The inositol-requiring enzyme 1 (IRE1?) RNAse inhibitor, 4m8C, is also a potent cellular antioxidant

Chan, S, Bernard, A, Miller, A and Herbert, T 2018, 'The inositol-requiring enzyme 1 (IRE1?) RNAse inhibitor, 4m8C, is also a potent cellular antioxidant', Biochemical Journal, vol. 475, no. 5, pp. 923-929.


Document type: Journal Article
Collection: Journal Articles

Title The inositol-requiring enzyme 1 (IRE1?) RNAse inhibitor, 4m8C, is also a potent cellular antioxidant
Author(s) Chan, S
Bernard, A
Miller, A
Herbert, T
Year 2018
Journal name Biochemical Journal
Volume number 475
Issue number 5
Start page 923
End page 929
Total pages 7
Publisher Portland Press
Abstract Inositol-requiring enzyme 1 alpha (IRE1?) is an endoplasmic reticulum (ER)-transmem-brane endonuclease that is activated in response to ER stress as part of the unfolded protein response (UPR). Chronic activation of the UPR has been implicated in the pathogenesis of many common diseases including diabetes, cancer, and neurological pathologies such as Huntingtons and Alzheimers disease. 7-Hydroxy-4-methyl-2-oxo-2H-chromene-8-carbaldehyde (4m8C) is widely used as a specific inhibitor of IRE1? ribonuclease activity (IC50 of 6.89 mM in cultured cells). However, in this paper, we demonstrate that 4m8C acts as a potent reactive oxygen species (ROS) scavenger, both in a cell-free assay and in cultured cells, at concentrations lower than that widely used to inhibit IRE1? activity. In vitro we show that, 4m8C effectively decreases xanthine/xanthine oxidase catalysed superoxide production with an IC50 of 0.2 mM whereas in cultured endothelial and clonal pancreatic ?-cells, 4m8C inhibits angiotensin II-induced ROS production with IC50 values of 1.92 and 0.29 mM, respectively. In light of this discovery, conclusions reached using 4m8C as an inhibitor of IRE1? should be carefully evaluated. However, this unexpected off-target effect of 4m8C may prove therapeutically advantageous for the treatment of pathologies that are thought to be caused by, or exacerbated by, both oxidative and ER stress such as endothelial dysfunction and/or diabetes.
Subject Chemical Sciences not elsewhere classified
DOI - identifier 10.1042/BCJ20170678
Copyright notice © 2018 The Author(s)
ISSN 0264-6021
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