Regulation of 4-hydroxynonenal-mediated signaling by glutathione S-transferases

doi:10.1016/j.freeradbiomed.2004.05.033

Free Radical Biology and Medicine

Volume 37, Issue 5, 1 September 2004, Pages 607-619

https://doi.org/10.1016/j.freeradbiomed.2004.05.033 Get rights and content

Abstract

4-Hydroxynonenal (HNE), one of the major end products of lipid peroxidation, has been shown to be involved in signal transduction and available evidence suggests that it can affect cell cycle events in a concentration-dependent manner. Glutathione S-transferases (GSTs) can modulate the intracellular concentrations of HNE by affecting its generation during lipid peroxidation by reducing hydroperoxides and also by converting it into a glutathione conjugate. We have recently demonstrated that overexpression of the Alpha class GSTs in cells leads to lower steady-state levels of HNE, and these cells acquire resistance to apoptosis induced by lipid peroxidation-causing agents such as H₂O₂, UVA, superoxide anion, and pro-oxidant xenobiotics, suggesting that signaling for apoptosis by these agents is transduced through HNE. Cells with the capacity to exclude HNE from the intracellular environment at a faster rate are relatively more resistant to apoptosis caused by H₂O₂, UVA, superoxide anion, and pro-oxidant xenobiotics as well as by HNE, suggesting that HNE may be a common denominator in mechanisms of apoptosis caused by oxidative stress. We have also shown that transfection of adherent cells with HNE-metabolizing GSTs leads to transformation of these cells due to depletion of HNE. These recent studies from our laboratories, which strongly suggest that HNE is a key signaling molecule and that GSTs, being determinants of its intracellular concentrations, can regulate stress-mediated signaling, are reviewed in this article.

Introduction

4-Hydroxynonenal (HNE), the most abundant 4-hydroxyalkenal formed in cells, is a toxic end product of lipid peroxidation contributing to the deleterious effects of oxidative stress, and it has been shown to be involved in the pathogenesis of a number of degenerative diseases such as Alzheimer's disease [1], [2], atherosclerosis [3], [4], cataract [5], and cancer [6], [7]. Since the pioneering work of Esterbauer and his associates in the discovery of HNE, studies by his group and various other investigators have demonstrated that HNE can cause apoptosis, cause differentiation, modulate cell growth, and affect various signal transduction pathways (see reviews [8], [9], [10], [11], [12], [13], [14], [15], [16]). Some of these studies suggest that HNE can differentially affect cell cycle signaling events in a concentration-dependent manner [17], [18], [19], implying that the regulation of its intracellular concentrations may be crucial for cells. The mechanisms of this concentration-dependent effect of HNE are not known and difficulty in manipulation of its intracellular concentration poses a problem in studies designed to elucidate these mechanisms.

Within cells, most HNE is generated through uncontrolled nonenzymatic reactions during lipid peroxidation and its homeostasis seems to be regulated primarily by its metabolism. In recent years, there has been a great deal of interest in enzymes responsible for the metabolism and disposition of HNE primarily because of its role in signaling mechanisms. Although a small portion of cellular HNE can be reduced to its corresponding alcohol by alcohol dehydrogenase and aldose reductase, or oxidized to acid by aldehyde dehydrogenase, the majority of HNE is metabolized via its conjugation to glutathione (GSH) through reactions catalyzed by glutathione S-transferases (GSTs) [20], [21]. The resulting conjugate of GSH and HNE (GS-HNE) can be further metabolized to mercapturic acid [22], or the aldehyde group of GS-HNE can be reduced to alcohol by aldose reductase [22], resulting in the formation of the corresponding alcohol. However, our recent studies with human erythrocytes and cell lines suggest that the majority of GS-HNE is transported as such, into the extracellular environment through an ATP-dependent process catalyzed by RLIP76 [23], [24], [25]. Ongoing studies in our laboratory have focused primarily on the role of GSTs in metabolism and detoxification of HNE. In this article, we review some of our recent studies suggesting that GSTs can modulate stress-mediated signaling by regulating the intracellular concentrations of HNE.

Section snippets

Role of HNE in signaling

The evidence for an important role for HNE in signal transduction is provided through studies using several different approaches. In the majority of these studies, the effect of HNE on cells has been studied by directly adding HNE to the media of cell cultures. In general, these studies have shown that moderately high concentrations of HNE can induce apoptosis [17], [23], [26], [27], [28], [29], induce differentiation [12], [17], and affect signaling pathways including activation of adenylate

GSTs: relevance to signaling

As an offshoot of our intensive interest in the studies on structure and function of GSTs and their pharmacological relevance to chemical carcinogenesis, chemoprevention, and the mechanisms of multidrug resistance, we have also studied possible physiological roles of GSTs as antioxidant enzymes [30], [34], [35], [36] because of their Se-independent glutathione peroxidase (GPx) activity [37], [38]. These studies suggest an important role for GSTs in the regulation of HNE homeostasis and cell

GSTs regulate intracellular concentrations of HNE

HNE is formed primarily from the degradation of ω-3 and ω-6 polyunsaturated fatty acids. GSTs can regulate intracellular levels of HNE by attenuating its formation through their GPx activity and also by conjugating it to GSH through their transferase activity. In mammalian tissues, a subgroup of Alpha class GST isozymes has high activity for conjugating HNE to GSH. Table 2 lists major Alpha class GST isozymes whose role in the regulation of intracellular levels of HNE has been established.

Modulation of stress-induced apoptosis by GSTs

Current studies in our laboratory are based on the hypothesis that signaling for apoptosis induced by HNE, or other agents such as H₂O₂, UV exposure, and xenobiotics, which induce apoptosis and also cause lipid peroxidation (hence a rise in HNE levels), can be modulated by altering GST expression. Results of these studies discussed below are, in general, supportive of this hypothesis and demonstrate that HNE is involved in signaling mechanisms, that at least a part of stress-mediated signaling

HNE-metabolizing GST isozymes can modulate stress-mediated signaling

Recent studies in our laboratory using two separate approaches have demonstrated that HNE-metabolizing GST isozymes can modulate HNE as well as stress-mediated signaling. We have shown that HNE-induced signaling for apoptosis in K562 and HL-60 cells can be blocked by stably transfecting these cells with mGSTA4-4 [17], [29]. Likewise, induction of HNE-metabolizing GSTs provides protection against not only HNE but also stress-mediated apoptosis. These studies further suggest that GSTs are

Depletion of HNE leads to transformation of adherent cells

One of the most striking pieces of evidence supporting the role of HNE as a signaling molecule is provided by our recent studies showing that adherent cells transfected with HNE-metabolizing GSTs undergo transformation and proliferate indefinitely in an anchorage-independent manner [52]. These studies show for the first time that incorporation of HNE-metabolizing GST isozyme hGSTA4-4 in adherent cell lines HLE-B3 and CCL-75, either by cDNA transfection or by microinjection of active enzyme,

Future directions

Studies highlighted in this review strongly suggest that HNE not only is involved in stress-mediated apoptosis but also can affect cell-cycle signaling events in a concentration-dependent manner. It is important to note that only a small increase (about 50%) in HNE levels triggers the activation of JNK upon UVA or heat exposure [23], [28]. Conversely, an only about 50% decrease in HNE levels in mGSTA4-transfected K562 or HL-60 cells causes the cells to proliferate [17], [29]. Attached cells,

Acknowledgements

This work was supported in part by NIH Grants EY 04396 (Y.C.A.), ES 12171 (Y.C.A.), and CA77495 (S.A.) and NIEHS Training Grant ES 007254 (B.P.).

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^☆: This article is part of a series of reviews on “4-Hydroxynonenal as a Signaling Molecule.” The full list of papers may be found on the home page of the journal.

View full text

Serial Review: 4-Hydroxynonenal as a Signaling MoleculeRegulation of 4-hydroxynonenal-mediated signaling by glutathione S-transferases☆

Abstract

Introduction

Section snippets

Role of HNE in signaling

GSTs: relevance to signaling

GSTs regulate intracellular concentrations of HNE

Modulation of stress-induced apoptosis by GSTs

HNE-metabolizing GST isozymes can modulate stress-mediated signaling

Depletion of HNE leads to transformation of adherent cells

Future directions

Acknowledgements

Atherosclerosis

Am. J. Clin. Nutr.

Free Radic. Biol. Med.

Free Radic. Biol. Med.

Exp. Cell Res.

Free Radic. Biol. Med.

Free Radic. Biol. Med.

Arch. Biochem. Biophys.

J. Biol. Chem.

Arch. Biochem. Biophys.

J. Biol. Chem.

J. Biol. Chem.

Arch. Biochem. Biophys.

J. Biol. Chem.

J. Biol. Chem.

Arch. Biochem. Biophys.

Biochem. Biophys. Res. Commun.

Arch. Biochem. Biophys.

J. Biol. Chem.

Toxicol. Appl. Pharmacol.

FEBS Lett.

Biochim. Biophys. Acta

Arch. Biochem. Biophys.

Toxicol. Appl. Pharmacol.

Biochem. Biophys. Res. Commun.

Biochem. Biophys. Res. Commun.

Biochem. Biophys. Res. Commun.

Free Radic. Biol. Med.

Free Radic. Biol. Med.

Mol. Aspects Med.

4-Hydroxynonenal-derived advanced lipid peroxidation end products are increased in Alzheimer's disease

J. Neurochem.

Immunohistochemical detection of 4-hydroxy-2-nonenal adducts in Alzheimer's disease is associated with inheritance of APOE4

Am. J. Pathol.

Michael addition-type 4-hydroxy-2-nonenal adducts in modified low-density lipoproteins: markers for atherosclerosis

Biochemistry

Inhibition of melanoma B16-F10 growth by lipid peroxidation product 4-hydroxynonenal

Cancer Biother.

4-Hydroxynonenal from pathology to physiology

Mol. Aspects Med.

Lipid peroxidation and cell cycle signaling: 4-hydroxynonenal, a key molecule in stress mediated signaling

Acta Biochim. Pol.

Serial Review: 4-Hydroxynonenal as a Signaling Molecule
Regulation of 4-hydroxynonenal-mediated signaling by glutathione S-transferases☆