Nrf2: Friend and Foe in Preventing Cigarette Smoking-Dependent

Review pubs.acs.org/crt

Nrf2: Friend and Foe in Preventing Cigarette Smoking-Dependent Lung Disease Thomas Müller* and Arnd Hengstermann Molecular Toxicology Consultant, Stockbergergasse 15, 51515 Kürten, Germany ABSTRACT: Chronic exposure to cigarette smoke (CS) generally confronts cellular defense systems with one of the strongest known environmental challenges. In particular, the continuous exposure of tissues of the respiratory tract to abundant concentrations of radicals; volatile compounds of the gas phase, mainly reactive oxygen and nitrogen species; and CS condensate deposits trigger a pleiotropic adaptive response, generally aimed at restoring tissue homeostasis. As documented by numerous studies published over the past decade, a hallmark of this defense system is the activation of the transcription factor NF-E2-related factor 2 (Nrf2), which, consequent to its established role as master regulator of the cellular antioxidant response, has been shown to orchestrate the first line of defense against cell- and tissue-damaging components present in CS. The key to CS-dependent Nrf2 activation is assumed to be based on the long-known phenomenon of a general strong sulfhydryl (−SH) reactivity inherent to CS. This chemical trait is virtually predestined to be sensitized by the major route leading to Nrf2 activation, characterized by its dependence on the interaction of electrophiles with specific cysteine residues inherited by Nrf2's negative cytosolic regulator Keap1 (Kelch-like ECH-associated protein 1). In addition, other pathways involving CS-activated protein kinases implicated in the upstream regulation of Nrf2, such as protein kinase C, represent an alternative/complementary mechanism of CS-induced Nrf2 activation. Because of the outstanding function of the Nrf2-Keap1 axis in defending cells and tissues against oxidant and chemical stress, either directly or indirectly via cross-talking with other defense pathways, changes in the Nrf 2 or Keap1 genotype have long been associated with disease development. In terms of the two major smoking-related diseases of the lung, that is, emphysema and lung cancer, a fully functional Nrf2 genotype seems to be necessary, although not sufficient by itself, to protect the smoker from acquiring emphysema. Contrasting with this protective role, however, Nrf2 function may be potentially fatal in smoking-related lung tumorigenesis: as concluded from recent clinical investigations, lung tumor tissues harbor increased mutation or, alternatively, aberrant expression rates in either the KEAP1 or the NRF2 gene, generally resulting in constitutive Nrf2 activation, suggesting that “abuse” of Nrf2 function is an advantageous strategy of the (developing) tumor to protect itself against oxidative stress in general. On the basis of the fundamental significance of the Nrf2 pathway in smoking-dependent disease development, several attempts have been described for dietary and pharmacological intervention, the majority of which are intended to activate Nrf2 aiming at emphysema prevention. The intention of this review is to compile and discuss the various aspects of CS−Nrf2/ Keap1 interaction in terms of mechanism, disease development, and chemoprevention.

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CONTENTS

1. Introduction 2. Mechanisms of Smoking-Dependent Nrf2 Pathway Activation 3. Genotype and Phenotype Responses to Smoking-Induced Nrf2 Activation: Results from Preclinical Studies 4. The Role of Smoking and Nrf2 Activation and Inactivation in Different Lung Disease Contexts 5. Smoking-Induced Lung Disease: A Case for Pharmacological Intervention of Nrf2 Signaling!? 6. Final Remarks Author Information Acknowledgments Abbreviations References © 2012 American Chemical Society

1. INTRODUCTION Cigarette smoking, especially in the context of chronic exposure, is a cause or confounder of a plethora of diseases and represents one of the most serious, current global health concerns. In particular, three major smoking-related diseases are among the leading pathologies linked with the highest rates of morbidity and mortality in the United States:1 (1) lung cancer; (2) chronic obstructive pulmonary disease (COPD), a syndrome that comprises respiratory disorders such as chronic bronchitis, bronchiolitis, small airway disease, and, in particular, emphysema; and (3) cardiovascular disease, including subclinical atherosclerosis, coronary heart disease, and stroke. In general, the personal risk for a chronic smoker to contract one

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Chemical Research in Toxicology

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polyphenols.24,25 Importantly, as shown in murine fibroblasts, the reaction of CS with GSH does not result in a notable increase of glutathione disulfide (GSSG) but, rather, in a net loss of GSH,26 indicating a direct oxidation of GSH by smoke constituents. A summary of oxidative modifications described for the nonprotein thiol GSH and for protein thiols is provided in Table 1. Finally, it is important to note that smoke exposure

(or more) smoking-related diseases is largely dependent on the chronically inhaled smoke dose (for lung cancer, see ref 2), but other factors, such as smoking intensity 3 or genetic susceptibility, must also be considered. Cigarette smoke (CS) is a complex aerosol, shown to release >60 International Agency for Research on Cancer (IARC)listed carcinogens (classes 1, 2A, and 2B) and 5000−8000 different chemicals (based on different estimations4) directly into the smoker's lung. Moreover, by interacting with hostderived molecules in the aqueous, O2-containing extra- and intracellular milieu of tissues of the respiratory tract, CS constituents may result indirectly, at least in part, in the formation of additional reactive toxicants, well-known examples of which are the hydroxyl radical5 and peroxynitrite.6,7 Therefore, it is highly unlikely that any of the numerous smoking-related diseases is caused by a limited number of constituents but, instead, is more likely the consequence of the chronic complex interplay between a vast variety of CS- and host-derived components resulting in tissue damage, (chronic) inflammation, and disease development. Nevertheless, during the toxicological and analytical exploration of mainstream and sidestream CS over the past 50 years, compounds belonging to chemical classes that exhibit similar toxicological mechanistic traits came under suspicion early as culprits in smokingdependent disease causation. For example, smoke constituents belonging to the chemical class of polycyclic aromatic hydrocarbons (PAHs), such as benzo[a]pyrene, were regarded as a potential molecular clue for the close epidemiological link between smoking and (lung) cancer formation. Mechanistically, PAHs are activated via cytochrome P450-dependent xenobiotic metabolism to highly reactive electrophiles, actually to become accessible for disposal, demonstrating the strong propensity to form DNA adducts and, consequently, oncogenic mutations (for review, see ref 8). Another characteristic hallmark of CS chemistry, also suspected early to take part in smoking-dependent disease formation, relates to its strong sulfhydryl (−SH) reactivity (summarized in ref 9). This chemical feature of CS was first described almost 50 years ago independently by several research groups,10−13 as summarized in ref 14. However, it was the work published by Leuchtenberger et al. that showed that the strong −SH reactivity inherent to CS could be linked directly to cytotoxic and carcinogenic effects in hamster lung cell cultures, as evidenced by the inhibition of DNA and protein synthesis, atypical proliferation, and malignant cell transformation.15,16 The conclusion drawn from these early toxicological investigations suggesting that protein and nonprotein thiol oxidation by smoke components may be a highly important factor of CS exposure-induced oxidative stress and thus may play a major role in smoking-dependent disease formation, has now been confirmed by numerous studies, in particular in the context of CS exposure-related COPD/ emphysema (summarized in ref 17). Aligning with this logic, glutathione (GSH), a well-characterized first-line defense extraand intracellular protective antioxidant small molecule, harboring a cysteine residue whose thiol function serves as an electron donor in detoxification reactions, has been demonstrated to be a prime target of CS exposure in vitro and in vivo with implications for disease formation (for review, see refs 17 and 18). CS-specific constituents identified to contribute to GSH oxidation (subsuming oxidation and alkylation reactions) originate from several unrelated chemical classes including, inter alia, tobacco-related aldehydes,19−22 metal ions,23 and

Table 1. Major Oxidative Modifications Seen in Protein and Nonprotein Thiols (Adapted from Ref 33 and Extended) oxidative modification

oxidized structure

primary oxidant

interdisulfide intradisulfidea alkylation sulfenic acid sulfinic acid sulfonic acid nitrosylation nitrothiolation S-glutathiolation

R1−S−S−R2 R1−S−S−R1 R1−S−(X)−COH R−SOH R−SO2H R−SO3H R−SNO R−SNO2 R−S−S−G

many many α,β-unsaturated aldehydes H2O2 H2O2 H2O2 NO ONOO− many

a

Not GSH; (X), (−CHR−CH2−); G, glutathion.

does not only deplete intracellular GSH but also compromises (by both direct and indirect means) the pools of other redoxactive components, such as thioredoxin and NAD(P)H, generally resulting in significantly elevated cellular redox potentials (for review, see ref 27). However, because low redox potentials are vital to sustain the fundamental maintenance processes that ensure biochemical homeostasis, both cells and tissues tolerate changes in their redox tone only within narrow ranges. In fact, to maintain homeostatic conditions, intricate mechanisms have evolved to sense and cope with even very small changes in the intracellular redox status. Thus, it is not very surprising that a main strategy of cell stress sensing and signaling systems makes use of cysteinyl thiols as functional redox sensors to translate oxidant signals into biological responses. Prominent examples of this concept are the transcription factors activator protein 1 (AP-1) and nuclear factor of κ light polypeptide gene enhancer in Bcells 1 (NF-κB), both of which depend on reduced thiol functions for efficient DNA binding and transcriptional activation, that is, Cys-62 in the p50/RelA subunit of NFκB28 and Cys-154 and -272 in the Fos and Jun subunits of AP1, respectively.29 Intriguingly, additional steps of redox regulation are included in the upstream control of transcription factors activated by oxditave stress, providing the cell with the potential to fine-tune the response according to the actual strength of the oxidant signal. A specific scheme in this respect is the redox-sensitive repression of transcription factors in the cytosol, which under homeostatic (normoxic) conditions are constantly degraded via the ubiquitin/proteasome system, although under stress, these factors become activated because they are no longer accessible to the degradation machinery. This principle of “derepression regulation” is realized in the control of transcription factors implicated in stress responses, that is, hypoxia inducible factor 1α (Hif-1α) and the cap'n'collar (CNC) bZIP transcription factor NF-E2-related factor 2 (Nrf2) (for review, see refs 30 and 31). Nrf2, an archaic protein that is highly conserved from fish to man and traceable to Drosophila and Caenorhabditis elegans, orchestrates the principal cellular response to pro-oxidant insults, and it is evident that, especially in this context, the 1806



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Figure 1. Potential mechanisms of Nrf2 activation by CS. (a) Under normoxic (homeostatic) conditions, Nrf2 is subject to a dual negative control mechanism through which it is (i) retained in the cytosol via two-site (“DLG” and “ETGE”) binding to the Kelch domains of homodimeric Keap1 and (ii) rapidly targeted for proteosomal degradation via Lys ubiquitination catalyzed by Cullin3 (Cul3), a ubiquitin E3 ligase natively complexed with Keap1, resulting in a half-life of Nrf2 of 20 cigarettes/day). The potential contribution of quercetin-dependent Nrf2 activation to this effect was reflected by the significantly elevated expression of genes encoding enzymes involved in GSHdependent detoxification reactions (i.e., GST) known to be regulated by Nrf2. Triterpenoids are another potent class of Nrf2 inducers in vitro and in vivo. Therefore, one of the most effective triterpenoid derivatives in this respect, that is, the synthetic compound 1-[2-cyano-3-,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Im),169,170 was evaluated for its potential to counteract CS-induced emphysema and cardiac dysfunction in a recent explorative preclinical study.171 According to the study design, Nrf 2−/− and wt mice bred on a C57BL/6 background were exposed to one dose of CS (∼450 μg/l × day) either once (5 h) or for 6 months (5 h/day, 5days/week) with and without CDDO-Im treatment from the first day of exposure, respectively, while using air-exposed mice of the same setup as control. The results indicate that CDDO-Im supplementation significantly protects Nrf 2+/+ mice against emphysematous changes from 6 months of smoke inhalation, as evidenced by reduced levels of alveolar destruction, pulmonary hypertension, and right ventricle function, as well as oxidative stress. In contrast, Nrf 2−/− mice and wt mice that did not receive CDDO-Im showed comparatively extreme responses, as indicated by, for example, up to 10-fold increases in 8-OHdG levels as determined by immunohistochemistry, or

important note that gain of function mutations in Nrf 2 show a clear link to patients with a history of chronic smoking while loss of function mutations in Keap1 are obviously unrelated to smoking.152,155 Intriguingly, mutations in Nrf 2 and Keap1 show strong preferences for histological subtypes in lung cancer, with Nrf2 mutations predominantly seen in squamous carcinomas,152 while adenocarcinomas harbor increased mutations in Keap1.150,153 Beyond mutation patterns, both adeno- and squamous carcinomas of the lung also show a dualism for the expression of Nrf2 and Keap1. As described by Solis et al.,155 immunohistochemical evaluation of clinical lung cancer samples showed Nrf2 expression significantly pronounced in squamous carcinomas, whereas low or missing expression of Keap1 was strongly associated with adenocarcinomas. In contrast to the studies on Nrf 2 and Keap1 mutations in human lung cancers referenced above, which revealed mutation frequencies of 10− 15% (in some instances even more), mutations in either of the two genes were found to be rare in the samples analyzed by Solis et al.,155 indicating that mechanisms other than mutation are involved in the hyperactivation of Nrf2 or inactivation of Keap1 as well. The obvious high relevance of sustained Nrf2 activation for the selection of cells undergoing tumorigenic transformation, also by means independent of mutation, was recently emphasized by the observation that activated oncogenes, that is, Kirsten rat sarcoma viral oncogene homologue (K-ras), v-raf murine sarcoma viral oncogene homologue B1 (B-Raf), and myelocytomatosis viral oncogene homologue (avian) (Myc), which are frequently activated in smoking-related lung cancer (for review, see ref 156), drive Nrf2 expression, for example, through Raf-ERK-Jun signaling, resulting in increased cellular levels of antioxidant molecules and enzymes.157 In addition, activated Nrf2 may directly create an antiapoptotic/cell survival environment by activating Bcl2 and in this way contribute to increased drug resistance.158 Finally, aberrant epigenetic changes, as indicated by methylation of three specific CpG sites of the Keap1 promoter, have been identified as an additional mechanism of Keap1 silencing and constitutive Nrf2 activation in lung tumorigenesis.159 Many cancer types are characterized by elevated cellular concentrations of ROS implicated in manifesting the cancer phenotype by, for example, inducing DNA damage and thus accelerating the frequency of cancer-related mutations or creating a chronic inflammatory phenotype supporting growth and survival. Conversely, cancer cells need to keep ROS and xenobiotics levels in check to avoid lethality from cytotoxic oxidant and/or drug concentrations. According to this logic, continuously increased activation of the Nrf2-dependent antioxidant program during oncogenic transformation, whether by mutational activation or transcriptional malfunction, represents an adaptive mechanism to these threats.160 Thus, increased Nrf2 function is not only advantageous, at least in some contexts, for normal cells as discussed above, but in the same way also for transformed cells. This, in turn, raises the crucial question of whether aberrant activation of Nrf2 signaling is only a bystander effect in lung tumorigenesis or if it represents a critical selection (“driving”) step during neoplastic transformation. The recent finding that Brusatol, which was characterized as specific inhibitor of Nrf2 function, sensitizes A549 cell-derived xenografts to cytostatic treatment may be regarded as a first hint to elucidate this issue.161 1817



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belonging to numerous, partly unrelated chemical classes, it is not surprising that the signal elicited by CS is received by various upstream sensors acting in different functional contexts, each transducing the signal for Nrf2 activation in a distinct way, while, conversely, some compounds, such as acrolein, may even stimulate Nrf2 by more than one route of activation. However, despite its long-known outstanding SH reactivity, no direct evidence has yet been presented showing that cigarette whole smoke, or at least a fraction thereof, is sensed by the “canonical” pathway of Nrf2 activation, that is, by SH modification of one of the three major cysteinyl sensors in Keap1. In fact, such investigations are qualified to significantly increase our knowledge of the mechanistic interplay between CS and cell signal reception, while offering the opportunity to identify compounds in smoke involved in this process. The prevalent mechanistic explanation, which was provided early on for the global beneficial, disease preventing effects of Nrf2 function, in particular in terms of CS-dependent emphysematous changes, refers to its apparent potential to interfere with the development of (“chronic” or “nonresolving”) inflammation. In fact, it is now common sense that chronic inflammation as characterized by the compromised/lost capability to terminate inflammatory processes in a controlled way is a main driver of disease development, especially of degenerative diseases such as cancer, obesity, and neurodegenerative diseases.175,176 On the other hand, oxidative stress, particularly under chronic conditions, has been mechanistically implicated in the development of chronic inflammatory phenotypes,177 thus supporting the idea that prevention of smoking-related diseases, especially emphysema, by Nrf2 activation is based on limiting inflammatory processes. If true, it would be an interesting question in this context, as to how a sustained anti-inflammatory effect raised by continuous Nrf2 activation as seen in lung tumor tissue (see above) would be compatible with (lung) cancer progression, which has been shown to depend, at least in part, on an inflammatory environment.178,179 However, data on inflammatory parameters in CS-related genetic and chemopreventive studies targeting at Nrf2 are partly inconsistent, thus requiring further insight into the relation of Nrf2 signaling, CS exposure, inflammation, and lung pathology. This further suggests that other inflammationunrelated Nrf2-dependent mechanisms of defending cells and tissues against the disease-promoting effects of CS exposure, such as cell survival and pro-proliferative mechanisms, must be taken into account. If continuously activated, these processes may be potentially more harmful than beneficial to cells and tissues. Clearly, all aspects of the obvious pleiotropic mode of action of Nrf2 signaling need to be further investigated and considered before the widespread use of Nrf2 intervention can be recommended.

proportions of up to 50% apoptotic lung cells. Clearly, the health status of mice with lungs that are damaged in such a dramatic way is tremendously compromised. PCR-based transcriptional analysis of selected Nrf2 response genes, that is, hmox1, Nqo1, Gclc, Gclm, and Srx1, revealed significantly elevated expression rates of these genes in CDDO-Imsupplemented versus untreated mice exposed for 6 months to CS, leading to the conclusion that the protective effects of CDDO-Im may be due to its Nrf2-inducing potential. Surprisingly, however, transcriptional levels of all genes except hmox1 were significantly lower in CDDO-Im-treated, airexposed mice when compared to smoke-exposed equivalents, pointing to an additive or even overadditive/synergistic effect of CS and CDDO-Im on Nrf2-dependent gene expression. Clearly, it would be interesting to know how this composite effect is mechanistically explained, especially in terms of the fact that CDDO-Im itself is a very strong inducer of Nrf2. In this context, a further interesting note in the paper by Sussan et al.171 relates to the finding that CDDO-Im treatment does obviously not affect inflammatory parameters as indicated by similar numbers of inflammatory cells in BALF in both CDDOIm-treated and -untreated CS-exposed mice, demonstrating that tissue protection by Nrf2 activation also involves mechanisms independent of inflammation attenuation. Although these few smoking-related studies point to beneficial effects from dietary- or pharmaceutical-based Nrf2 targeting in smoking-related disease development, some critical questions remain. For example, because CS exposure (acute and chronic) itself is a strong inducer of Nrf2-dependent genes in both the rodent and the human lung,108,109,172 potentially involving various pathways of activation, how is the benefit from additional pharmacological induction of Nrf2 explained? Quantitatively, how much “more” Nrf2 activation, in addition to the CS-elicited response, is necessary to achieve beneficial effects (see also discussion on the “inflection point” by Kensler and Wakabayashi162)? Which part of the protective effects is contributed by “off-target” effects? Sussan et al.171 supplemented mice with CDDO-Im in parallel to CS exposure. Does the intake of Nrf2-stimulating compounds prevent, or at least ameliorate, further disease progression if emphysematous changes have already occurred, as this is the more realistic scenario in human smoking? In fact, as intensively discussed by Churg and colleagues, numerous compounds targeting at various defensive and inflammatory pathways were found to protect against smoking-induced emphysema in preclinical studies but showed only limited success in human studies.173,174 Finally, although no adverse health effects have been described so far from the use of “hormetic” Nrf2 inducers, the question of whether “chronic” supplementation with these compounds and continuous activation of Nrf2 interferes with lung cancer development in chronic smokers needs to be addressed, for example, by using mice chronically fed with these compounds or hypomorphic mice with globally reduced Keap1 expression (as a genetic mimetic), each in the presence or absence of chronic CS exposure.

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AUTHOR INFORMATION

Corresponding Author

*Fax: +49-2268-901343. E-mail: [email protected]. Notes

6. FINAL REMARKS Because of its fundamental nature to generally defend cells and tissues against the potential damage from and the deleterious effects of compounds causing chemical and oxidant stress, the Nrf2 pathway has emerged as a prime target of CS-induced cellular stress. On the basis of the enormous chemical complexity of smoke, with its more than 5000 constituents

The authors declare the following competing financial interest(s): Both authors are former employees of Philip Morris Research Laboratories GmbH, Cologne, an affiliate of Philip Morris International (PMI). Views, opinions, and positions expressed by the authors do not necessarily reflect the views, opinions or positions of PMI or its affiliates. T.M. holds stocks of PMI Inc. 1818



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ACKNOWLEDGMENTS

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ABBREVIATIONS

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REFERENCES

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We thank Dr. Jan Wooten (Richmond, VA) for his valuable comments and suggestions on the manuscript and Lynda Conroy (Cologne, Germany) for her expert editorial support.

4-HNE, 4-hydroxy-nonenal; 8-OH-dG, 8-oxo-7,8-dihydro-2′deoxyguanosine; A1AT, α1-antitrypsin; Ah, aryl hydrocarbon; AP-1, activator protein 1; ARE, antioxidant response element; BALF, bronchioalveolar lavage fluid; B-Raf, v-raf murine sarcoma viral oncogene homologue B1; BTB, broad complex tramtrack, bric-a-brac; bZIP, basic-leucine zipper; CBP, CREB binding protein; CDDO-Im, 1-[2-cyano-3-,12-dioxooleana1,9(11)-dien-28-oyl]imidazole; CKO, conditional knockout; CNC, cap'n'collar; COPD, chronic obstructive pulmonary disease; CS, cigarette smoke; CYP1A1, cytochrome P450 1A1; DGR, double glycine repeat; DJ-1, Parkinson disease (autosomal recessive, early onset) 7; EAGLE, Environment and Genetics in Lung Cancer Etiology; EGR-1, early growth response 1; EpRE, electrophile response element; ER, endoplasmic reticulum; ERK, extracellular-regulated kinase; Gclc, glutamate-cysteine ligase, catalytic subunit; Gclm, glutamate-cysteine ligase, modifier subunit; GCR, glucocorticoid receptor; GPx2, GSH peroxidase isoform 2; GSH, glutathione; GSSG, glutathione disulfide; GST, glutathione Stransferase; HDAC2, histone deacetylase 2; Hif-1α, hypoxia inducible factor 1α; HO-1, heme oxygenease-1; HUVEC, human umbilical vein endothelial cells; IARC, International Agency for Research on Cancer; ICR, imprinting control region; IVR, intervening region; JNK, Jun-N-terminal kinase; Keap1, Kelch-like ECH-associated protein 1; K-ras, Kirsten rat sarcoma viral oncogene homologue; LC3B, microtubuleassociated protein 1 light chain 3 β; MAPK, mitogen-activated protein kinase; MCP-1 (CCL2), monocyte chemotatic protein1; Myc, myelocytomatosis viral oncogene homologue (avian); NF-κB, nuclear factor of κ light polypeptide gene enhancer in B-cells 1; NO, nitric oxide; NQO1, NAD(P)H dehydrogenase, quinone 1; Nrf2, NF-E2-related factor 2; PAH, polycyclic aromatic hydrocarbon; PERK, RNA-dependent protein kinase R (PKR)-like endoplasmic reticulum kinase; PI3K, phosphatidylinositol 3-kinase; PKC, protein kinase C; RNS, reactive nitrogen species; ROS, reactive oxygen species; SH, sulfhydryl; Slpi, secretory leukoprotease inhibitor; Srx1, sulfiredoxin 1; TPM, total particulate matter; UPR, unfolded protein response; wt, wild-type; XRE, xenobiotic response element

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