2013
• Subjects: Allyl Compounds - pharmacology; anti-inflammatory activity; Antioxidant pathway; antioxidants; Apoptosis; cell cycle checkpoints; Cell Line; cells; Eukaryotic Initiation Factor-2 - genetics; Eukaryotic Initiation Factor-2 - metabolism; Gene Expression Regulation, Enzymologic - drug effects; Gene Expression Regulation, Enzymologic - physiology; genes; Heme Oxygenase-1 - biosynthesis; Heme Oxygenase-1 - genetics; Humans; hydrogen peroxide; luciferase; NF-E2-Related Factor 2 - genetics; NF-E2-Related Factor 2 - metabolism; oxidative stress; pretreatment; promoter regions; reactive oxygen species; Reactive oxygen species (ROS); Redox reagent; Response Elements - physiology; signal transduction; Signal Transduction - drug effects; Signal Transduction - physiology; signals; stress response; Sulfides - pharmacology; superoxide anion; Superoxides - metabolism; Thiol; thiols; Up-Regulation - drug effects; Up-Regulation - physiology; Western blotting; Redox reagent; Thiol; Reactive oxygen species (ROS); Antioxidant pathway; Apoptosis
• ISSN: 0304-4165; 0006-3002; 1872-8006
• DOI: 10.1016/j.bbagen.2012.10.003

Diallyl polysulfanes have been shown to exert cell cycle arrest, anti-tumor and anti-inflammatory activities in a variety of in vitro and in vivo models. Although diallyl polysulfanes cause oxidative stress, little is known about the underlying signaling cascades leading to antioxidant defense or apoptosis. Cells were treated with DATTS at different concentrations and for different time periods. Reactive oxygen species and thiol concentrations were determined by commercially available kits. The expression levels of signal molecules were determined by Western Blot analysis. A direct influence of Nrf2 on the promoter of HO-1 gene was determined by a luciferase assay with the StRE promoter element from the HO-1 gene. We found an immediate increase in the level of the superoxide anion radical O2− and hydrogen peroxide H2O2 and an overall thiol depletion. DATTS treatment of HCT116 cells also caused an up-regulation of phospho-eIF2α, nuclear Nrf2 and HO-1 protein levels in a time and concentration-dependent manner. Pre-treatment of cells with antioxidants significantly reduced the elevated expression levels of these proteins. A direct contribution of Nrf2 was shown by its interaction with the stress–response element of the HO-1 promoter. DATTS activates the ROS-eIF2α/Nrf2 HO-1 signaling cascades leading to the up-regulation of HO-1. However, this antioxidant defense is not sufficient to protect HCT116 cells from apoptosis. This study shows for the first time a parallel but not equal activation of signaling pathways by DATTS with a competitive ultimate cellular outcome. [Display omitted] ► Diallyl tetrasulfane (DATTS) causes an immediate increase in reactive oxygen species. ► DATTS treatment of cells leads to an immediate decrease in total thiol level. ► DATTS induces signaling pathways leading to an antioxidant response and/or apoptosis. ► A competition between antioxidant defense and apoptosis determines the cellular outcome.