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

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2021 Nov 13

PMID 34769282

Citations 4

Authors

Olga Lyublinskaya

Julia Kornienko

Julia Ivanova

Natalia Pugovkina

Larisa Alekseenko

Ekaterina Lyublinskaya

Irina Tyuryaeva

Irina Smirnova

Tatiana Grinchuk

Mariia Shorokhova

Anna Krasnenko

Nikolay Plotnikov

Nikolay Nikolsky

Affiliations

Soon will be listed here.

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.

Citing Articles

Cellular senescence of renal tubular epithelial cells in acute kidney injury.

Chen J, Zhang H, Yi X, Dou Q, Yang X, He Y Cell Death Discov. 2024; 10(1):62.

PMID: 38316761 PMC: 10844256. DOI: 10.1038/s41420-024-01831-9.

Heterogeneity of mesenchymal cells in human amniotic membrane at term.

Cortes-Sandoval S, Seco-Rovira V, Beltran-Frutos E, Serrano-Sanchez M, Martinez-Hernandez J, Ferrer C Histol Histopathol. 2023; 39(5):573-593.

PMID: 37721417 DOI: 10.14670/HH-18-660.

Expected and Unexpected Effects of Pharmacological Antioxidants.

Tyuryaeva I, Lyublinskaya O Int J Mol Sci. 2023; 24(11).

PMID: 37298254 PMC: 10252755. DOI: 10.3390/ijms24119303.

The Role of Antioxidants in the Interplay between Oxidative Stress and Senescence.

Varesi A, Chirumbolo S, Campagnoli L, Pierella E, Piccini G, Carrara A Antioxidants (Basel). 2022; 11(7).

PMID: 35883714 PMC: 9311946. DOI: 10.3390/antiox11071224.

References

Samali A, Fitzgerald U, Deegan S, Gupta S . Methods for monitoring endoplasmic reticulum stress and the unfolded protein response. Int J Cell Biol. 2010; 2010:830307. PMC: 2821749. DOI: 10.1155/2010/830307. View

Wilcox C . Effects of tempol and redox-cycling nitroxides in models of oxidative stress. Pharmacol Ther. 2010; 126(2):119-45. PMC: 2854323. DOI: 10.1016/j.pharmthera.2010.01.003. View

Villanueva C, Kross R . Antioxidant-induced stress. Int J Mol Sci. 2012; 13(2):2091-2109. PMC: 3292009. DOI: 10.3390/ijms13022091. View

Cabrera E, Hernandez-Perez S, Koundrioukoff S, Debatisse M, Kim D, Smolka M . PERK inhibits DNA replication during the Unfolded Protein Response via Claspin and Chk1. Oncogene. 2016; 36(5):678-686. DOI: 10.1038/onc.2016.239. View

Fox J, Sakamuru S, Huang R, Teneva N, Simmons S, Xia M . High-throughput genotoxicity assay identifies antioxidants as inducers of DNA damage response and cell death. Proc Natl Acad Sci U S A. 2012; 109(14):5423-8. PMC: 3325711. DOI: 10.1073/pnas.1114278109. View

Sun S . N-acetylcysteine, reactive oxygen species and beyond. Cancer Biol Ther. 2009; 9(2):109-10. PMC: 2854288. DOI: 10.4161/cbt.9.2.10583. View

Gamalei I, Polozov I, Kirpichnikova K, Aksenov N, Tararova N, Pospelova T . [Distribution of rat embryonal fibroblasts through cell cycle phases in the presence of inhibitors of active oxygen species formation and N-acetylcysteine]. Tsitologiia. 2001; 43(7):633-8. View

Mitchell L, Hobbs G, Aghajanian A, Campbell S . Redox regulation of Ras and Rho GTPases: mechanism and function. Antioxid Redox Signal. 2012; 18(3):250-8. PMC: 3518547. DOI: 10.1089/ars.2012.4687. View

Gostner J, Becker K, Ueberall F, Fuchs D . The good and bad of antioxidant foods: An immunological perspective. Food Chem Toxicol. 2015; 80:72-79. DOI: 10.1016/j.fct.2015.02.012. View

10.

Harman D . Aging: a theory based on free radical and radiation chemistry. J Gerontol. 1956; 11(3):298-300. DOI: 10.1093/geronj/11.3.298. View

11.

Neha K, Haider M, Pathak A, Shahar Yar M . Medicinal prospects of antioxidants: A review. Eur J Med Chem. 2019; 178:687-704. DOI: 10.1016/j.ejmech.2019.06.010. View

12.

Sies H, Jones D . Reactive oxygen species (ROS) as pleiotropic physiological signalling agents. Nat Rev Mol Cell Biol. 2020; 21(7):363-383. DOI: 10.1038/s41580-020-0230-3. View

13.

Funato Y, Miki H . Redox regulation of Wnt signalling via nucleoredoxin. Free Radic Res. 2010; 44(4):379-88. DOI: 10.3109/10715761003610745. View

14.

Ferro E, Goitre L, Retta S, Trabalzini L . The Interplay between ROS and Ras GTPases: Physiological and Pathological Implications. J Signal Transduct. 2011; 2012:365769. PMC: 3235814. DOI: 10.1155/2012/365769. View

15.

Lu L, Ou N, Lu Q . Antioxidant induces DNA damage, cell death and mutagenicity in human lung and skin normal cells. Sci Rep. 2013; 3:3169. PMC: 3821017. DOI: 10.1038/srep03169. View

16.

Bhat KPL , Kosmeder 2nd J, Pezzuto J . Biological effects of resveratrol. Antioxid Redox Signal. 2002; 3(6):1041-64. DOI: 10.1089/152308601317203567. View

17.

Kim K, Rhim T, Choi I, Kim S . N-acetylcysteine induces cell cycle arrest in hepatic stellate cells through its reducing activity. J Biol Chem. 2001; 276(44):40591-8. DOI: 10.1074/jbc.M100975200. View

18.

da Silva D, Correia T, Pereira R, da Silva R, Augusto O, Queiroz R . Tempol reduces inflammation and oxidative damage in cigarette smoke-exposed mice by decreasing neutrophil infiltration and activating the Nrf2 pathway. Chem Biol Interact. 2020; 329:109210. DOI: 10.1016/j.cbi.2020.109210. View

19.

Menon S, Sarsour E, Kalen A, Venkataraman S, Hitchler M, Domann F . Superoxide signaling mediates N-acetyl-L-cysteine-induced G1 arrest: regulatory role of cyclin D1 and manganese superoxide dismutase. Cancer Res. 2007; 67(13):6392-9. DOI: 10.1158/0008-5472.CAN-07-0225. View

20.

Zhang J, Wang X, Vikash V, Ye Q, Wu D, Liu Y . ROS and ROS-Mediated Cellular Signaling. Oxid Med Cell Longev. 2016; 2016:4350965. PMC: 4779832. DOI: 10.1155/2016/4350965. View