Molecular features in arsenic-induced lung tumors
- Roland Hubaux†1,
- Daiana D Becker-Santos†1,
- Katey SS Enfield1,
- David Rowbotham1,
- Stephen Lam1,
- Wan L Lam1 and
- Victor D Martinez1Email author
© Hubaux et al.; licensee BioMed Central Ltd. 2013
Received: 17 November 2012
Accepted: 7 March 2013
Published: 19 March 2013
Arsenic is a well-known human carcinogen, which potentially affects ~160 million people worldwide via exposure to unsafe levels in drinking water. Lungs are one of the main target organs for arsenic-related carcinogenesis. These tumors exhibit particular features, such as squamous cell-type specificity and high incidence among never smokers. Arsenic-induced malignant transformation is mainly related to the biotransformation process intended for the metabolic clearing of the carcinogen, which results in specific genetic and epigenetic alterations that ultimately affect key pathways in lung carcinogenesis. Based on this, lung tumors induced by arsenic exposure could be considered an additional subtype of lung cancer, especially in the case of never-smokers, where arsenic is a known etiological agent. In this article, we review the current knowledge on the various mechanisms of arsenic carcinogenicity and the specific roles of this metalloid in signaling pathways leading to lung cancer.
KeywordsArsenic Arsenite Lung cancer Epigenetic Reactive oxygen species Epidermal growth factor receptor Phosphatidylinositol 3-kinases NFE2-related factor 2
Common types of tumors associated with arsenic exposure are found in skin, bladder, liver and lung. Following arsenic exposure, lung cancer has proven to be amongst the most deadly cancer types [13, 14]. Lung adenocarcinoma is the most common type of lung cancer worldwide, however, the most frequent histological subtypes observed in arsenic-induced lung tumors - among both smokers and non-smokers - are squamous cell carcinomas (SqCC) and small cell carcinomas (SCC) . Lung tumors derived from individuals exposed to arsenic also exhibit differential genetic and epigenetic changes when compared to histologically matched tumors derived from an arsenic-free environment. The differential molecular alterations seen in arsenic-induced tumors may not arise from inorganic arsenic, but instead from more damaging arsenic species generated through its metabolism . In this article, we discuss mechanisms that enhance the carcinogenic potential of arsenic, such as its biotransformation, as well as the impact of this carcinogen and its derivatives at a molecular pathway level.
Molecular mechanisms involved in arsenic-induced carcinogenesis
Arsenical species induce genetic alterations
Arsenic as a co-mutagen
Inorganic arsenic does not interact directly with DNA and is not considered to be mutagenic at non-toxic doses . However, as previously described, methylated arsenic species and other byproducts generated in the biotransformation process are potent clastogens and mutagens [27, 28]. Furthermore, low doses of arsenic can potentiate mutagenic effects through other carcinogens such as UV light, N-methyl-N-nitrosourea, diepoxybutane, X-rays, methylmethane sulfonate and tobacco [29–34].
Arsenic induces DNA damage via generation of reactive oxygen and nitrogen species
Arsenic-induced ROS may be generated by either cycling of AsIII and AsV or through disruption of the mitochondrial electron transport chain  (Figure 2). Most of the known arsenic-related mechanisms of ROS generation involve the latter mechanism. Typically, mitochondrial ROS is generated through monomethylarsonous acid (MMAIII)-mediated inhibition of mitochondrial complexes II and IV , which results in a back-log of electrons and, eventually, electron leakage from complexes I and III . Liberation of electrons from the electron transport chain (ETC) leads to formation of superoxide anion radicals (O2•-), hydrogen peroxide (H2O2), and hydroxyl radicals (OH•) [19, 38]. Arsenic-mediated production of free-radical species has been associated with the formation of DNA adducts, DNA double-stranded breaks, DNA cross linking, chromosomal aberrations, DNA mutations and DNA deletions (Figure 2) [39–41].
Arsenic can also induce generation of reactive nitrogen species (RNS). The mechanisms involved are not completely understood; however, they are thought to occur in a tissue-specific manner . The increase in amounts of RNS such as peroxynitrite has been shown to cause DNA alkylation, deamination, and oxidative DNA damage [43–47].
Arsenic interferes with DNA repair processes
Arsenic can affect cellular DNA repair capacity, by altering both nucleotide- (NER) and base-excision repair (BER) mechanisms (Figure 2). Arsenic interferes with NER by reducing the frequency of incision steps of the repair process , reducing the expression of NER-associated genes and decreasing expression and protein levels of Xeroderma pigmentosum complementation group C (XPC) [48–50]. In addition, methylated AsIII species generated by the biotransformation process impair the expression and activity of human PARP1, a promoter of NER that acts in response to DNA damage . Arsenic metabolites also decrease gene expression and protein levels of BER-related components, such as 8-oxoguanine DNA glycosylase 1 (hOGG1), DNA ligase IIIα (LIGIIIα), and X-ray cross complementing protein 1 (XRCC1) . In arsenic-exposed murine lung tissue, the expression of several genes related to BER - such as apurinic/apyrimidinic, endonuclease/redox effector-1 (APE1), ligase I, DNA, ATP-dependent (LIG1), 8-oxoguanine DNA glycosylase (OGG1), and poly (ADP-ribose) polymerase 1 (PARP1) - were elevated .
Arsenic induces chromosomal and genomic instability
Arsenic-treated cells demonstrate significantly increased micronuclei formation as well as chromosomal aneuploidy, likely by an effect on sulfhydryl groups of tubulin and microtubule-associated proteins and consequential cell spindle assembly disruption [53–57]. Additional studies have shown that the p53-dependent increase in p21 expression observed in normal cells following DNA damage is inhibited in cells exposed to arsenic, leading to cell cycle progression despite heavy DNA damage and genomic instability [58–61]. Similarly, arsenic-induced disruption of PARP1 activity contributes to genomic instability by allowing the survival of cells with significant DNA lesions [51, 62]. Studies comparing DNA copy number alterations in arsenic-exposed and non-exposed lung tumor cells indicate the location and frequency of alterations differ between the two cases. Genomes of lung tumors from patients who never smoke, as well as those chronically exposed to arsenic harbor segmental DNA amplifications at 19q13.31 and 19q13.33 and segmental DNA losses at chromosomal locus 1q21, among others [63, 64]. Interestingly, genes in 19q13.33, such as Spleen focus forming virus (SFFV), proviral integration oncogene B (SPIB), and Nuclear receptor subfamily 1, group H, member 2 (NR1H2) have been shown to be oncogenic in mouse models [65–67].
Arsenic-induced epigenetic alterations
Arsenic biotransformation depletes SAM resulting in aberrant DNA methylation
Arsenic detoxification requires the use of S-Adenosyl methionine (SAM) as a methyl donor (Figure 2); consequently, arsenic-related epigenetic effects mainly derive from deprivation of the cellular pool of methyl (-CH3) groups . Although cellular levels of SAM itself are not likely affected, a high demand of SAM due to chronic arsenic exposure will affect the availability of the cellular pool of methyl groups [69–71]. Since SAM is the major methyl donor for DNA-methyltransferases (DNMT), depletion of methyl groups can lead to global hypomethylation and changes in chromatin remodeling [72, 73]. Such epigenetic modifications have been shown to promote malignant transformation in a variety of cell types, including lung [74–76]. Arsenic has been shown to induce global hypomethylation, as demonstrated by reduction in LINE-1 methylation and total 5-methyldeoxycytidine content in lymphoblastoid cells . Importantly, even low-level arsenic exposure resulted in DNA hypomethylation in rat models . Moreover, arsenic-induced SAM deprivation can alter CpG methylation status of promoters for specific genes, such as Deleted In Bladder Cancer 1 (DBC1), Death-Associated Protein Kinase 1 (DAPK), and P53 [68, 78–86]. ROS generated during arsenic biotransformation can also interfere with DNA methylation and contribute to aberrant epigenetic modifications and deregulation of gene expression .
Interestingly, individuals chronically exposed to high yet non-lethal levels of arsenic exhibit a significantly higher degree of DNA methylation in promoter regions of P53 and CDKN2A compared to non-exposed controls . Lung cancer cell models have also shown that arsenic exposure resulted in P53 promoter hypermethylation and subsequent transcriptional silencing of this gene . Promoter hypermethylation of tumor suppressors CDKN2A and RASSF1A was also observed in lung tumors of mice exposed to inorganic arsenate .
Arsenic changes gene expression patterns by altering histone modification
Arsenic-mediated reduction of global levels of H4K16 acetylation, a mark of gene activation, has been demonstrated in cell models . Further, arsenic exposure has been shown to modify H3K4, H3K9, and H3K27 histone methylation patterns in both malignant and non-malignant lung cell lines, leading to a decrease in the expression of genes associated with histone acetylation and DNA methylation changes [80, 90]. Arsenic has also been reported to alter the chromatin landscape of arsenic-induced cancer cells through loss of the repressive histone modifications H3 triMe-K27 and H3 diMe-K9 and an increase in the levels of activating Ac-H3 and diMe-K4 at the WNT5A locus - resulting in the ectopic expression of WNT family genes .
Arsenic induces epithelial-to-mesenchymal transition and other biological effects through changes in micro-RNA expression
A study using human bronchial epithelial cells (HBEC) demonstrated that chronic arsenic exposure of P53-knock down cells induced malignant transformation accompanied by epithelial-to-mesenchymal transition (EMT) . A reduction in expression of a miR-200 family member was correlated with this exposure, and was shown to occur through increased promoter methylation. Re-establishment of miR-200b expression alone was capable of entirely reversing and preventing arsenic-induced EMT and malignant transformation .
Arsenic exposure can alter miRNA expression levels in vitro and in vivo in other cell types and tissues. For example, in a study using chick embryos, arsenic decreaseD expression of miR-9, -181b, -124, and -125b. Decrease of miR-9 and miR-181b resulted in expression of their common target Nrp1, leading to cell migration, tube formation and angiogenesis . Arsenite induced overexpression of several miRNAs, including miR-222, in human peripheral blood-derived cells from individuals with insufficient dietary folate. Overexpression of miR-222 was reversed by the restoration of normal folate levels .
Arsenic targets key pathways associated with lung cancer
Arsenic stimulates the EGFR signaling pathway
Alteration in the EGFR pathway can result from mutation and/or amplification events at the epidermal growth factor receptor (EGFR) locus. The consequence of either genetic event is a structural alteration that destabilizes the auto-inhibitory loop of EGFR, forcing the receptor into a constitutive and ligand-independent active state .
Arsenic and the PI3K/AKT signaling pathway
Signaling through the PI3K/AKT pathway starts with the activation of receptor tyrosine kinases (RTK’s) through binding to an extracellular growth factor. Binding of the extracellular ligand to its receptor leads to the dimerization and activation of the RTK . The consequence of RTK activation, is the successive recruitment and activation of PI3K, AKT, and hundreds of target proteins that drive increased cell growth, metabolism, survival, and proliferation .
Although acute activation of this pathway is thought to be mediated by arsenic-induced ROS, the specific role of arsenic on PI3K/AKT signalling during chronic exposure remains to be clearly demonstrated .
Arsenic and the Nrf2-KEAP1 signaling pathway
The transcription factor nuclear factor erythroid-derived factor 2–related factor 2 (NRF2) plays a key role in the activation of oxidative stress response. NRF2 contains a leucine-zipper DNA binding domain capable of binding to both antioxidant response elements (ARE’s) and electrophile response elements (ERE’s). Under normal conditions, NRF2 is actively sequestered by KEAP1 and targeted for proteolytic degradation ; however, under conditions of oxidative or chemical stress, NRF2 dissociates from KEAP1 and migrates to the nucleus to initiate a stress-related response. The KEAP1 E3-ubiquitin ligase complex is frequently affected by genetic disruption and aberrant expression in non-small cell lung cancer, resulting in NF-κB activation, is characteristic of lung tumorigenesis .
Conclusion and future directions
Lung cancer is the leading cause of cancer-related deaths in North America, affecting over 200,000 men and women each year . Arsenic poisoning through contaminated drinking water leading to arsenic-induced lung cancer is a major public health concern; consequently, the mechanisms underlying the carcinogenic effects of arsenic in lung cancer has become an important avenue of research.
Undoubtedly, the biotransformation of AsV into AsIII and its methylated conjugates plays a crucial role in arsenic carcinogenicity at both genetic and epigenetic levels. Genetic changes are acquired mainly through the induction of ROS during the biotransformation process, while the competition for methyl groups between AsV detoxification enzymes and DMT’s contribute to epigenetic abnormalities.
Arsenic species directly modulate several oncogenic pathways - most notably the EGFR, PI3K/AKT and the NRF2/KEAP1 pathways - and these specific pathways possess actionable targets for therapy in lung cancer. A greater understanding of the molecular mechanisms governing arsenic-related lung tumorigenesis may therefore yield promising translatable findings. Deep characterization of arsenic-related tumors and/or cell models at both the genetic and epigenetic levels, and the comparison of arsenic-related and unrelated SqCC tumors may provide such insights. On the other hand, mechanisms associated with anti-tumoral effects of As2O3 in the treatment of APL (not discussed in this review) should also be considered in order to increase the understanding of the molecular effects of arsenic in the human body.
In conclusion, arsenic can induce specific alterations affecting pathways that drive malignant transformation in lung cells. Current evidence suggests that arsenic-induced lung tumors represent a unique class of lung cancer, based on histology and underlying molecular characteristics. Further characterization of the mechanisms by which arsenic affects its targets will certainly give support to preventing and/or reducing the effects of arsenic toxicity, especially among those populations chronically exposed to arsenic.
Epidermal Growth Factor
Human Bronchial Epithelial Cells
NFE2-Related Factor 2
Reactive Oxygen Species
Receptor Tyrosine Kinase
Small Cell Carcinomas
Squamous Cell Carcinomas.
This work was supported by grants from the Canadian Institutes for Health Research (CIHR), NIH/NCI 1R01CA164783-01 and Department of Defence (CDMRP W81XWH-10-1-0634). D.D.B.S. and K.S.S.E. are supported by scholarships from the University of British Columbia and CIHR.
- IARC: Some drinking-water disinfectants and contaminants, including arsenic. Monographs on chloramine, chloral and chloral hydrate, dichloroacetic acid, trichloroacetic acid and 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone. IARC Monogr Eval Carcinog Risks Hum. 2004, 84: 269-477. 10.1186/1476-4598-12-20
- Smedley PL, Kinniburgh DG: A review of the source, behaviour and distribution of arsenic in natural waters. Appl Geochem. 2002, 17: 517-568. 10.1016/S0883-2927(02)00018-5
- Smith AH, Lingas EO, Mahfuzar R: Contamination of drinking-water by arsenic in bangladesh: a public health emergency. Bull World Health Organ. 2000, 78: 1093-1103.PubMed CentralPubMed
- Putila JJ, Guo NL: Association of arsenic exposure with lung cancer incidence rates in the united states. PLoS One. 2011, 6: e25886- 10.1371/journal.pone.0025886PubMed CentralPubMed
- U. S. Environmental Protection Agency: National primary drinking water regulations; arsenic and clarifications to compliance and New source contaminants monitoring; final rule. Book national primary drinking water regulations; arsenic and clarifications to compliance and New source contaminants monitoring; final rule vol. 66. 2001, 6975-
- Kumar A, Adak P, Gurian PL, Lockwood JR: Arsenic exposure in US public and domestic drinking water supplies: a comparative risk assessment. J Expo Sci Environ Epidemiol. 2010, 20: 245-254. 10.1038/jes.2009.24PubMed
- Nieder AM, MacKinnon JA, Fleming LE, Kearney G, Hu JJ, Sherman RL, Huang Y, Lee DJ: Bladder cancer clusters in florida: identifying populations at risk. J Urol. 2009, 182: 46-50. discussion 51, 10.1016/j.juro.2009.02.149PubMed
- Iland HJ, Seymour JF: Role of arsenic trioxide in acute promyelocytic leukemia. Curr Treat Options Oncol. 2013, [Epub ahead of print]
- Mi J: Current treatment strategy of acute promyelocytic leukemia. Frontiers of medicine. 2011, 5: 341-347. 10.1007/s11684-011-0169-zPubMed
- McGuigan CF, Hamula CLA, Huang S, Gabos S, Le XC: A review on arsenic concentrations in canadian drinking water. Environmental Reviews. 2010, 18: 291-307. 10.1139/A10-012. 10.1139/A10-012
- Ryker SJ: Mapping arsenic in groundwater. Geotimes. 2001, 46: 34-36.
- Nordstrom DK: Public health. Worldwide occurrences of arsenic in ground water. Science. 2002, 296: 2143-2145. 10.1126/science.1072375PubMed
- Smith AH, Hopenhayn-Rich C, Bates MN, Goeden HM, Hertz-Picciotto I, Duggan HM, Wood R, Kosnett MJ, Smith MT: Cancer risks from arsenic in drinking water. Environ Health Perspect. 1992, 97: 259-267.PubMed CentralPubMed
- Mead MN: Arsenic: in search of an antidote to a global poison. Environ Health Perspect. 2005, 113: A378-386. 10.1289/ehp.113-a378PubMed CentralPubMed
- Guo HR, Wang NS, Hu H, Monson RR: Cell type specificity of lung cancer associated with arsenic ingestion. Cancer epidemiology, biomarkers & prevention: a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2004, 13: 638-643.
- Barrett JC, Lamb PW, Wiseman RW: Multiple mechanisms for the carcinogenic effects of asbestos and other mineral fibers. Environ Health Perspect. 1989, 81: 81-89.PubMed CentralPubMed
- Ebert F, Weiss A, Bultemeyer M, Hamann I, Hartwig A, Schwerdtle T: Arsenicals affect base excision repair by several mechanisms. Mutat Res. 2011, 715: 32-41. 10.1016/j.mrfmmm.2011.07.004PubMed
- Pomroy C, Charbonneau SM, McCullough RS, Tam GK: Human retention studies with 74As. Toxicol Appl Pharmacol. 1980, 53: 550-556. 10.1016/0041-008X(80)90368-3PubMed
- Wang Y, Fang J, Leonard SS, Rao KM: Cadmium inhibits the electron transfer chain and induces reactive oxygen species. Free Radic Biol Med. 2004, 36: 1434-1443. 10.1016/j.freeradbiomed.2004.03.010PubMed
- Dilda PJ, Hogg PJ: Arsenical-based cancer drugs. Cancer Treat Rev. 2007, 33: 542-564. 10.1016/j.ctrv.2007.05.001PubMed
- Nemeti B, Regonesi ME, Tortora P, Gregus Z: Polynucleotide phosphorylase and mitochondrial ATP synthase mediate reduction of arsenate to the more toxic arsenite by forming arsenylated analogues of ADP and ATP. Toxicological sciences: an official journal of the Society of Toxicology. 2010, 117: 270-281. 10.1093/toxsci/kfq141. 10.1093/toxsci/kfq141
- Kala SV, Neely MW, Kala G, Prater CI, Atwood DW, Rice JS, Lieberman MW: The MRP2/cMOAT transporter and arsenic-glutathione complex formation are required for biliary excretion of arsenic. J Biol Chem. 2000, 275: 33404-33408. 10.1074/jbc.M007030200PubMed
- Cullen WR, Reimer KJ: Arsenic speciation in the environment. Chem Rev. 1989, 89: 713-10.1021/cr00094a002
- Styblo M, Drobna Z, Jaspers I, Lin S, Thomas DJ: The role of biomethyl-ation in toxicity and carcinogenicity of arsenic: a research update. Environ Health Persp. 2002, 110: 767-10.1289/ehp.02110s5767. 10.1289/ehp.02110s5767
- Thomas DJ, Styblo M, Lin S: The cellular metabolism and systemic toxicity of arsenic. Toxicol Appl Pharmacol. 2001, 176: 127-144. 10.1006/taap.2001.9258PubMed
- Klein CB, Leszczynska J, Hickey C, Rossman TG: Further evidence against a direct genotoxic mode of action for arsenic-induced cancer. Toxicol Appl Pharmacol. 2007, 222: 289-297. 10.1016/j.taap.2006.12.033PubMed CentralPubMed
- Kligerman AD, Doerr CL, Tennant AH, Harrington-Brock K, Allen JW, Winkfield E, Poorman-Allen P, Kundu B, Funasaka K, Roop BC: Methylated trivalent arsenicals as candidate ultimate genotoxic forms of arsenic: induction of chromosomal mutations but not gene mutations. Environ Mol Mutagen. 2003, 42: 192-205. 10.1002/em.10192PubMed
- Rossman TG, Klein CB: Genetic and epigenetic effects of environmental arsenicals. Metallomics: integrated biometal science. 2011, 3: 1135-1141. 10.1039/c1mt00074h. 10.1039/c1mt00074h
- Rossman TG, Uddin AN, Burns FJ: Evidence that arsenite acts as a cocarcinogen in skin cancer. Toxicol Appl Pharmacol. 2004, 198: 394-404. 10.1016/j.taap.2003.10.016PubMed
- Hartwig A, Groblinghoff UD, Beyersmann D, Natarajan AT, Filon R, Mullenders LH: Interaction of arsenic(III) with nucleotide excision repair in UV-irradiated human fibroblasts. Carcinogenesis. 1997, 18: 399-405. 10.1093/carcin/18.2.399PubMed
- Jha AN, Noditi M, Nilsson R, Natarajan AT: Genotoxic effects of sodium arsenite on human cells. Mutat Res. 1992, 284: 215-221. 10.1016/0027-5107(92)90005-MPubMed
- Wiencke JK, Yager JW: Specificity of arsenite in potentiating cytogenetic damage induced by the DNA crosslinking agent diepoxybutane. Environ Mol Mutagen. 1992, 19: 195-200. 10.1002/em.2850190303PubMed
- Li JH, Rossman TG: Mechanism of comutagenesis of sodium arsenite with n-methyl-n-nitrosourea. Biol Trace Elem Res. 1989, 21: 373-381. 10.1007/BF02917278PubMed
- Lee TC, Huang RY, Jan KY: Sodium arsenite enhances the cytotoxicity, clastogenicity, and 6-thioguanine-resistant mutagenicity of ultraviolet light in chinese hamster ovary cells. Mutat Res. 1985, 148: 83-89. 10.1016/0027-5107(85)90210-6PubMed
- Flora SJ: Arsenic-induced oxidative stress and its reversibility. Free Radic Biol Med. 2011, 51: 257-281. 10.1016/j.freeradbiomed.2011.04.008PubMed
- Rossman TG: Mechanism of arsenic carcinogenesis: an integrated approach. Mutat Res. 2003, 533: 37-65. 10.1016/j.mrfmmm.2003.07.009PubMed
- Naranmandura H, Xu S, Sawata T, Hao WH, Liu H, Bu N, Ogra Y, Lou YJ, Suzuki N: Mitochondria are the main target organelle for trivalent monomethylarsonous acid (MMA(III))-induced cytotoxicity. Chem Res Toxicol. 2011, 24: 1094-1103. 10.1021/tx200156kPubMed
- Turrens JF: Superoxide production by the mitochondrial respiratory chain. Biosci Rep. 1997, 17: 3-8. 10.1023/A:1027374931887PubMed
- Kitchin KT, Wallace K: Evidence against the nuclear in situ binding of arsenicals–oxidative stress theory of arsenic carcinogenesis. Toxicol Appl Pharmacol. 2008, 232: 252-257. 10.1016/j.taap.2008.06.021PubMed
- Halliwell B: Oxidative stress and cancer: have we moved forward?. Biochem J. 2007, 401: 1-11.PubMed
- Martinez VD, Vucic EA, Becker-Santos DD, Gil L, Lam WL: Arsenic exposure and the induction of human cancers. J Toxicol. 2011, 2011: 431287-PubMed CentralPubMed
- Gurr J-R, Yih L-H, Samikkannu T, Bau D-T, Lin S-Y, Jan K-Y: Nitric oxide production by arsenite. Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis. 2003, 533: 173-182. 10.1016/j.mrfmmm.2003.08.024PubMed
- Wink DA, Kasprzak KS, Maragos CM, Elespuru RK, Misra M, Dunams TM, Cebula TA, Koch WH, Andrews AW, Allen JS: DNA deaminating ability and genotoxicity of nitric oxide and its progenitors. Science. 1991, 254: 1001-1003. 10.1126/science.1948068PubMed
- Radi R, Beckman JS, Bush KM, Freeman BA: Peroxynitrite oxidation of sulfhydryls. The cytotoxic potential of superoxide and nitric oxide. The Journal of biological chemistry. 1991, 266: 4244-4250.PubMed
- Leaf CD, Wishnok JS, Tannenbaum SR: Endogenous incorporation of nitric oxide from L-arginine into N-nitrosomorpholine stimulated by escherichia coli lipopolysaccharide in the rat. Carcinogenesis. 1991, 12: 537-539. 10.1093/carcin/12.3.537PubMed
- Tsuda M, Kurashima Y: Tobacco smoking, chewing, and snuff dipping: factors contributing to the endogenous formation of N-nitroso compounds. Crit Rev Toxicol. 1991, 21: 243-253. 10.3109/10408449109017912PubMed
- Beckman JS, Beckman TW, Chen J, Marshall PA, Freeman BA: Apparent hydroxyl radical production by peroxynitrite: implications for endothelial injury from nitric oxide and superoxide. Proc Natl Acad Sci USA. 1990, 87: 1620-1624. 10.1073/pnas.87.4.1620PubMed CentralPubMed
- Andrew AS, Karagas MR, Hamilton JW: Decreased DNA repair gene expression among individuals exposed to arsenic in united states drinking water. Int J Cancer. 2003, 104: 263-268. 10.1002/ijc.10968PubMed
- Andrew AS, Burgess JL, Meza MM, Demidenko E, Waugh MG, Hamilton JW, Karagas MR: Arsenic exposure is associated with decreased DNA repair in vitro and in individuals exposed to drinking water arsenic. Environ Health Perspect. 2006, 114: 1193-1198. 10.1289/ehp.9008PubMed CentralPubMed
- Nollen M, Ebert F, Moser J, Mullenders LH, Hartwig A, Schwerdtle T: Impact of arsenic on nucleotide excision repair: XPC function, protein level, and gene expression. Mol Nutr Food Res. 2009, 53: 572-582. 10.1002/mnfr.200800480PubMed
- Walter I, Schwerdtle T, Thuy C, Parsons JL, Dianov GL, Hartwig A: Impact of arsenite and its methylated metabolites on PARP-1 activity, PARP-1 gene expression and poly(ADP-ribosyl)ation in cultured human cells. DNA Repair. 2007, 6: 61-70. 10.1016/j.dnarep.2006.08.008PubMed
- Osmond MJ, Kunz BA, Snow ET: Age and exposure to arsenic alter base excision repair transcript levels in mice. Mutagenesis. 2010, 25: 517-522. 10.1093/mutage/geq037PubMed
- Wen G, Calaf GM, Partridge MA, Echiburu-Chau C, Zhao Y, Huang S, Chai Y, Li B, Hu B, Hei TK: Neoplastic transformation of human small airway epithelial cells induced by arsenic. Mol Med. 2008, 14: 2-10.PubMed CentralPubMed
- Zhao Y, Toselli P, Li W: Microtubules as a critical target for arsenic toxicity in lung cells in vitro and in vivo. Int J Environ Res Public Health. 2012, 9: 474-495. 10.3390/ijerph9020474PubMed CentralPubMed
- Sciandrello G, Caradonna F, Mauro M, Barbata G: Arsenic-induced DNA hypomethylation affects chromosomal instability in mammalian cells. Carcinogenesis. 2004, 25: 413-417.PubMed
- Sciandrello G, Barbaro R, Caradonna F, Barbata G: Early induction of genetic instability and apoptosis by arsenic in cultured chinese hamster cells. Mutagenesis. 2002, 17: 99-103. 10.1093/mutage/17.2.99PubMed
- Vega L, Gonsebatt ME, Ostrosky-Wegman P: Aneugenic effect of sodium arsenite on human lymphocytes in vitro: an individual susceptibility effect detected. Mutat Res. 1995, 334: 365-373. 10.1016/0165-1161(95)90074-8PubMed
- Vogt BL, Rossman TG: Effects of arsenite on p53, p21 and cyclin D expression in normal human fibroblasts — a possible mechanism for arsenite’s comutagenicity. Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis. 2001, 478: 159-168. 10.1016/S0027-5107(01)00137-3. 10.1016/S0027-5107(01)00137-3PubMed
- Tang F, Liu G, He Z, Ma WY, Bode AM, Dong Z: Arsenite inhibits p53 phosphorylation, DNA binding activity, and p53 target gene p21 expression in mouse epidermal JB6 cells. Mol Carcinog. 2006, 45: 861-870. 10.1002/mc.20245PubMed
- Huang Y, Zhang J, McHenry KT, Kim MM, Zeng W, Lopez-Pajares V, Dibble CC, Mizgerd JP, Yuan ZM: Induction of cytoplasmic accumulation of p53: a mechanism for low levels of arsenic exposure to predispose cells for malignant transformation. Cancer Res. 2008, 68: 9131-9136. 10.1158/0008-5472.CAN-08-3025PubMed CentralPubMed
- Komissarova EV, Rossman TG: Arsenite induced poly(ADP-ribosyl)ation of tumor suppressor P53 in human skin keratinocytes as a possible mechanism for carcinogenesis associated with arsenic exposure. Toxicol Appl Pharmacol. 2010, 243: 399-404. 10.1016/j.taap.2009.12.014PubMed CentralPubMed
- Qin XJ, Liu W, Li YN, Sun X, Hai CX, Hudson LG, Liu KJ: Poly(ADP-ribose) polymerase-1 inhibition by arsenite promotes the survival of cells with unrepaired DNA lesions induced by UV exposure. Toxicological sciences: an official journal of the Society of Toxicology. 2012, 127: 120-129. 10.1093/toxsci/kfs099
- Martinez VD, Buys TP, Adonis M, Benitez H, Gallegos I, Lam S, Lam WL, Gil L: Arsenic-related DNA copy-number alterations in lung squamous cell carcinomas. Br J Cancer. 2010, 103: 1277-1283. 10.1038/sj.bjc.6605879PubMed CentralPubMed
- Tonon G, Wong KK, Maulik G, Brennan C, Feng B, Zhang Y, Khatry DB, Protopopov A, You MJ, Aguirre AJ: High-resolution genomic profiles of human lung cancer. Proc Natl Acad Sci USA. 2005, 102: 9625-9630. 10.1073/pnas.0504126102PubMed CentralPubMed
- Venkatesan RN, Treuting PM, Fuller ED, Goldsby RE, Norwood TH, Gooley TA, Ladiges WC, Preston BD, Loeb LA: Mutation at the polymerase active site of mouse DNA polymerase delta increases genomic instability and accelerates tumorigenesis. Mol Cell Biol. 2007, 27: 7669-7682. 10.1128/MCB.00002-07PubMed CentralPubMed
- Parsons JL, Preston BD, O'Connor TR, Dianov GL: DNA polymerase delta-dependent repair of DNA single strand breaks containing 3'-end proximal lesions. Nucleic Acids Res. 2007, 35: 1054-1063. 10.1093/nar/gkl1115PubMed CentralPubMed
- Goldsby RE, Hays LE, Chen X, Olmsted EA, Slayton WB, Spangrude GJ, Preston BD: High incidence of epithelial cancers in mice deficient for DNA polymerase delta proofreading. Proc Natl Acad Sci USA. 2002, 99: 15560-15565. 10.1073/pnas.232340999PubMed CentralPubMed
- Simeonova PP, Luster MI: Mechanisms of arsenic carcinogenicity: genetic or epigenetic mechanisms?. J Environ Pathol Toxicol Oncol. 2000, 19: 281-286.PubMed
- Mazumder DN: Effect of chronic intake of arsenic-contaminated water on liver. Toxicol Appl Pharmacol. 2005, 206: 169-175. 10.1016/j.taap.2004.08.025PubMed
- Tseng CH, Chong CK, Chen CJ, Tai TY: Dose–response relationship between peripheral vascular disease and ingested inorganic arsenic among residents in blackfoot disease endemic villages in taiwan. Atherosclerosis. 1996, 120: 125-133. 10.1016/0021-9150(95)05693-9PubMed
- Engel RR, Hopenhayn-Rich C, Receveur O, Smith AH: Vascular effects of chronic arsenic exposure: a review. Epidemiol Rev. 1994, 16: 184-209.PubMed
- Intarasunanont P, Navasumrit P, Woraprasit S, Chaisatra K, Suk WA, Mahidol C, Ruchirawat M: Effects of arsenic exposure on DNA methylation in cord blood samples from newborn babies and in a human lymphoblast cell line. Environmental health: a global access science source. 2012, 11: 31-
- Jensen TJ, Wozniak RJ, Eblin KE, Wnek SM, Gandolfi AJ, Futscher BW: Epigenetic mediated transcriptional activation of WNT5A participates in arsenical-associated malignant transformation. Toxicol Appl Pharmacol. 2009, 235: 39-46. 10.1016/j.taap.2008.10.013PubMed CentralPubMed
- Reichard JF, Puga A: Effects of arsenic exposure on DNA methylation and epigenetic gene regulation. Epigenomics. 2010, 2: 87-104. 10.2217/epi.09.45PubMed CentralPubMed
- Cui X, Wakai T, Shirai Y, Hatakeyama K, Hirano S: Chronic oral exposure to inorganic arsenate interferes with methylation status of p16INK4a and RASSF1A and induces lung cancer in a/J mice. Toxicological sciences: an official journal of the Society of Toxicology. 2006, 91: 372-381. 10.1093/toxsci/kfj159. 10.1093/toxsci/kfj159
- Marsit CJ, Eddy K, Kelsey KT: MicroRNA responses to cellular stress. Cancer Res. 2006, 66: 10843-10848. 10.1158/0008-5472.CAN-06-1894PubMed
- Zhao CQ, Young MR, Diwan BA, Coogan TP, Waalkes MP: Association of arsenic-induced malignant transformation with DNA hypomethylation and aberrant gene expression. Proc Natl Acad Sci USA. 1997, 94: 10907-10912. 10.1073/pnas.94.20.10907PubMed CentralPubMed
- Mass MJ, Wang L: Arsenic alters cytosine methylation patterns of the promoter of the tumor suppressor gene p53 in human lung cells: a model for a mechanism of carcinogenesis. Mutat Res. 1997, 386: 263-277. 10.1016/S1383-5742(97)00008-2PubMed
- Chiang PK, Gordon RK, Tal J, Zeng GC, Doctor BP, Pardhasaradhi K, McCann PP: S-adenosylmethionine and methylation. FASEB journal: official publication of the Federation of American Societies for Experimental Biology. 1996, 10: 471-480.
- Jensen TJ, Novak P, Eblin KE, Gandolfi AJ, Futscher BW: Epigenetic remodeling during arsenical-induced malignant transformation. Carcinogenesis. 2008, 29: 1500-1508. 10.1093/carcin/bgn102PubMed CentralPubMed
- Ren X, McHale CM, Skibola CF, Smith AH, Smith MT, Zhang L: An emerging role for epigenetic dysregulation in arsenic toxicity and carcinogenesis. Environ Health Perspect. 2011, 119: 11-19.PubMed CentralPubMed
- Salnikow K, Zhitkovich A: Genetic and epigenetic mechanisms in metal carcinogenesis and cocarcinogenesis: nickel, arsenic, and chromium. Chem Res Toxicol. 2008, 21: 28-44. 10.1021/tx700198aPubMed CentralPubMed
- Loenen WA: S-adenosylmethionine: jack of all trades and master of everything?. Biochem Soc Trans. 2006, 34: 330-333.PubMed
- Chen WT, Hung WC, Kang WY, Huang YC, Chai CY: Urothelial carcinomas arising in arsenic-contaminated areas are associated with hypermethylation of the gene promoter of the death-associated protein kinase. Histopathology. 2007, 51: 785-792. 10.1111/j.1365-2559.2007.02871.xPubMed
- Chai CY, Huang YC, Hung WC, Kang WY, Chen WT: Arsenic salts induced autophagic cell death and hypermethylation of DAPK promoter in SV-40 immortalized human uroepithelial cells. Toxicol Lett. 2007, 173: 48-56. 10.1016/j.toxlet.2007.06.006PubMed
- Vogt BL, Rossman TG: Effects of arsenite on p53, p21 and cyclin D expression in normal human fibroblasts – a possible mechanism for arsenite’s comutagenicity. Mutat Res. 2001, 478: 159-168. 10.1016/S0027-5107(01)00137-3PubMed
- Ziech D, Franco R, Pappa A, Panayiotidis MI: Reactive oxygen species (ROS)–induced genetic and epigenetic alterations in human carcinogenesis. Mutat Res. 2011, 711: 167-173. 10.1016/j.mrfmmm.2011.02.015PubMed
- Chanda S, Dasgupta UB, Guhamazumder D, Gupta M, Chaudhuri U, Lahiri S, Das S, Ghosh N, Chatterjee D: DNA hypermethylation of promoter of gene p53 and p16 in arsenic-exposed people with and without malignancy. Toxicological sciences: an official journal of the Society of Toxicology. 2006, 89: 431-437. 10.1093/toxsci/kfj030. 10.1093/toxsci/kfj030
- Jo WJ, Ren X, Chu F, Aleshin M, Wintz H, Burlingame A, Smith MT, Vulpe CD, Zhang L: Acetylated H4K16 by MYST1 protects UROtsa cells from arsenic toxicity and is decreased following chronic arsenic exposure. Toxicol Appl Pharmacol. 2009, 241: 294-302. 10.1016/j.taap.2009.08.027PubMed CentralPubMed
- Zhou X, Sun H, Ellen TP, Chen H, Costa M: Arsenite alters global histone H3 methylation. Carcinogenesis. 2008, 29: 1831-1836. 10.1093/carcin/bgn063PubMed CentralPubMed
- Wang Z, Zhao Y, Smith E, Goodall GJ, Drew PA, Brabletz T, Yang C: Reversal and prevention of arsenic-induced human bronchial epithelial cell malignant transformation by microRNA-200b. Toxicological sciences: an official journal of the Society of Toxicology. 2011, 121: 110-122. 10.1093/toxsci/kfr029
- Cui Y, Han Z, Hu Y, Song G, Hao C, Xia H, Ma X: MicroRNA-181b and microRNA-9 mediate arsenic-induced angiogenesis via NRP1. J Cell Physiol. 2012, 227: 772-783. 10.1002/jcp.22789PubMed
- Yarden Y, Sliwkowski MX: Untangling the ErbB signalling network. Nat Rev Mol Cell Biol. 2001, 2: 127-137. 10.1038/35052073PubMed
- Andrew AS, Mason RA, Memoli V, Duell EJ: Arsenic activates EGFR pathway signaling in the lung. Toxicological sciences: an official journal of the Society of Toxicology. 2009, 109: 350-357. 10.1093/toxsci/kfp015
- Sung TI, Wang YJ, Chen CY, Hung TL, Guo HR: Increased serum level of epidermal growth factor receptor in liver cancer patients and its association with exposure to arsenic. Sci Total Environ. 2012, 424: 74-78.PubMed
- Biscardi JS, Maa MC, Tice DA, Cox ME, Leu TH, Parsons SJ: c-Src-mediated phosphorylation of the epidermal growth factor receptor on Tyr845 and Tyr1101 is associated with modulation of receptor function. J Biol Chem. 1999, 274: 8335-8343. 10.1074/jbc.274.12.8335PubMed
- Tice DA, Biscardi JS, Nickles AL, Parsons SJ: Mechanism of biological synergy between cellular Src and epidermal growth factor receptor. Proc Natl Acad Sci USA. 1999, 96: 1415-1420. 10.1073/pnas.96.4.1415PubMed CentralPubMed
- Simeonova PP, Luster MI: Arsenic carcinogenicity: relevance of c-Src activation. Mol Cell Biochem. 2002, 234–235: 277-282.PubMed
- Li G, Lee LS, Li M, Tsao SW, Chiu JF: Molecular changes during arsenic-induced cell transformation. J Cell Physiol. 2011, 226: 3225-3232. 10.1002/jcp.22683PubMed
- Liu LZ, Jiang Y, Carpenter RL, Jing Y, Peiper SC, Jiang BH: Role and mechanism of arsenic in regulating angiogenesis. PLoS One. 2011, 6: e20858- 10.1371/journal.pone.0020858PubMed CentralPubMed
- Cheng HY, Li P, David M, Smithgall TE, Feng L, Lieberman MW: Arsenic inhibition of the JAK-STAT pathway. Oncogene. 2004, 23: 3603-3612. 10.1038/sj.onc.1207466PubMed
- Liu J, Chen B, Lu Y, Guan Y, Chen F: JNK-dependent Stat3 phosphorylation contributes to Akt activation in response to arsenic exposure. Toxicological sciences: an official journal of the Society of Toxicology. 2012, 129: 363-371. 10.1093/toxsci/kfs199
- Herbert KJ, Snow ET: Modulation of arsenic-induced epidermal growth factor receptor pathway signalling by resveratrol. Chem Biol Interact. 2012, 198: 38-48. 10.1016/j.cbi.2012.05.004PubMed
- Verma A, Mohindru M, Deb DK, Sassano A, Kambhampati S, Ravandi F, Minucci S, Kalvakolanu DV, Platanias LC: Activation of Rac1 and the p38 mitogen-activated protein kinase pathway in response to arsenic trioxide. J Biol Chem. 2002, 277: 44988-44995. 10.1074/jbc.M207176200PubMed
- Cheng L, Alexander RE, Maclennan GT, Cummings OW, Montironi R, Lopez-Beltran A, Cramer HM, Davidson DD, Zhang S: Molecular pathology of lung cancer: key to personalized medicine. Modern pathology: an official journal of the United States and Canadian Academy of Pathology, Inc. 2012, 25: 347-369. 10.1038/modpathol.2011.215
- Papadimitrakopoulou V: Development of PI3K/AKT/mTOR pathway inhibitors and their application in personalized therapy for non-small-cell lung cancer. Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer. 2012, 7: 1315-1326. 10.1097/JTO.0b013e31825493eb
- Stueckle TA, Lu Y, Davis ME, Wang L, Jiang BH, Holaskova I, Schafer R, Barnett JB, Rojanasakul Y: Chronic occupational exposure to arsenic induces carcinogenic gene signaling networks and neoplastic transformation in human lung epithelial cells. Toxicol Appl Pharmacol. 2012, 261: 204-216. 10.1016/j.taap.2012.04.003PubMed CentralPubMed
- Gao N, Shen L, Zhang Z, Leonard SS, He H, Zhang XG, Shi X, Jiang BH: Arsenite induces HIF-1alpha and VEGF through PI3K, Akt and reactive oxygen species in DU145 human prostate carcinoma cells. Mol Cell Biochem. 2004, 255: 33-45.PubMed
- Dong Z: The molecular mechanisms of arsenic-induced cell transformation and apoptosis. Environ Health Perspect. 2002, 110 Suppl 5: 757-759.PubMed
- Chen B, Liu J, Chang Q, Beezhold K, Lu Y, Chen F: JNK and STAT3 signaling pathways converge on Akt-mediated phosphorylation of EZH2 in bronchial epithelial cells induced by arsenic. Cell Cycle. 2012, 12:
- Beezhold K, Liu J, Kan H, Meighan T, Castranova V, Shi X, Chen F: miR-190-mediated downregulation of PHLPP contributes to arsenic-induced Akt activation and carcinogenesis. Toxicological sciences: an official journal of the Society of Toxicology. 2011, 123: 411-420. 10.1093/toxsci/kfr188. 10.1093/toxsci/kfr188
- Wang Z, Yang J, Fisher T, Xiao H, Jiang Y, Yang C: Akt activation is responsible for enhanced migratory and invasive behavior of arsenic-transformed human bronchial epithelial cells. Environ Health Perspect. 2012, 120: 92-97.PubMed CentralPubMed
- Zhang Y, Bhatia D, Xia H, Castranova V, Shi X, Chen F: Nucleolin links to arsenic-induced stabilization of GADD45alpha mRNA. Nucleic Acids Res. 2006, 34: 485-495. 10.1093/nar/gkj459PubMed CentralPubMed
- Tokar EJ, Diwan BA, Waalkes MP: Arsenic exposure transforms human epithelial stem/progenitor cells into a cancer stem-like phenotype. Environ Health Perspect. 2010, 118: 108-115.PubMed CentralPubMed
- Ling M, Li Y, Xu Y, Pang Y, Shen L, Jiang R, Zhao Y, Yang X, Zhang J, Zhou J: Regulation of miRNA-21 by reactive oxygen species-activated ERK/NF-kappaB in arsenite-induced cell transformation. Free Radic Biol Med. 2012, 52: 1508-1518. 10.1016/j.freeradbiomed.2012.02.020PubMed
- Zhang DD: Mechanistic studies of the Nrf2-Keap1 signaling pathway. Drug Metab Rev. 2006, 38: 769-789. 10.1080/03602530600971974PubMed
- Thu KL, Pikor LA, Chari R, Wilson IM, Macaulay CE, English JC, Tsao MS, Gazdar AF, Lam S, Lam WL, Lockwood WW: Genetic disruption of KEAP1/CUL3 E3 ubiquitin ligase complex components is a key mechanism of NF-kappaB pathway activation in lung cancer. Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer. 2011, 6: 1521-1529. 10.1097/JTO.0b013e3182289479
- Wang XJ, Sun Z, Chen W, Eblin KE, Gandolfi JA, Zhang DD: Nrf2 Protects human bladder urothelial cells from arsenite and monomethylarsonous acid toxicity. Toxicol Appl Pharmacol. 2007, 225: 206-213. 10.1016/j.taap.2007.07.016PubMed CentralPubMed
- Zheng Y, Tao S, Lian F, Chau BT, Chen J, Sun G, Fang D, Lantz RC, Zhang DD: Sulforaphane prevents pulmonary damage in response to inhaled arsenic by activating the Nrf2-defense response. Toxicol Appl Pharmacol. 2012, 265: 292-299. 10.1016/j.taap.2012.08.028PubMed CentralPubMed
- Andujar P, Wang J, Descatha A, Galateau-Salle F, Abd-Alsamad I, Billon-Galland MA, Blons H, Clin B, Danel C, Housset B: p16INK4A Inactivation mechanisms in non-small-cell lung cancer patients occupationally exposed to asbestos. Lung Cancer. 2010, 67: 23-30. 10.1016/j.lungcan.2009.03.018PubMed
- Wang XJ, Sun Z, Chen W, Li Y, Villeneuve NF, Zhang DD: Activation of Nrf2 by arsenite and monomethylarsonous acid is independent of Keap1-C151: enhanced Keap1-Cul3 interaction. Toxicol Appl Pharmacol. 2008, 230: 383-389. 10.1016/j.taap.2008.03.003PubMed CentralPubMed
- American Cancer Society: Cancer facts & figures 2012. Book cancer facts & figures 2012. 2012, Atlanta: American Cancer Society
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.