Induction of Premature Cell Senescence Stimulated by High Doses of Antioxidants Is Mediated by Endoplasmic Reticulum Stress.

Olga Lyublinskaya,Mariia Shorokhova,Ekaterina Lyublinskaya,Tatiana Grinchuk,Anna Krasnenko,Larisa Alekseenko,Nikolay Nikolsky,Julia Kornienko,Irina Tyuryaeva,Natalia Pugovkina,Nikolay Plotnikov,Irina Smirnova,Julia Ivanova

doi:10.3390/ijms222111851

Abstract

In our previous study, we found that high doses of several substances with antioxidant capacities (Tempol, resveratrol, diphenyleneiodonium) can cause genotoxic stress and induce premature senescence in the human mesenchymal stem cells (MSCs). Here, using whole-transcriptome analysis, we revealed the signs of endoplasmic reticulum stress and unfolded protein response (UPR) in MSCs stressed with Tempol and resveratrol. In addition, we found the upregulation of genes, coding the UPR downstream target APC/C, and E3 ubiquitin ligase that regulate the stability of cell cycle proteins. We performed the molecular analysis, which further confirmed the untimely degradation of APC/C targets (cyclin A, geminin, and Emi1) in MSCs treated with antioxidants. Human fibroblasts responded to antioxidant applications similarly. We conclude that endoplasmic reticulum stress and impaired DNA synthesis regulation can be considered as potential triggers of cell damage and premature senescence stimulated by high-dose antioxidant treatments.

Highlights

Antioxidants (AOs) are usually understood as substances of natural or synthetic origin that can reduce the oxidative load in cells and tissues of an organism
At 14 h post-seeding, when the large fraction of the mesenchymal stem cells (MSCs) was in the late-G1 /early-S phase of the cell cycle, 2 mM of Tempol or 40 μM of resveratrol were added to the cell medium
We have shown that replication stress induced in the MSC cultures by high doses of antioxidants (Tempol and resveratrol) is accompanied by the upregulation of genes associated with stress, DNA damage, and cellular senescence and affects pathways associated with redox-dependent signaling, endoplasmic reticulum (ER) stress, and unfolded protein response (UPR)

Summary

Introduction

Antioxidants (AOs) are usually understood as substances of natural or synthetic origin that can reduce the oxidative load in cells and tissues of an organism. Among these effects are inhibition of cell proliferation [11,12,13,14,15,16,17,18], DNA damage [19,20,21], apoptosis [20,21], and chromosomal abnormalities [19] Sometimes, researchers obtain such data when analyzing the responses of cells to treatment with one single AO substance [11,13,15,16,22], and other times when testing a wide range of AOs [14,18,19,20]. It turns out that the administration of AOs at concentrations that rescue cells under oxidative stress conditions has a damaging effect on cells under normal physiological conditions

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