Abstract
Arsenic has been a recognized contaminant and toxicant, as well as a medicinal compound throughout human history. Populations throughout the world are exposed to arsenic and these exposures have been associated with a number of human cancers. Not much is known about the role of arsenic as a human carcinogen and more recently its role in non-cancerous diseases, such as cardiovascular disease, hypertension and diabetes mellitus have been uncovered. The health effects associated with arsenic are numerous and the association between arsenic exposure and human disease has intensified the search for molecular mechanisms that describe the biological activity of arsenic in humans and leads to the aforementioned disease states. Arsenic poses a human health risk due in part to the regulation of cellular signal transduction pathways and over the last few decades, some cellular mechanisms that account for arsenic toxicity, as well as, signal transduction pathways have been discovered. However, given the ubiquitous nature of arsenic in the environment, making sense of all the data remains a challenge. This review will focus on our knowledge of signal transduction pathways that are regulated by arsenic.
Similar content being viewed by others
References
Achanzar WE, Brambila EM, Diwan BA, Webber MM, Waalkes MP (2002) Inorganic arsenite-induced malignant transformation of human prostate epithelial cells. J Natl Cancer Inst 94:1888–1891
Alessi DR, James SR, Downes CP, Holmes AB, Gaffney PR, Reese CB, Cohen P (1997) Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Balpha. Curr Biol 7:261–269
Benbrahim-Tallaa L, Waterland RA, Styblo M, Achanzar WE, Webber MM, Waalkes MP (2005) Molecular events associated with arsenic-induced malignant transformation of human prostatic epithelial cells: aberrant genomic DNA methylation and K-Ras oncogene activation. Toxicol Appl Pharmacol 206:288–298
Benbrahim-Tallaa L, Webber MM, Waalkes MP (2007) Mechanisms of acquired androgen independence during arsenic-induced malignant transformation of human prostate epithelial cells. Environ Health Perspect 115:243–247
Bennett RL, Malamy MH (1970) Arsenate resistant mutants of Escherichia coli and phosphate transport. Biochem Biophys Res Commun 40:496–503
Berg P, Lindelof B (1997) Differences in malignant melanoma between children and adolescents. A 35-year epidemiological study. Arch Dermatol 133:295–297
Bird A (2002) DNA methylation patterns and epigenetic memory. Genes Dev 16:6–21
Bredfeldt TG, Jagadish B, Eblin KE, Mash EA, Gandolfi AJ (2006) Monomethylarsonous acid induces transformation of human bladder cells. Toxicol Appl Pharmacol 216:69–79
Bun-ya M, Shikata K, Nakade S, Yompakdee C, Harashima S, Oshima Y (1996) Two new genes, PHO86 and PHO87, involved in inorganic phosphate uptake in Saccharomyces cerevisiae. Curr Genet 29:344–351
Carbrey JM, Song L, Zhou Y, Yoshinaga M, Rojek A, Wang Y, Liu Y, Lujan HL, DiCarlo SE, Nielsen S, Rosen BP, Agre P, Mukhopadhyay R (2009) Reduced arsenic clearance and increased toxicity in aquaglyceroporin-9-null mice. Proc Natl Acad Sci USA 106:15956–15960
Carter DE, Aposhian HV, Gandolfi AJ (2003) The metabolism of inorganic arsenic oxides, gallium arsenide, and arsine: a toxicochemical review. Toxicol Appl Pharmacol 193:309–334
Chappell WR, Abernathy CO, Calderon RL (1999) Arsenic exposure and health effects. In: Proceedings of the 3rd international conference on arsenic exposure and health effects, San Diego, CA. Chapman & Hall, Amsterdam, New York, 12–15 July 1998
Chattopadhyay S, Bhaumik S, Purkayastha M, Basu S, Nag Chaudhuri A, Das Gupta S (2002) Apoptosis and necrosis in developing brain cells due to arsenic toxicity and protection with antioxidants. Toxicol Lett 136:65–76
Chaudhuri AN, Basu S, Chattopadhyay S, Das Gupta S (1999) Effect of high arsenic content in drinking water on rat brain. Indian J Biochem Biophys 36:51–54
Chen CJ, Kuo TL, Wu MM (1988) Arsenic and cancers. Lancet 1:414–415
Chen GQ, Shi XG, Tang W, Xiong SM, Zhu J, Cai X, Han ZG, Ni JH, Shi GY, Jia PM, Liu MM, He KL, Niu C, Ma J, Zhang P, Zhang TD, Paul P, Naoe T, Kitamura K, Miller W, Waxman S, Wang ZY, de The H, Chen SJ, Chen Z (1997) Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia (APL): I. As2O3 exerts dose-dependent dual effects on APL cells. Blood 89:3345–3353
Chen YC, Lin-Shiau SY, Lin JK (1998) Involvement of reactive oxygen species and caspase 3 activation in arsenite-induced apoptosis. J Cell Physiol 177:324–333
Chen PH, Lan CC, Chiou MH, Hsieh MC, Chen GS (2005) Effects of arsenic and UVB on normal human cultured keratinocytes: impact on apoptosis and implication on photocarcinogenesis. Chem Res Toxicol 18:139–144
Chowdhury R, Chowdhury S, Roychoudhury P, Mandal C, Chaudhuri K (2009) Arsenic induced apoptosis in malignant melanoma cells is enhanced by menadione through ROS generation, p38 signaling and p53 activation. Apoptosis 14:108–123
de Boer IH, Rue TC, Kestenbaum B (2009) Serum phosphorus concentrations in the third National Health and Nutrition Examination Survey (NHANES III). Am J Kidney Dis 53:399–407
de la Fuente H, Portales-Perez D, Baranda L, Diaz-Barriga F, Saavedra-Alanis V, Layseca E, Gonzalez-Amaro R (2002) Effect of arsenic, cadmium and lead on the induction of apoptosis of normal human mononuclear cells. Clin Exp Immunol 129:69–77
Delnomdedieu M, Basti MM, Otvos JD, Thomas DJ (1993) Transfer of arsenite from glutathione to dithiols: a model of interaction. Chem Res Toxicol 6:598–602
Drobna Z, Jaspers I, Thomas DJ, Styblo M (2003) Differential activation of AP-1 in human bladder epithelial cells by inorganic and methylated arsenicals. Faseb J 17:67–69
Eblin KE, Bredfeldt TG, Buffington S, Gandolfi AJ (2007) Mitogenic signal transduction caused by monomethylarsonous acid in human bladder cells: role in arsenic-induced carcinogenesis. Toxicol Sci 95:321–330
Eblin KE, Hau AM, Jensen TJ, Futscher BW, Gandolfi AJ (2008) The role of reactive oxygen species in arsenite and monomethylarsonous acid-induced signal transduction in human bladder cells: acute studies. Toxicology 250:47–54
Felix K, Manna SK, Wise K, Barr J, Ramesh GT (2005) Low levels of arsenite activates nuclear factor-kappaB and activator protein-1 in immortalized mesencephalic cells. J Biochem Mol Toxicol 19:67–77
Gamble MV, Liu X, Ahsan H, Pilsner R, Ilievski V, Slavkovich V, Parvez F, Levy D, Factor-Litvak P, Graziano JH (2005) Folate, homocysteine, and arsenic metabolism in arsenic-exposed individuals in Bangladesh. Environ Health Perspect 113:1683–1688
Gomez-Rubio P, Meza-Montenegro MM, Cantu-Soto E Klimecki WT (2009) Genetic association between intronic variants in AS3MT and arsenic methylation efficiency is focused on a large linkage disequilibrium cluster in chromosome 10. J Appl Toxicol
Gurr JR, Liu F, Lynn S, Jan KY (1998) Calcium-dependent nitric oxide production is involved in arsenite-induced micronuclei. Mutat Res 416:137–148
Hays AM, Lantz RC, Rodgers LS, Sollome JJ, Vaillancourt RR, Andrew AS, Hamilton JW, Camenisch TD (2008) Arsenic-induced decreases in the vascular matrix. Toxicol Pathol 36:805–817
He XQ, Chen R, Yang P, Li AP, Zhou JW, Liu QZ (2007) Biphasic effect of arsenite on cell proliferation and apoptosis is associated with the activation of JNK and ERK1/2 in human embryo lung fibroblast cells. Toxicol Appl Pharmacol 220:18–24
Huang Y, Zhang J, McHenry KT, Kim MM, Zeng W, Lopez-Pajares V, Dibble CC, Mizgerd JP, Yuan ZM (2008) Induction of cytoplasmic accumulation of p53: a mechanism for low levels of arsenic exposure to predispose cells for malignant transformation. Cancer Res 68:9131–9136
Hughes MF (2009) Arsenic methylation, oxidative stress and cancer—is there a link? J Natl Cancer Inst 101:1660–1661
Ivanov VN, Hei TK (2005) Combined treatment with EGFR inhibitors and arsenite upregulated apoptosis in human EGFR-positive melanomas: a role of suppression of the PI3K-AKT pathway. Oncogene 24:616–626
Jensen TJ, Novak P, Wnek SM, Gandolfi AJ, Futscher BW (2009) Arsenicals produce stable progressive changes in DNA methylation patterns that are linked to malignant transformation of immortalized urothelial cells. Toxicol Appl Pharmacol 241:221–229
Jiang XH, Wong BC, Yuen ST, Jiang SH, Cho CH, Lai KC, Lin MC, Kung HF, Lam SK (2001) Arsenic trioxide induces apoptosis in human gastric cancer cells through up-regulation of p53 and activation of caspase-3. Int J Cancer 91:173–179
Jones PL, Veenstra GJ, Wade PA, Vermaak D, Kass SU, Landsberger N, Strouboulis J, Wolffe AP (1998) Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription. Nat Genet 19:187–191
Kapahi P, Takahashi T, Natoli G, Adams SR, Chen Y, Tsien RY, Karin M (2000) Inhibition of NF-kappa B activation by arsenite through reaction with a critical cysteine in the activation loop of Ikappa B kinase. J Biol Chem 275:36062–36066
Kitchin KT, Wallace K (2008) The role of protein binding of trivalent arsenicals in arsenic carcinogenesis and toxicity. J Inorg Biochem 102:532–539
Kohn AD, Summers SA, Birnbaum MJ, Roth RA (1996) Expression of a constitutively active Akt Ser/Thr kinase in 3T3–L1 adipocytes stimulates glucose uptake and glucose transporter 4 translocation. J Biol Chem 271:31372–31378
Kozul CD, Ely KH, Enelow RI, Hamilton JW (2009) Low-dose arsenic compromises the immune response to influenza A infection in vivo. Environ Health Perspect 117:1441–1447
Lantz RC, Chau B, Sarihan P, Witten ML, Pivniouk VI, Chen GJ (2009) In utero and postnatal exposure to arsenic alters pulmonary structure and function. Toxicol Appl Pharmacol 235:105–113
Laplante M, Sabatini DM (2009) mTOR signaling at a glance. J Cell Sci 122:3589–3594
Le XC, Lu X, Ma M, Cullen WR, Aposhian HV, Zheng B (2000) Speciation of key arsenic metabolic intermediates in human urine. Anal Chem 72:5172–5177
Leonard SS, Harris GK, Shi X (2004) Metal-induced oxidative stress and signal transduction. Free Radic Biol Med 37:1921–1942
Lewis DR, Southwick JW, Ouellet-Hellstrom R, Rench J, Calderon RL (1999) Drinking water arsenic in Utah: a cohort mortality study. Environ Health Perspect 107:359–365
Li S, Chen Y, Rosen BP (2001) Role of vicinal cysteine pairs in metalloid sensing by the ArsD As(III)-responsive repressor. Mol Microbiol 41:687–696
Liu Y, Guyton KZ, Gorospe M, Xu Q, Lee JC, Holbrook NJ (1996) Differential activation of ERK, JNK/SAPK and P38/CSBP/RK map kinase family members during the cellular response to arsenite. Free Radic Biol Med 21:771–781
Liu Z, Shen J, Carbrey JM, Mukhopadhyay R, Agre P, Rosen BP (2002) Arsenite transport by mammalian aquaglyceroporins AQP7 and AQP9. Proc Natl Acad Sci USA 99:6053–6058
Luster MI, Simeonova PP (2004) Arsenic and urinary bladder cell proliferation. Toxicol Appl Pharmacol 198:419–423
Mann KK, Colombo M, Miller WH Jr (2008) Arsenic trioxide decreases AKT protein in a caspase-dependent manner. Mol Cancer Ther 7:1680–1687
Mure K, Uddin AN, Lopez LC, Styblo M, Rossman TG (2003) Arsenite induces delayed mutagenesis and transformation in human osteosarcoma cells at extremely low concentrations. Environ Mol Mutagen 41:322–331
Nan X, Ng HH, Johnson CA, Laherty CD, Turner BM, Eisenman RN, Bird A (1998) Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex. Nature 393:386–389
Navas-Acien A, Silbergeld EK, Pastor-Barriuso R, Guallar E (2008) Arsenic exposure and prevalence of type 2 diabetes in US adults. JAMA 300:814–822
Navas-Acien A, Silbergeld EK, Pastor-Barriuso R Guallar E (2009) Rejoinder: arsenic exposure and prevalence of type 2 diabetes: updated findings from the National Health Nutrition and Examination Survey, 2003–2006. Epidemiology 20:816–820 (discussion e1–e2)
Ooi SK, Bestor TH (2008) The colorful history of active DNA demethylation. Cell 133:1145–1148
Paul DS, Harmon AW, Devesa V, Thomas DJ, Styblo M (2007) Molecular mechanisms of the diabetogenic effects of arsenic: inhibition of insulin signaling by arsenite and methylarsonous acid. Environ Health Perspect 115:734–742
Petrick JS, Ayala-Fierro F, Cullen WR, Carter DE, Vasken Aposhian H (2000) Monomethylarsonous acid (MMA(III)) is more toxic than arsenite in Chang human hepatocytes. Toxicol Appl Pharmacol 163:203–207
Pi J, He Y, Bortner C, Huang J, Liu J, Zhou T, Qu W, North SL, Kasprzak KS, Diwan BA, Chignell CF, Waalkes MP (2005) Low level, long-term inorganic arsenite exposure causes generalized resistance to apoptosis in cultured human keratinocytes: potential role in skin co-carcinogenesis. Int J Cancer 116:20–26
Pi J, Bai Y, Zhang Q, Wong V, Floering LM, Daniel K, Reece JM, Deeney JT, Andersen ME, Corkey BE, Collins S (2007) Reactive oxygen species as a signal in glucose-stimulated insulin secretion. Diabetes 56:1783–1791
Pysher MD, Sollome JJ, Regan S, Cardinal TR, Hoying JB, Brooks HL, Vaillancourt RR (2007) Increased hexokinase II expression in the renal glomerulus of mice in response to arsenic. Toxicol Appl Pharmacol 224:39–48
Qian Y, Castranova V, Shi X (2003) New perspectives in arsenic-induced cell signal transduction. J Inorg Biochem 96:271–278
Qu W, Bortner CD, Sakurai T, Hobson MJ, Waalkes MP (2002) Acquisition of apoptotic resistance in arsenic-induced malignant transformation: role of the JNK signal transduction pathway. Carcinogenesis 23:151–159
Roboz GJ, Dias S, Lam G, Lane WJ, Soignet SL, Warrell RP Jr, Rafii S (2000) Arsenic trioxide induces dose- and time-dependent apoptosis of endothelium and may exert an antileukemic effect via inhibition of angiogenesis. Blood 96:1525–1530
Rossman TG, Uddin AN, Burns FJ, Bosland MC (2001) Arsenite is a cocarcinogen with solar ultraviolet radiation for mouse skin: an animal model for arsenic carcinogenesis. Toxicol Appl Pharmacol 176:64–71
Sarbassov DD, Guertin DA, Ali SM, Sabatini DM (2005) Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307:1098–1101
Scheid MP, Marignani PA, Woodgett JR (2002) Multiple phosphoinositide 3-kinase-dependent steps in activation of protein kinase B. Mol Cell Biol 22:6247–6260
Shi W, Dong J, Scott RA, Ksenzenko MY, Rosen BP (1996) The role of arsenic-thiol interactions in metalloregulation of the ars operon. J Biol Chem 271:9291–9297
Shi H, Shi X, Liu KJ (2004) Oxidative mechanism of arsenic toxicity and carcinogenesis. Mol Cell Biochem 255:67–78
Simeonova PP, Wang S, Hulderman T, Luster MI (2002) c-Src-dependent activation of the epidermal growth factor receptor and mitogen-activated protein kinase pathway by arsenic role in carcinogenesis. J Biol Chem 277:2945–2950
Smith AH, Goycolea M, Haque R, Biggs ML (1998) Marked increase in bladder and lung cancer mortality in a region of Northern Chile due to arsenic in drinking water. Am J Epidemiol 147:660–669
Srivastava S, Vladykovskaya EN, Haberzettl P, Sithu SD, D’Souza SE, States JC (2009) Arsenic exacerbates atherosclerotic lesion formation and inflammation in ApoE−/− mice. Toxicol Appl Pharmacol 241:90–100
Steinmaus C, Yuan Y, Liaw J, Smith AH (2009) Low-level population exposure to inorganic arsenic in the United States and diabetes mellitus: a reanalysis. Epidemiology 20:807–815
Straub AC, Clark KA, Ross MA, Chandra AG, Li S, Gao X, Pagano PJ, Stolz DB, Barchowsky A (2008) Arsenic-stimulated liver sinusoidal capillarization in mice requires NADPH oxidase-generated superoxide. J Clin Invest 118:3980–3989
Straub AC, Klei LR, Stolz DB, Barchowsky A (2009) Arsenic requires sphingosine-1-phosphate type 1 receptors to induce angiogenic genes and endothelial cell remodeling. Am J Pathol 174:1949–1958
Styblo M, Del Razo LM, Vega L, Germolec DR, LeCluyse EL, Hamilton GA, Reed W, Wang C, Cullen WR, Thomas DJ (2000) Comparative toxicity of trivalent and pentavalent inorganic and methylated arsenicals in rat and human cells. Arch Toxicol 74:289–299
Sun H, Ma L, Hu XC, Zhang TD (1992) Ai-Lin I treated 32 cases of acute promyelocytic leukemia. Chin J Integrat Chinese Western Med 12:170–172
Sun D, Xu D, Zhang B (2006) Rac signaling in tumorigenesis and as target for anticancer drug development. Drug Resist Updat 9:274–287
Suzuki S, Arnold LL, Pennington KL, Kakiuchi-Kiyota S, Cohen SM (2009) Effects of co-administration of dietary sodium arsenite and an NADPH oxidase inhibitor on the rat bladder epithelium. Toxicology 261:41–46
Thomas DJ, Styblo M, Lin S (2001) The cellular metabolism and systemic toxicity of arsenic. Toxicol Appl Pharmacol 176:127–144
Thomas DJ, Li J, Waters SB, Xing W, Adair BM, Drobna Z, Devesa V, Styblo M (2007) Arsenic (+3 oxidation state) methyltransferase and the methylation of arsenicals. Exp Biol Med (Maywood) 232:3–13
Ueda Y, Richmond A (2006) NF-kappaB activation in melanoma. Pigment Cell Res 19:112–124
Waalkes MP, Liu J, Ward JM, Diwan BA (2004) Animal models for arsenic carcinogenesis: inorganic arsenic is a transplacental carcinogen in mice. Toxicol Appl Pharmacol 198:377–384
Wang XJ, Sun Z, Chen W, Li Y, Villeneuve NF, Zhang DD (2008) Activation of Nrf2 by arsenite and monomethylarsonous acid is independent of Keap1–C151: enhanced Keap1-Cul3 interaction. Toxicol Appl Pharmacol 230:383–389
Yang P, He XQ, Peng L, Li AP, Wang XR, Zhou JW, Liu QZ (2007) The role of oxidative stress in hormesis induced by sodium arsenite in human embryo lung fibroblast (HELF) cellular proliferation model. J Toxicol Environ Health A 70:976–983
Yu Z, Kone BC (2004) Hypermethylation of the inducible nitric-oxide synthase gene promoter inhibits its transcription. J Biol Chem 279:46954–46961
Zhao CQ, Young MR, Diwan BA, Coogan TP, Waalkes MP (1997) Association of arsenic-induced malignant transformation with DNA hypomethylation and aberrant gene expression. Proc Natl Acad Sci USA 94:10907–10912
Zhu J, Chen Z, Lallemand-Breitenbach V, de The H (2002) How acute promyelocytic leukaemia revived arsenic. Nat Rev Cancer 2:705–713
Acknowledgments
The research herein was made possible by the NIEHS Superfund Basic Research Program (ES 04940) and the Southwest Environmental Health Sciences Center (ES 06694).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Druwe, I.L., Vaillancourt, R.R. Influence of arsenate and arsenite on signal transduction pathways: an update. Arch Toxicol 84, 585–596 (2010). https://doi.org/10.1007/s00204-010-0554-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00204-010-0554-4