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

Nathaniel Edward Bennett Saidu1, Rania Touma, Imad Abu Asali

  • 1Medical Biochemistry and Molecular Biology, University of the Saarland, Homburg, Germany.

Biochimica Et Biophysica Acta
|October 11, 2012
PubMed
Abstract

Insights

Diallyl trisulfide (DATTS) activates antioxidant defenses via the ROS-eIF2α/Nrf2-HO-1 pathway in HCT116 cells. However, this response does not prevent apoptosis, revealing a complex cellular outcome.

Area of Science:

  • Cell biology
  • Molecular signaling
  • Oxidative stress research

Background:

  • Diallyl polysulfanes exhibit anti-tumor and anti-inflammatory properties.
  • The signaling pathways mediating oxidative stress responses to diallyl polysulfanes, including antioxidant defense and apoptosis, are not well understood.

Purpose of the Study:

  • To elucidate the signaling cascades activated by diallyl trisulfide (DATTS) in HCT116 cells.
  • To investigate the role of the ROS-eIF2α/Nrf2-HO-1 pathway in cellular response to DATTS.
  • To determine the ultimate cellular fate (antioxidant defense vs. apoptosis) following DATTS treatment.

Main Methods:

  • HCT116 cells were treated with varying concentrations and durations of DATTS.
  • Reactive oxygen species (ROS) and thiol levels were quantified.
  • Western blotting was used to assess the expression of key signaling molecules.
  • Luciferase assays confirmed Nrf2's direct interaction with the HO-1 promoter.

Main Results:

  • DATTS induced rapid oxidative stress, evidenced by increased ROS and thiol depletion.
  • Upregulation of phospho-eIF2α, nuclear Nrf2, and HO-1 protein was observed in a dose- and time-dependent manner.
  • Antioxidant pre-treatment attenuated the DATTS-induced expression of these signaling proteins.
  • Nrf2 was confirmed to directly bind to the stress-response element of the HO-1 gene.

Conclusions:

  • DATTS triggers the ROS-eIF2α/Nrf2-HO-1 signaling pathway, leading to HO-1 upregulation.
  • The induced antioxidant defense is insufficient to protect HCT116 cells from apoptosis.
  • DATTS elicits parallel but unequal signaling pathway activations, resulting in competing cellular outcomes.

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