O6-methylguanine-DNA methyltransferase (MGMT): impact on cancer risk in response to tobacco smoke

Mutation Research 736 (2012) 64–74

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Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis journal homepage: www.elsevier.com/locate/molmut Community address: www.elsevier.com/locate/mutres

Review

O6 -methylguanine-DNA methyltransferase (MGMT): impact on cancer risk in response to tobacco smoke Markus Christmann, Bernd Kaina ∗ Institute of Toxicology, University Medical Center Mainz, Obere Zahlbacher Str. 67, D-55131 Mainz, Germany

a r t i c l e

i n f o

Article history: Received 24 February 2011 Received in revised form 23 May 2011 Accepted 8 June 2011 Available online 14 June 2011 Keywords: MGMT DNA repair Cancer protection Tobacco Lung cancer Biomarker

a b s t r a c t Tobacco, smoked, snuffed and chewed, contains powerful mutagens and carcinogens. At least three of them, N-dimethylnitrosamine, N -nitrosonornicotine and 4-(methylnitrosamino)-1-(3-pyridyl)-1butanone, attack DNA at the O6 -position of guanine. The resulting O6 -alkylguanine adducts are repaired by the suicide enzyme O6 -methylguanine-DNA methyltransferase (MGMT), which is known to protect against the mutagenic, genotoxic and carcinogenic effects of monofunctional alkylating agents. While in rat liver MGMT was shown to be subject to regulation by genotoxic stress leading to adaptive changes in its activity, in humans evidence of adaptive modulation of MGMT levels is still lacking. Several polymorphisms are known, which are suspected to impact on the risk of developing cancer. In this review we focus on three questions: (a) Has tobacco consumption by smoking or chewing an impact on MGMT expression and MGMT promoter methylation in normal and tumor tissue? (b) Is there an association between MGMT polymorphisms and cancer risk and is this risk related to smoking? (c) Does MGMT protect against tobacco-associated cancer? There are several lines of evidence for an increase of MGMT activity in the normal tissue of smokers compared to non-smokers. Furthermore, in tumors developed in smokers a tendency towards an increase of MGMT expression was found. The data points to the possibility that agents in tobacco smoke are able to trigger upregulation of MGMT in normal and tumor tissue. For MGMT promoter methylation data is conflicting. There is some evidence for an association between MGMT polymorphisms and smoking-induced cancer risk. The key question whether or not MGMT protects against tobacco smoke-induced cancer is difficult to answer since prospective studies on smokers versus non-smokers are lacking and appropriate animal studies with MGMT transgenic mice exposed to the complex mixture of tobacco smoke have not been performed, which indicates the need for further explorations. © 2011 Elsevier B.V. All rights reserved.

Contents 1. 2. 3. 4.

5. 6. 7. 8.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Tobacco-smoke carcinogens target the O6 -position of guanine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . O6 -methylguanine-DNA methyltransferase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Regulation of MGMT expression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Regulation by promoter methylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Transcriptional regulation of MGMT expression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. MGMT polymorphisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Impact of smoking on MGMT expression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Impact of MGMT polymorphisms on cancer development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Impact of MGMT polymorphisms on smoking related cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Does MGMT protect against smoking-induced cancer? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

∗ Corresponding author. Tel.: +49 6131 17 9217; fax: +49 6131 230 506. E-mail addresses: [email protected] (M. Christmann), [email protected] (B. Kaina). 0027-5107/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.mrfmmm.2011.06.004

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1. Introduction Smoking is dangerous. The first large-scale epidemiological studies on cigarette smoking and lung cancer published in 1950 clearly demonstrated a dose-dependent association between the number of cigarettes smoked and the risk of lung cancer [1,2]. Up to now smoking has been associated with the development of several types of cancer such as lung, esophagus, larynx, mouth, throat, kidney, bladder, pancreas, stomach and cervix cancer, as well as acute myeloid leukemia [3,4]. At least 80 potentially carcinogenic compounds have been identified in cigarette smoke to date [5]. Among them are N-nitroso compounds, which represent the most common source of DNA alkylation damage in humans. They are also important in connection with occupation and diet and have been shown to be a major source of the mutagenic and carcinogenic potential of smoking (Fig. 1) and environmental and food-borne exposures. Already in 1962 Druckrey and Preussmann suggested that N-nitroso compounds could be present in the human environment [6]. The first N-nitroso compound identified in the tobacco smoke was dimethylnitrosamine (DMN, also known as N-nitrosodimethylamine), which was detected in amounts ranging from not detectable to 140 ng/cigarette [7]. DMN is also the prevalent chemically characterized N-nitroso compound present in the diet [8]. A high amount of DMN in food has been shown especially in cured meat (10–100 ␮g/kg) and beer (up to 70 ␮g/l) [8]. Besides DMN other nitrosamines, which are specific to tobacco, have been identified in cigarettes. The most carcinogenic of these tobacco-specific N-nitrosamines are N -nitrosonornicotine (NNN), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and its metabolite 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) [9], which have been shown to enhance the risk of

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experimental cancer development [10–12]. Other tobacco specific nitrosamines are N-nitroso-anabasine (NAB) and N-nitrosoanatabine (NAT). The concentration of tobacco-specific nitrosamines like NNN and NNK, which are formed during the curing and processing of tobacco, is highly variable between different brands. Thus in Canadian cigarettes the NNN concentration in the tobacco ranged from 265 to 979 ng/cigarette and the NNK concentration was between 465 and 878 ng/cigarette [13]. In cigarettes produced in Europe and USA, the NNN concentration was between 45 and 12,454 ng/cigarette and the NNK concentration between non-detectable levels and 10,745 ng/cigarette in the (non-smoked) tobacco [14]. NNN and NNK present in tobacco represent the main source of tobacco-specific nitrosamines in the mainstream smoke. Neither addition of nitrate nor nicotine to the tobacco prior to smoking changed the concentrations of DMN, NNN or NNK in smoke, indicating that pyrosynthesis of NNN and NNK is very unlikely [15,16]. In contrast, the concentration of N -nitroso-anabasine (NAB) and N -nitroso-anatabine (NAT) increased after addition of nitrate to cigarettes, suggesting they are formed during smoking. Harmful health effects arise not only by direct smoking, but also from passive smoking. Tobacco-specific nitrosamines are not only found in the main stream, but also in the side stream of cigarette smoke. In smoke of the same cigarette, NNN was found in the main stream in amounts between 240 and 3700 ng/cigarette and in the side stream between 150 and 6100 ng/cigarette; NNK was found in the main stream in amounts between 110 and 420 ng/cigarette and in the side stream between 190 and 660 ng/cigarette [17]. DMN was detected in tobacco condensate in amounts ranging from not detectable to 140 ␮g/cigarette [7] and in the main stream and side stream smoke in amounts ranging from 0.1 to 140 and 143 to 415 ng/cigarette, respectively [18,19].

2. Tobacco-smoke carcinogens target the O6 -position of guanine

Fig. 1. Induction of the DNA adducts O6 -methylguanine (O6 MeG) and O(6)-[4-oxo4-(3-pyridyl)butyl]guanine (O6 pobG) by carcinogens in the tobacco smoke. DMN, dimethylnitrosamine; NNN, N -nitrosonornicotine; NNK, 4-(methylnitrosamino)1-(3-pyridyl)-1-butanone; NNAL, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol, which is a metabolization product of NNK [17]. Both O6 MeG and O6 pobG are mutagenic lesions. For O6 MeG it is well established that the lesion induces chromosomal breakage and by the mediation of mismatch repair DNA double-strand breaks (DSB) that trigger cell death. Both repair of the adducts and elimination of genetically damaged cells by apoptosis [47] counteracts the process of carcinogenesis.

During the metabolism of nitrosamines present in the tobacco, highly reactive products are formed which give rise to different DNA adducts. Several of these reactive products alkylate DNA via SN 1 reaction, which is dependent on the formation of electrophilic carbocations [20]. In the case of DMN upon metabolic activation reactive carbenium ions are formed that attack several nucleophilic sites in the DNA. One of them is the O6 -position of guanine, resulting in the formation of O6 -methylguanine (O6 MeG) in the DNA (Fig. 2). In the case of NNK carbenium ions and pyridyloxobutylating species are produced, which generate O6 MeG and O(6)-[4-oxo-4(3-pyridyl)butyl]guanine (O6 pobG) in the DNA (Fig. 2). For NNN only the formation of O6 pobG was reported [21]. Upon NNK exposure it has been shown that the formation and persistence of O6 MeG are critical events in the initiation of lung tumors in A/J mouse, which is susceptible to lung cancer formation [22]. This, however, has not been reported for other mouse strains that differ in lung cancer susceptibility. In NNK exposed rats O6 pobG represents the second frequent pyridyloxobutylation product after the corresponding N7 alkylguanine adduct [23]. O6 pobG is a replication blocking lesion that is tolerated by translesion synthesis, which is error prone [24]. This explains that it contributes significantly to the mutagenic risk [25,26]. Both DNA methylation and DNA pyridyloxobutylation are considered to be important factors in rat nasal cavity carcinogenesis induced by NNK and NNN [27]. Since NNK has a higher carcinogenic potency than NNN [21], it is reasonable to posit that O6 MeG, which is formed by NNK but not NNN, is the major pre-mutagenic and pre-carcinogenic lesion induced by alkylating agents in the tobacco smoke.

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Fig. 2. Metabolism of the tobacco-specific carcinogens NNK and NNN. Both O6 MeG and O6 pobG are repaired by MGMT (for explanation see text).

3. O6 -methylguanine-DNA methyltransferase O6 MeG induced by DMN and NNK is repaired by O6 methylguanine-DNA methyltransferase (MGMT) by transfer of the methyl group from guanine to a cysteine residue in the active center of the repair protein [28]. Besides O6 MeG, longer alkyl adducts can also be repaired by MGMT such as ethyl-, n-propyl-, n-butyl-, 2-chloroethyl-, 2-hydroxyethyl-, iso-propyl- and iso-butyl adducts, however, with increasing size of the alkyl group the transfer rate to MGMT decreases [29]. The adduct size is not the only factor that determines the repair of O6 -guanine adducts by MGMT [30]. Of special importance for the toxicity of smoking is the finding that besides O6 MeG also O6 pobG is repaired by MGMT in vitro [31–33] and in vivo [34] (Fig. 2). Despite the repair of O6 pobdG by MGMT the mutation rate following exposure to NNKOAc was not affected [35], indicating other large adducts tolerated by translesion synthesis may contribute to mutagenesis. A recent study showed that nucleotide excision repair (NER) is also involved in the repair of NNK-induced pyridyloxobutylation [36,37], which makes it even more difficult to assess the role of MGMT in the protection against NNN and NNK induced carcinogenesis. Taken together, the evidence suggests that NNK is able to induce O6 MeG and O6 pobG, whereas NNN induces predominantly O6 pobG in the DNA. DMN only generates O6 MeG (together with N-methylations and the minor mutagenic adduct O4 -methyl thymine). The tobacco induced

DNA adducts, which are repaired by MGMT, are potentially mutagenic and genotoxic. Therefore, it can be concluded that MGMT has a clear potential in protecting against some of the powerful carcinogens taken up during tobacco smoking, and also tobacco chewing and snuffing (see below). Following alkyl group transfer, MGMT is rendered inactive and the alkylated MGMT becomes ubiquitinated and targeted to proteasomal degradation [38]. Because of the high mispairing properties of O6 -alkylguanine adducts, MGMT is considered to be the main node of protection against tumor formation by O6 -methylating agents. This gained strong support from the findings that transgenic mice over-expressing MGMT in their skin display a significantly reduced rate of tumor initiation and conversion of benign into malignant tumors in the skin-tumor model upon exposure to N-methyl-N-nitrosourea [39–41]. In other target systems it was shown that MGMT protects against methylation-induced liver cancer [42], lung cancer [43,44], thymic lymphomas [45,46] and colon cancer [47] in the mouse model. In the absence of MGMT, O6 MeG leads via replication and the involvement of mismatch repair to DNA double-strand breaks, the induction of chromosomal aberrations and cell death [48]. Overwhelming evidence suggests that MGMT is a main defense factor of cells against the cytotoxic, mutagenic, genotoxic and carcinogenic effects of widely distributed methylating environmental, tobacco smoke and food born mutagens/carcinogens [49]. MGMT is also a key factor of resistance to

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methylating and chloroethylating anticancer drugs [50–53] and therefore several clinical trials were conducted to inhibit MGMT during cancer therapy [54]. 4. Regulation of MGMT expression Since each molecule of MGMT reacts only once (it is a suicide enzyme) and cofactors are not needed, the capacity for repair of O6 alkylguanine depends clearly on the amount of MGMT molecules per cell. MGMT expression rests mainly on the 5-methylcytosine status of the MGMT promoter, and several polymorphic forms are known, which differ in their biological activity. Regulation by different transcription factors has also been reported. In the following we review the work published on MGMT regulation and its impact on tobacco-related cancers. 4.1. Regulation by promoter methylation MGMT expression is highly regulated via methylation (i.e. the presence in the DNA of 5-methylcytosine, which is not a reaction product of methylating genotoxins) of several CpG islands within the promoter [55,56]. Hypermethylation of these CpG islands, which consist of 10 hexanucleotide motifs (CCGCCC), provokes transcriptional silencing [57–59] by altering the position of nucleosomes and thereby shielding the transcription start site against components of the transcription machinery [55,60,61]. Methylation of the CpG islands of the MGMT promoter correlates with the loss of MGMT mRNA expression and activity and can be detected via methylation specific PCR (MSP) [62,63]. Besides promoter methylation also methylation within the body of the gene has been reported to impact MGMT expression. In contrast to the methylation of the MGMT promoter, methylation of MspI/HpaII sites in the exoncontaining regions of the gene has also been reported [64] and related to dry resistance [65]. 4.2. Transcriptional regulation of MGMT expression Induction of MGMT was first described at the activity level in rat hepatocytes upon exposure to 1,2-dimethylhydrazine, N-diethylN-nitrosamine [66] or N-methyl-N -nitro-N-nitrosoguanidine (MNNG) [67] and in rat liver following genotoxic stress induced by MNNG, methyl methanesulfonate (MMS) or ethyl methanesulfonate (EMS) [68]. At RNA level MGMT induction was most consistently observed in rat hepatocytes [69]. MGMT induction was shown to occur via transcriptional activation, which was investigated in great detail in different rodent systems upon treatment with corticosteroids, ultraviolet (UV) light, ionising radiation and alkylating agents [69–71]. An important transcription factor involved in the induction of MGMT in rodents appears to be p53 since p53 knockout mice do not show MGMT induction upon whole body irradiation [72]. In addition, the MGMT promoter was activated only in p53 wild-type but not p53 deficient mouse fibroblasts [73]. The human MGMT promoter contains several transcription factor binding sites such as glucocorticoid responsive elements, AP-1 and Sp-1 sites [57]. The two AP-1 binding sites can be transactivated by co-expression of c-Fos and c-Jun and their deletion attenuates MGMT promoter activation [74]. In addition, the MGMT expression level was increased in HeLa S3 cells upon treatment with different activators of protein kinase C (PKC) such as phorbol-12-myristate-13-acetate (TPA) and 1,2-diacylglycerol (DAG) [74]. NF-␬B is also involved in MGMT regulation via the interaction with two specific binding sites within the MGMT promoter region and forced expression of the NF-␬B subunit p65 resulted in increased MGMT expression in HEK293 cells [75]. An important question is whether MGMT is also inducible by genotoxic stress and/or hormones in humans in vivo. Surprisingly,

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only few studies addressed this issue. Thus, it has been shown that metastatic melanoma cells obtained by a biopsy after alkylating agent treatment of the patient had higher MGMT activity than those studied before therapy [76,77]. Also in glioma patients a higher MGMT activation and expression and a reduced promoter methylation was observed in recurrences from patients who received alkylating anticancer drugs and radiotherapy compared to the pretreatment tumor [78–80]. In human glioblastoma xenografts grown in immunodeficient mice temozolomide treatment resulted in the induction of MGMT [81]. In other reports MGMT was not found to be induced following treatment with methylating agents or ionising radiation in human fibroblasts [69], human glioma cells [82] and other cell systems (own unpublished data). Certain knowledge of MGMT upregulation following genotoxic stress (including smoking) in humans would be extremely important because it might provide a basis for explaining why only a limited number of longterm smokers (up to 16%) suffer from lung cancer. 4.3. MGMT polymorphisms In humans, several polymorphisms in the MGMT gene have been detected. Three of them, Leu84Phe, Ile143Val and Lys178Arg are supposed to alter the MGMT activity. The Ile143Val and Lys178Arg polymorphisms are in close proximity to the cysteine alkylresidue in the active site at position 145. In assays performed in Escherichia coli, the human Ile143Val and Lys178Arg polymorphism did not affect the enzymatic activity or in vitro mutagenesis [83,84]. The Val143 variant, however, was more resistant to inactivation by the MGMT pseudosubstrate O(6)-(4-bromothenyl)guanine [85]. Another study reported that the Val143 and the Arg178 variant show no difference in the repair of O6 pobG, the adduct formed by NNK and NNN [86]. However the repair of this lesion by MGMT is strongly influenced by the sequence context and the Val143 and the Arg178 variants are less sensitive to variations in the surrounding sequence [87]. In contrast to Ile143Val and Lys178Arg polymorphisms, the Leu84Phe is not located in close proximity to the active center. Similar to the Ile143Val and Lys178Arg polymorphisms, the repair of O6 MeG or O6 pobG by the 84Phe variant [88] was not different from wt MGMT [83,87,89]. It is, however, very close to the residues 98–102, which form a LXXLL motif that has been supposed to interact with the estrogen receptor. It was shown that MGMT can bind to the estrogen receptor via the LXXLL motif blocking its binding to its coactivator (steroid receptor coactivator-1) and, thereby, may negatively affect estrogen receptor mediated transcriptional activity and estrogen receptor-mediated cell proliferation [90]. We should note that the interaction between the Leu84Phe variant of MGMT and the estrogen receptor has not been replicated in other studies, which renders this mechanism (i.e. the binding of MGMT to the estrogen receptor) up to now not confirmed. The above experiments, which show no impact of MGMT polymorphisms on MGMT activity and mutagenesis, were performed in vitro and in E. coli. The possibility should be considered that in human cells MGMT polymorphisms have a different outcome. To this end, a study was conducted in which MGMT activity was measured in human lymphocytes obtained from 131 individuals. Three of the individuals showed the Ile143Val and Lys178Arg polymorphisms and displayed a higher MGMT activity than individuals carrying no polymorphism (15.5 vs. 8.4 fmol/␮g DNA) [85], which was explained by the hypothesis that the polymorphism lead to altered MGMT steady state levels. For the polymorphisms Leu84Phe and Ile143Val in lymphocytes a suboptimal repair of genetic damage and an increased sensitivity against NNK was detected via the formation of chromosomal aberrations in vitro [91]. This study was performed with a higher number of individuals carrying the polymorphism. Of the 114 individuals, 66 were

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homozygous wild-type, while 37 inherited either the Leu84Phe or the Ile143Val polymorphism and 9 individuals inherited both. For the polymorphisms Leu84Phe, but not Ile143Val, suboptimal repair was also associated with increased mutation frequency in lymphocytes from smokers compared to smokers carrying the wild-type allele [92]. 5. Impact of smoking on MGMT expression Since MGMT expression and activity can be regulated via genotoxic stress, the question arises whether exposure to cigarette smoke in humans results in changes in MGMT expression. In vitro, exposure of buccal cell cultures to various products related to the use of tobacco and betel quid led to a decrease of MGMT activity [93]. Also in vivo an association between the MGMT status and smoking habit was observed, both in normal tissue and in various tumors. Most reports (compiled in Table 1) showed in PBLCs and solid tissues of healthy smokers increased MGMT protein expression or activity. Thus, a slightly higher MGMT activity was observed in peripheral blood lymphocytes of smokers than non-smokers [94]. In the pharyngeal mucosa of smokers increased MGMT activity was observed, which was accompanied by an increased activity in peripheral blood lymphocytes (PBLCs) of the corresponding individuals [95]. In normal peripheral lung tissues of smokers MGMT activity was also higher than in non-smokers and this study also revealed that more than one year of abstinence from smoking was necessary to reduce the MGMT activity in former smokers to the level detected in non-smokers [96]. In contrast, the MGMT activity was lower in lung bronchial epithelial cells from smokers compared to non-smokers [97], whereas this study reported no differences in the MGMT activity in PBLCs. In tumors of smokers MGMT expression was frequently observed at higher level than in tumors of non-smokers (see Table 1). Thus, in precancerous oral leukoplakia a higher MGMT expression was found in smokers compared to non-smokers [98]. In line with this, in non-small cell lung cancer (NSCL) from smokers a higher expression of MGMT was reported compared with tumor tissue from non-smokers [99]. In the smoker group the MGMT expression level was even higher in tumors of patients smoking

>20 cigarettes/day than in patients smoking <20 cigarettes/day, and abstinence from smoking resulted in a decrease of MGMT expression [99]. MGMT expression was also higher in the tumor of smoking than non-smoking patients suffering from squamous cell carcinoma of the esophagus [100]. The MGMT activity was also higher in normal and malignant colon tissue of smokers (1–19 cigarettes/day) compared to non-smokers [101]. In contrast, in oral squamous cell carcinomas a higher MGMT expression was observed in non-smokers than in smokers [98]; this study is limited however because of the low number of cases included (5 nonsmokers). Not only MGMT activity, but also promoter methylation (determined by means of methylation-specific PCR) was compared between smokers and non-smokers. In NSCLCs of smokers (373 cases) versus non-smokers (132 cases) an increased frequency of tumors exhibiting a methylated promoter was reported in smokers [102]. In another study performed on lung cancer, a significantly increased frequency of tumors with methylated MGMT promoter was observed in smokers compared to non-smokers [103]; the same result was found in this study for the subgroup of adenocarcinomas [103]. In another study, a decreased frequency of adenocarcinomas containing a methylated MGMT promoter was observed in smokers compared to non-smokers [104]. In SCCHN of smokers and non-smokers no association of MGMT promoter methylation with the smoking status was observed [105]. In Southeast Asia, not the consumption of cigarettes but the chewing of tobacco in form of betel quid with tobacco or Khaini, a mixture of tobacco and lime, is most prevalent [106]. The use of these “smokeless tobacco” products is constantly rising, and smokeless tobacco is associated with the development of oral cancer and has been classified as carcinogenic to humans [107]. Especially Khaini contains high levels of nitrosamines [106]. Both the chewing of betel quid and Khaini were associated with loss of MGMT expression in 107 oral squamous cell carcinomas and 78 oral precancerous lesions [108]. Interestingly this effect is observed only in consumers of Khaini (30 vs. 61% MGMT expression in OSCCs; 23 vs. 73% MGMT expression in oral precancerous lesions), whereas in the same study the effect of tobacco smoking was not clearly associated with MGMT expression (59 vs. 61% MGMT

Table 1 Impact of smoking on MGMT expression. MGMT

Normal tissue

Smoker/non-smoker

MGMT status (smoker vs. non-smoker)

Ref.

Activity Activity Activity Activity Activity Activity Activity

Lung tissue PBLCs Pharyngeal mucosa PBLCs Lung bronchial epithelial cells PBLCs Colon tissue

59/22 30/10 7/19 7/19 26/72 40/97 14/36

Increased activity (67 vs. 49 fmol/mg protein) Increased activity (124 vs. 94 fmol/106 cells) Increased activity (180 vs. 50 fmol/mg protein) Increased activity (798 vs. 671 fmol/mg protein) Decreased activity (0.71 vs. 1.25 fmol/␮g DNA) No differences Increased activity (119 vs. 199 fmol/mg protein)

[96] [94] [95] [95] [97] [97] [101]

MGMT

Tumor tissue

Smoker/non-smoker

MGMT status (smoker vs. non-smoker)

Activity

Colon tumor

8/26

ICH ICH IHC IHC MSP MSP MSP MSP

Oral leukoplakia OSCC NSCLC OSCC Lung tumor Adenocarcinomas of the lung Adenocarcinomas of the lung SCCHN

23/13 28/5 45/21 79/21 81/41 49/23 157/46 42/4

Increased activity (210 vs. 127 fmol/mg protein) No differences in Rectum tumor Increased expression (87 vs. 77%) Decreased expression (43 vs. 80%) Increased expression (82 vs. 43%) Increased expression (63 vs. 28.6%) Increased promoter methylation (39.5 vs. 12.2%) Increased promoter methylation (36.7 vs. 17.4%) Decreased promoter methylation (44 vs. 66%) No association with smoking

MGMT

Cancer type

Chewing/non-chewing

MGMT status (chewer vs. non-chewer)

IHC IHC IHC MSP

Oral leukoplakia OSCC OSCC OSCC

67/11 9/21 35/15 27/9

Decreased expression (37 vs. 73%) Decreased expression (43 vs. 61%) Decreased expression (17 vs. 47%) Increased promoter methylation (48 vs. 22%)

[101] [98] [98] [99] [100] [103] [103] [104] [105]

[108] [108] [109] [109]

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expression in OSCCs; 54 vs. 73% MGMT expression in oral precancerous lesions). In another study on oral squamous cell carcinomas increased promoter methylation and decreased MGMT expression was associated with chewing of betel quid [109]. Also in this study tobacco smoking showed a weak association with decreased MGMT expression (23% in OSCCs of smokers vs. 43% in OSCCs of nonsmokers), however, data are limited because only 7 non-smokers were included and 4 of them consumed betel quid. Taken together, most studies performed with normal tissue (PBLCs, pharyngeal mucosa and lung), precancerous lesions and fully developed cancers revealed an increase of MGMT activity in smokers vs. non-smokers (Table 1). This could be explained by positing that increase in MGMT activity observed in smokers is part of the cell’s protection strategy and thus individuals having a low constitutive activity and low MGMT upregulation capacity may be predisposed to tumor development following smoking. It is clear that prospective studies are needed in which the individual MGMT status is considered in relation to smoking (and other exposures such as alcohol) and the probability of cancer formation. Also the impact of MGMT promoter methylation on carcinogenesis should be studied in more detail. Thus, contrary to the data obtained on MGMT activity, most studies showed increased MGMT promoter methylation status in smokers. The discrepancy could be explained by a direct effect of smoking on promoter-methylation. Thus it was shown that NNK induces DNA methyltransferase 1 (DNMT1), which leads to tumor suppressor gene hypermethylation [110]. The question whether NNK provokes hypermethylation also of the MGMT promoter has not been addressed.

6. Impact of MGMT polymorphisms on cancer development MGMT is a repair protein that shows large inter-individual variation. Thus, in blood lymphocytes a sevenfold variation of MGMT repair activity has been detected between individuals and a particular expression level was maintained for several weeks of

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investigation, indicating its inherent regulation [94]. The molecular basis of this variation is unknown [49,85]. Since all lymphocyte samples displayed MGMT activity, which is in contrast to tumors that are MGMT lacking with a frequency of 5–20% [111], it is unlikely that in normal tissue, at least in lymphocytes, MGMT is regulated by promoter methylation. In fact, lymphocytes isolated from human blood are MGMT promoter unmethylated [79]. We cannot exclude specific methylation sites in the promoter and even the body of the gene that were not subject to screening and play a role in epigenetic MGMT regulation. More likely, however, is regulation at the level of transcription factors that may be influenced by environmental stimuli such as tobacco smoke. Also, polymorphisms could account for differences in MGMT activity. In the following we will discuss the question whether MGMT polymorphisms can influence the risk of cancer development and whether this could be the case in individuals exposed to tobacco smoke. Multiple studies analyzed the association between the different polymorphisms and cancer development (Table 2); the data are highly controversial (for recent reviews see [112,113]). Thus, an increased risk for lung cancer was observed in individuals carrying the Ile143Val polymorphism [114]. Ile143Val and Lys178Arg were also associated with increased risk of Non-Hodgkin-Lymphoma [115], Ile143Val and Lys178Arg, but not Leu84Phe polymorphisms were associated with increased risk for cervical carcinoma [116], and Leu84Phe showed a significant association with increased malignant glioma risk [117]. A weak positive association of the polymorphisms Leu84Phe and Ile143Val with development of malignant glioma was also observed in another study [118]. In squamous cell carcinoma of the upper aerodigestive tract an increased risk was observed for Leu84Phe [119]. For breast cancer Leu84Phe, but not the Ile143Val polymorphism was associated with increased risk [120] and the Ile143Val polymorphism was associated with increased risk of adenomas of the esophagus (EAC) [121]. In other studies no association between MGMT polymorphisms and cancer risk was found. Thus, there was no association between polymorphism Lys178Arg and lung cancer

Table 2 Impact of MGMT polymorphisms on cancer risk (independent of smoking status). Polymorphism

Cancer type

Case/control

Cancer risk

Ref.

Ile143Val Lys178Arg Leu84Phe Ile143Val Ile143Val Leu84Phe/Ile143Val/Lys178Arg Leu84Phe Ile143Val Ile143Val Ile143Val

NHL Glioma Glioma Glioma Breast cancer Breast cancer Breast cancer Breast cancer Colorectal cancer

562/506 463/549 445/519 373/365 1067/1110 1311/1760

[115] [118] [118] [117] [133] [120] [120] [137] [137]

Ile143Val Leu84Phe/Ile143Val

Prostate cancer Colorectal cancer

Leu84Phe Leu84Phe Ile143Val/Leu84Phe Ile143Val/Lys178Arg Leu84Phe Leu84Phe Leu84Phe Lys178Arg Leu84Phe/Ile143Val Ile143Val/Lys178Arg Lys178Arg Leu84Phe Ile143Val Leu84Phe Leu53Leu

Colon cancer Rectal cancer Gastric cancer Cervix cancer Cervix cancer Endometrial cancer UADT cancer Lung cancer Lung cancer Lung cancer Lung cancer Head and neck cancer Bladder cancer

312/1486 197/2500 Female 271/451 Male 180/1176 130/1176 281/390 1012/800

Ile143Val Ile143Val Leu84Phe/Ile143Val/Lys178Arg

EAC EGJAC OSCC

Increased Increased Increased Increased No association Increased No association No association Increased in individuals with high consumption of red or processed meat No association Decreased No association Decreased No association No association Increased No association Decreased Increased No association Increased Increased Decreased Decreased Increased in individuals carrying both polymorphisms Increased No association No association

276/1498 273/2984

456/1134 811/1983 92/85 1121/1163 136/133 255/362 555/792 176/204 263/1337 303/1337 176/110

[137] [126] [124] [124] [125] [116] [116] [128] [119] [122] [134] [135] [136] [127] [131] [121] [121] [123]

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[122], Leu84Phe, Ile143Val and Lys178Arg and oral cancer risk [123], Leu84Phe and rectal cancer [124], Ile143Val and Leu84Phe polymorphism and gastric cancer risk [125] and Ile143Val polymorphism and risk of adenomas of the esophago-gastric junction (EGJAC) [121]. In some cases even a decreased cancer risk was reported for specific polymorphisms. Thus, a decreased risk for colon cancer was associated with Leu(84)Phe [124], and in another study with Leu84Phe and Ile143Val in female, but not in male [126], a decreased risk of head and neck cancer was observed for Leu84Phe and Ile143Val [127], and a decreased risk of endometrial cancer was observed for Leu84Phe [128]. Besides polymorphisms in the gene, polymorphisms in the promoter-enhancer region of MGMT are also known. One of these polymorphisms is 1099 C → T that was shown to be associated with increased MGMT promoter-enhancer activity in cell lines (16–64% enhancement) [129]. In case that a single polymorphism was not associated with cancer risk, some studies showed that the combined presence of more than one polymorphism can have an impact on cancer risk. For example, for SCCHN an increased risk was associated with the combined presence of three to four polymorphisms (Leu53Leu and Leu84Phe and two polymorphisms in the promoter region: rs1711646 and rs1625649), which alone had no effect on cancer risk [130]. In another study neither polymorphism Leu53Leu nor Leu84Phe alone had a significant effect, but individuals carrying both polymorphisms showed an increased risk to develop bladder cancer [131]. In a recent meta-analysis, assessing the impact of the MGMT polymorphisms Leu84Phe and Ile143Val in a large cohort of 13,069 cancer patients and 20,290 controls, only a significant association between the Leu84Phe and cancer risk was shown; this protective effect was found only in colorectal cancer [132]. On the other hand, no significant association between polymorphism Ile143Val and cancer risk was found.

7. Impact of MGMT polymorphisms on smoking related cancer The data discussed above relating MGMT polymorphisms to cancer development are highly inconsistent. This, however, is not unexpected since the end point “cancer” is affected by many variables such as gender, ethnic background, multiple exposures by environmental carcinogens and tobacco smoke. An intriguing question is whether MGMT polymorphisms have an impact on cancer risk in smokers compared to non-smokers. Interestingly, all studies with smokers report on an association between a given MGMT polymorphism and cancer risk (Table 3). For example, in women smoking >31 packs of cigarettes per year, a significantly increased breast cancer risk was observed in individuals carrying the polymorphism Leu84Phe [133]. Similar, an increased risk of lung cancer was reported for individuals carrying 1 out of 4 variants of polymorphism Leu84Phe, Ile143Val, the promoter polymorphism SNP 135 G → T and SNP 485 C → A, compared to individuals not exhibiting a polymorphism [134]. An increased risk for cancer development was even more pronounced in women and current smokers, and sub-type analysis showed that these polymorphisms are associated with increased risk for adenocarcinoma or small cell carcinoma, but not for squamous cell carcinoma [134]. Increased lung cancer risk

was also observed in smokers carrying the Ile143Val and Lys178Arg polymorphism [135]. In contrast, a decreased lung cancer risk was associated with polymorphism Lys178Arg, which was most evident in heavy smokers and insignificant in light smokers [136]. An association with a decreased risk of cancer was shown in individuals suffering from endometrial cancer carrying the Ile143Val MGMT polymorphism and smoked >30 packs per day [128]. It should be noted that not only smoking, but also nutrition seems to impact the association between MGMT and cancer risk. Whereas Ile143Val polymorphism was not overall associated with colorectal cancer, it provoked increased colorectal cancer risk in individuals with high consumption of red and processed meat [137].

8. Does MGMT protect against smoking-induced cancer? About 80 potentially carcinogenic and co-carcinogenic compounds are present in tobacco smoke. This makes it difficult to determine which of the agents and DNA lesions induced by them are most important for the generation of lung and other cancers in smokers. An answer might be provided by the mutation spectrum induced by carcinogens present in tobacco. O6 MeG is a miscoding lesion producing GC → AT transitions [138], which is expected the predominant mutation type induced by N-nitrosamines in the tobacco. Investigating the mutation spectrum in the k-ras gene in 482 lung adenocarcinomas (81 non-smokers vs. 316 smokers) a similar frequency of tumors of non-smokers (15%) and smokers (22%) exhibited k-ras mutation. In this study, GC → TA but not GC → AT mutations were more frequently observed in smokers than non-smokers [139]. An analysis of tp53, hprt and k-ras mutations in lung cancers and T-lymphocytes of lung cancer patients showed an increased frequency of GC → TA mutations in smokers and an increased frequency of GC → AT mutations in non-smokers [140–142]. These findings are contrary to the expectation if O6 MeG is the major mutagenic lesion produced by tobacco smoke. While GC → AT transitions are induced by NNK [143], GC → TA transversions present a typical signature of mutations caused by another important mutagenic component of tobacco smoke, benzo[a]pyrene [144,145]. This might be taken to indicate that a significant fraction of mutations found in critical genes of lung cancers from smokers are caused by non-alkylating tobacco smoke carcinogens. Site-specific mutagenesis showed that O6 pobG is mutagenic in human cells producing mainly GC → AT transitions, but also a small number of GC → TA transversions [25]. Also exposure of A/J mice to the NNK metabolite NNKOAc, which pyridyloxobutylates DNA, lead to the formation of GC → AT transitions and GC → TA transversions [146]. It should be noted that, besides O6 pobG other pyridyloxobutyl DNA adducts such as 7-pobG, O2 -pobC and O2 pobT could impact the overall mutation spectrum (for review see [147]). Thus, upon exposure to NNKOAc also AT → TA transversion were observed, which may arise by O2 -pobdT [35]. GC → TA mutations are also formed upon the induction of 8oxoguanin in the DNA by reactive oxygen species (ROS) [148,149], which are present in tobacco smoke at large amounts. In addition, elevated 8-oxoguanine levels were detected in the lung of mice and rats treated with NNK [150]. The level of 8-oxoguanine-DNA

Table 3 Impact of MGMT polymorphisms on cancer risk of smokers. Polymorphism

Cancer type

Case/control

Cancer risk of smokers

Ref.

Ile143Val Leu84Phe Leu84Phe/Ile143Val Ile143Val/Lys178Arg Lys178Arg

Endometrial cancer Breast cancer Lung cancer Lung cancer Lung cancer

456/1134 1067/1110 1121/1163 136/133 255/362

Decreased Increased Increased Increased Decreased

[128] [133] [134] [135] [136]

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glycosylase (OGG-1) correlates with lung cancer incidence, which was taken to indicate that ROS is responsible for smoke-induced lung cancer (for review see [151]). It should be noted that mutations in several target genes are required for neoplastic transformation and thus the possibility remains that in a critical not yet defined target gene(s) GC → AT mutations have to be induced in order to obtain the malignant phenotype. If MGMT is involved in the protection against smoking-induced cancer it is expected that MGMT has a strong impact on lung cancer in experimental settings. Comparing wild-type transgenic mice that expressed the human MGMT and showed a low O6 MeG adduct level in lung tissue following NNK treatment, a significant lower frequency of lung tumors was observed in transgenic individuals [44]. Another study addressed the impact of MGMT on the mutation frequency in lung and liver of MGMT deficient mice following injection of NNK and showed an increase of GC → AT transitions in liver and lung [152]. It is obvious that more animal studies are needed to assess the influence of MGMT on lung cancer development, including also treatments with DMN and NNN. In summary, the mutation spectrum observed in lung cancers as well as the response of MGMT transgenic and knockout mice does neither prove nor disprove DMN, NNN and NNK as critical carcinogens in the tobacco. It is reasonable to posit that nitrosamines together with B(a)P, ROS and presumably also other genotoxins contribute to lung carcinogenesis following tobacco consumption. In view of the importance of the subject, it is clear that more studies are required to draw a conclusion as to the role of MGMT in protection against tobacco-induced cancers, and the use of MGMT as a biomarker for screening individuals at high cancer risk. Conflict of interest None. Acknowledgement Work is supported by DFG KA724 and Deutsche Krebshilfe. References [1] R. Doll, A.B. Hill, Smoking and carcinoma of the lung; preliminary report, Br. Med. J. 2 (1950) 739–748. [2] E.L. Wynder, E.A. Graham, Tobacco smoking as a possible etiologic factor in bronchiogenic carcinoma; a study of 684 proved cases, J. Am. Med. Assoc. 143 (1950) 329–336. [3] A.J. Sasco, M.B. Secretan, K. Straif, Tobacco smoking and cancer: a brief review of recent epidemiological evidence, Lung Cancer 45 (Suppl. 2) (2004) S3–S9. [4] S. Gandini, E. Botteri, S. Iodice, M. Boniol, A.B. Lowenfels, P. Maisonneuve, P. Boyle, Tobacco smoking and cancer: a meta-analysis, Int. J. Cancer 122 (2008) 155–164. [5] IARC, IARC Monographs on the Evaluation of Carcinogenic Risks to Humans: Tobacco smoke and Involuntary Smoking, vol. 83. Lyon: IARC Press, 2004. [6] H. Duckrey, R. Preussmann, Die Naturwissenschaften 49 (1962) 498–499. [7] J.W. Rhoades, D.E. Johnson, N-dimethylnitrosamine in tobacco smoke condensate, Nature 236 (1972) 307–308. [8] W. Lijinsky, N-Nitroso compounds in the diet, Mutat. Res. 443 (1999) 129–138. [9] S.S. Hecht, DNA adduct formation from tobacco-specific N-nitrosamines, Mutat. Res. 424 (1999) 127–142. [10] S.S. Hecht, C.B. Chen, N. Hirota, R.M. Ornaf, T.C. Tso, D. Hoffmann, Tobaccospecific nitrosamines: formation from nicotine in vitro and during tobacco curing and carcinogenicity in strain A mice, J. Natl. Cancer Inst. 60 (1978) 819–824. [11] S.S. Hecht, A. Rivenson, J. Braley, J. DiBello, J.D. Adams, D. Hoffmann, Induction of oral cavity tumors in F344 rats by tobacco-specific nitrosamines and snuff, Cancer Res. 46 (1986) 4162–4166. [12] S.S. Hecht, D. Hoffmann, Tobacco-specific nitrosamines, an important group of carcinogens in tobacco and tobacco smoke, Carcinogenesis 9 (1988) 875–884. [13] S. Fischer, A. Castonguay, M. Kaiserman, B. Spiegelhalder, R. Preussmann, Tobacco-specific nitrosamines in Canadian cigarettes, J. Cancer Res. Clin. Oncol. 116 (1990) 563–568. [14] S. Fischer, B. Spiegelhalder, R. Preussmann, Tobacco-specific nitrosamines in European and USA cigarettes, Arch. Geschwulstforsc. 60 (1990) 169–177.

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