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

BackgroundDiallyl 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.MethodsCells 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.ResultsWe 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.ConclusionsDATTS 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.General significanceThis study shows for the first time a parallel but not equal activation of signaling pathways by DATTS with a competitive ultimate cellular outcome.

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► 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.