Regulatory roles of glutathione-S-transferases and 4-hydroxynonenal in stress-mediated signaling and toxicity

doi:10.1016/j.freeradbiomed.2016.10.493

Free Radical Biology and Medicine

Volume 111, October 2017, Pages 235-243

https://doi.org/10.1016/j.freeradbiomed.2016.10.493 Get rights and content

Highlights

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HNE mediates stress signaling in a concentration-dependent, hormetic manner.
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HNE signals for survival at low concentrations and apoptosis at high concentrations.
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Being determinants of cellular HNE levels, GSTs regulate the signaling by HNE.
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Hormetic signaling by HNE is crucial to cellular homeostasis in oxidative stress.

Abstract

Glutathione-S-Transferases (GSTs) have primarily been thought to be xenobiotic metabolizing enzymes that protect cells from toxic drugs and environmental electrophiles. However, in last three decades, these enzymes have emerged as the regulators of oxidative stress–induced signaling and toxicity. 4-Hydroxy-trans 2-nonenal (HNE) an end-product of lipid peroxidation, has been shown to be a major determinant of oxidative stress–induced signaling and toxicity. HNE is involved in signaling pathways, including apoptosis, proliferation, modulation of gene expression, activation of transcription factors/repressors, cell cycle arrest, and differentiation. In this article, available evidence for a major role of GSTs in the regulation of HNE-mediated cell signaling processes through modulation of the intracellular levels of HNE is discussed.

Graphical abstract

Introduction

Since the seminal discovery of 4-hydroxy-trans 2-nonenal (HNE) as an end product of lipid peroxidation by Esterbauer's group [1], [2], HNE has attracted a great deal of attention because of its potential toxicity as well as its physiological roles, particularly in cell cycle signaling [1], [3], [4], [5], [6], [7], [8]. HNE is the major end-product from the peroxidation of n-6-polyunsaturated fatty acids and is sufficiently stable. Due to its carbonyl group at position 1 and the reactive 2,3-unsaturated double bond that is rendered more reactive by the presence of a hydroxyl group at the position 4, HNE is believed to impart its toxicity through interactions with nucleophilic groups of cellular components including proteins, nucleic acids and phospholipids [9], [10]. Initially thought to be merely a “toxic end-product”, in recent years HNE has acquired reputation as a major “second messenger” that affects cell cycle signaling in a concentration-dependent manner and has been one of the most extensively studied molecule during the past three decades with more than four thousand published studies on its multifarious effects on cellular processes.

Glutathione S-transferases (GSTs) use HNE as a substrate [11] and it has been shown that these enzymes function as the major determinants of cellular levels of HNE by attenuating its formation during lipid peroxidation and also through its metabolism via conjugation to glutathione (GSH) [11], [12], [13], [14]. Recent studies by us and others provide credible evidence that by modulating the intracellular levels of HNE, GSTs play a major role in the regulation of oxidative stress–induced toxicity and signaling [1], [3], [4], [5], [6], [7], [8]. In this article, the role of HNE in oxidative stress-induced signaling and its regulation by GSTs is reviewed against the back drop of general mechanism of stress signaling.

Section snippets

HNE and signaling

Whereas many of the initial studies on the role of HNE in signaling, e.g. stimulation of adenylate cyclase [15], phospholipase C [16], [17], effects on chemo-taxis [18], and DNA synthesis [19] did not attract much attention, in recent years major roles of HNE in the cell cycle signaling including the induction of apoptosis as well as the activation of many cellular protective mechanisms in response to stress have been widely recognized and it is now considered as one of the major signaling

Physiological significance of maintaining HNE homeostasis

Earlier studies have shown that low levels of exogenously added HNE in the medium promote proliferation of certain cell types while at relatively higher concentrations in the medium, HNE mediates signaling for various cellular processes, including apoptosis [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39]. It is noteworthy that such hormetic effect of H₂O₂ has also been observed in studies where low levels of H₂O₂ promote DNA and protein

GSTs and HNE metabolism

Generation of HNE from lipid peroxidation of n-6-polyunsaturated fatty acids is an uncontrollable process depending on the ever-changing levels of endogenous ROS as well as the environmental factors such as exposure to oxidants, radiation, and drugs/xenobiotics that cause oxidative stress. Therefore, the major burden of maintaining cellular HNE homeostasis must be on enzymes that metabolize HNE and eliminate the resultant metabolites from the cells. HNE being sufficiently electrophilic can

Regulation of HNE-mediated signaling by GSTs

Voluminous literature is available demonstrating involvement of HNE in signaling process and many of these studies have been covered in several excellent reviews [3], [4], [5], [6], [7], [8]. Majority of these studies focus on the effect of HNE on a specific target using a single cell line. Studies on the effect of HNE depletion using several human cell lines of different tissue origin as well as a regulatory role of GSTs in the various processes are worth noting here because these studies

Role of HNE and GSTs in the regulation of cell cycle arrest and DNA repair

HNE also causes cell cycle arrest through mechanisms similar to those known for DNA damage-induced G1/G0 or G2/M cell cycle arrest and seems to be involved in the mechanisms of cell cycle arrest during DNA-damage [37], [101], [102]. As discussed above, HNE can simultaneously activate both pro- and anti-apoptotic singling pathways and that these are regulated by GSTA4-4 [8]. Our recent studies show that HNE induces G2/M phase cell cycle arrest during which ataxia telangiectasia mutated and Rad3

Future perspectives

The available evidence strongly indicate that GSTs regulate HNE-mediated toxicity and signaling by either attenuating HNE formation or through its conjugate GS-HNE formation that is eventually eliminated from cells through RLIP76-mediated transport. As detailed above, the Alpha class of GST enzymes GSTA1-1 and GSTA2-2 that prevent HNE formation and GSTA4-4 that catalyze the conjugation of HNE to GSH play an important role in this process. However, the role of other GST isozymes particularly GST

Acknowledgments

Supported by funding from NIH, United States Grants CA129383 and DK104786.

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Review ArticleRegulatory roles of glutathione-S-transferases and 4-hydroxynonenal in stress-mediated signaling and toxicity

Highlights

Abstract

Graphical abstract

Introduction

Section snippets

HNE and signaling

Physiological significance of maintaining HNE homeostasis

GSTs and HNE metabolism

Regulation of HNE-mediated signaling by GSTs

Role of HNE and GSTs in the regulation of cell cycle arrest and DNA repair

Future perspectives

Acknowledgments

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4-hydroxynonenal and cell signaling

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Role of 4-hydroxynonenal and its metabolites in signaling

Redox Rep.

Review Article
Regulatory roles of glutathione-S-transferases and 4-hydroxynonenal in stress-mediated signaling and toxicity