Abstract
Cigarette smoking is associated with a plethora of different diseases. Nicotine is the addictive component of cigarette but also acts onto cells of the non-neuronal system, including immune effector cells. Although nicotine itself is usually not referred to as a carcinogen, there is ongoing debate whether nicotine functions as a ‘tumor enhancer.' By binding to nicotinic acetylcholine receptors, nicotine deregulates essential biological processes like angiogenesis, apoptosis, and cell-mediated immunity. Apoptosis plays critical roles in a wide variety of physiologic processes during fetal development and in adult tissue and is also a fundamental aspect of the biology of malignant diseases. This review provides an overlook how nicotine influences apoptotic processes and is thus directly involved in the etiology of pathological conditions like cancer and obstructive diseases.
Similar content being viewed by others
References
Sasco AJ, Secretan MB, Straif K (2004) Tobacco smoking and cancer: a brief review of recent epidemiological evidence. Lung Cancer 45(Suppl 2):S3–9
Hecht SS (2002) Cigarette smoking and lung cancer: chemical mechanisms and approaches to prevention. Lancet Oncol 3:461–469
Gallowitsch-Puerta M, Tracey KJ (2005) Immunologic role of the cholinergic anti-inflammatory pathway and the nicotinic acetylcholine alpha 7 receptor. Ann NY Acad Sci 1062:209–219
Kawashima K, Fujii T (2003) The lymphocytic cholinergic system and its contribution to the regulation of immune activity. Life Sci 74:675–696
Benowitz N, Porchet H, Jacob P (1990) Pharmacokinetics, metabolism and pharmacodynamics of nicotine. In: Wonnacott S, Russell M, Stolerman I (eds) Nicotine psychopharmacology. Oxford University Press, Oxford, pp. 112–157
Russell MA, Jarvis M, Iyer R, Feyerabend C (1980) Relation of nicotine yield of cigarettes to blood nicotine concentrations in smokers. Br Med J 280:972–976
Suzuki J, Bayna E, Dalle Molle E, Lew WY (2003) Nicotine inhibits cardiac apoptosis induced by lipopolysaccharide in rats. J Am Coll Cardiol 41:482–488
Wang H, Liao H, Ochani M, Justiniani M, Lin X, Yang L, Al-Abed Y, Wang H, Metz C, Miller EJ, Tracey KJ, Ulloa L (2004) Cholinergic agonists inhibit HMGB1 release and improve survival in experimental sepsis. Nat Med 10:1216–1221
Wielgus JJ, Corbin Downey L, Ewald KW, Hatley ME, Wilson KC, Yeilding RH (2004) Exposure to low concentrations of nicotine during cranial nerve development inhibits apoptosis and causes cellular hypertrophy in the ventral oculomotor nuclei of the chick embryo. Brain Res 1000:123–133
Bordel R, Laschke MW, Menger MD, Vollmar B (2006) Nicotine does not affect vascularization but inhibits growth of freely transplanted ovarian follicles by inducing granulosa cell apoptosis. Hum Reprod 21:610–617
Demiralay R, Gursan N, Erdem H (2006) The effects of erdosteine, N-acetylcysteine, and vitamin E on nicotine-induced apoptosis of pulmonary cells. Toxicology 219:197–207
Machaalani R, Waters KA, Tinworth KD (2005) Effects of postnatal nicotine exposure on apoptotic markers in the developing piglet brain. Neuroscience 132:325–333
Mechawar N, Saghatelyan A, Grailhe R, Scoriels L, Gheusi G, Gabellec MM, Lledo PM, Changeux JP (2004) Nicotinic receptors regulate the survival of newborn neurons in the adult olfactory bulb. Proc Natl Acad Sci USA 101:9822–9826
Holloway AC, Lim GE, Petrik JJ, Foster WG, Morrison KM, Gerstein HC (2005) Fetal and neonatal exposure to nicotine in Wistar rats results in increased beta cell apoptosis at birth and postnatal endocrine and metabolic changes associated with type 2 diabetes. Diabetologia 48:2661–2666
Jang MH, Shin MC, Jung SB, Lee TH, Bahn GH, Kwon YK, Kim EH, Kim CJ (2002) Alcohol and nicotine reduce cell proliferation and enhance apoptosis in dentate gyrus. Neuroreport 13:1509–1513
Matsubayashi H, Inoue A, Amano T, Seki T, Nakata Y, Sasa M, Sakai N (2004) Involvement of alpha7- and alpha4beta2-type postsynaptic nicotinic acetylcholine receptors in nicotine-induced excitation of dopaminergic neurons in the substantia nigra: a patch clamp and single-cell PCR study using acutely dissociated nigral neurons. Brain Res Mol Brain Res 129:1–7
Wang H, Yu M, Ochani M, Amella CA, Tanovic M, Susarla S, Li JH, Wang H, Yang H, Ulloa L, Al-Abed Y, Czura CJ, Tracey KJ (2003) Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation. Nature 421:384–388
Heeschen C, Weis M, Aicher A, Dimmeler S, Cooke JP (2002) A novel angiogenic pathway mediated by non-neuronal nicotinic acetylcholine receptors. J Clin Invest 110:527–536
Heeschen C, Jang JJ, Weis M, Pathak A, Kaji S, Hu RS, Tsao PS, Johnson FL, Cooke JP (2001) Nicotine stimulates angiogenesis and promotes tumor growth and atherosclerosis. Nat Med 7:833–839
Utsumi T, Shimoke K, Kishi S, Sasaya H, Ikeuchi T, Nakayama H (2004) Protective effect of nicotine on tunicamycin-induced apoptosis of PC12h cells. Neurosci Lett 370:244–247
West KA, Brognard J, Clark AS, Linnoila IR, Yang X, Swain SM, Harris C, Belinsky S, Dennis PA (2003) Rapid Akt activation by nicotine and a tobacco carcinogen modulates the phenotype of normal human airway epithelial cells. J. Clin. Invest 111:81–90
Tohgi H, Utsugisawa K, Nagane Y (2000) Protective effect of nicotine through nicotinic acetylcholine receptor alpha 7 on hypoxia-induced membrane disintegration and DNA fragmentation of cultured PC12 cells. Neurosci Lett 285:91–94
Hejmadi MV, Dajas-Bailador F, Barns SM, Jones B, Wonnacott S (2003) Neuroprotection by nicotine against hypoxia-induced apoptosis in cortical cultures involves activation of multiple nicotinic acetylcholine receptor subtypes. Mol Cell Neurosci 24:779–786
Utsugisawa K, Nagane Y, Obara D, Tohgi H (2002) Overexpression of alpha7 nicotinic acetylcholine receptor prevents G1-arrest and DNA fragmentation in PC12 cells after hypoxia. J Neurochem 81:497–505
Copeland RLJ, Leggett YA, Kanaan YM, Taylor RE, Tizabi Y (2005) Neuroprotective effects of nicotine against salsolinol-induced cytotoxicity: implications for Parkinson’s disease. Neurotox Res 8:289–293
Shaw S, Bencherif M, Marrero MB (2002) Janus kinase 2, an early target of alpha 7 nicotinic acetylcholine receptor-mediated neuroprotection against Abeta-(1–42) amyloid. J. Biol. Chem. 277:44920–44924
Shaw S, Bencherif M, Marrero MB (2003) Angiotensin II blocks nicotine-mediated neuroprotection against beta-amyloid (1–42) via activation of the tyrosine phosphatase SHP-1. J Neurosci 23:11224–11228
Liu Q, Zhao B (2004) Nicotine attenuates beta-amyloid peptide-induced neurotoxicity, free radical and calcium accumulation in hippocampal neuronal cultures. Br J Pharmacol 141:746–754
Sun X, Liu Y, Hu G, Wang H (2004) Protective effects of nicotine against glutamate-induced neurotoxicity in PC12 cells. Cell Mol Biol Lett 9:409–422
Pugh PC, Margiotta JF (2000) Nicotinic acetylcholine receptor agonists promote survival and reduce apoptosis of chick ciliary ganglion neurons. Mol Cell Neurosci 15:113–122
Tizabi Y, Manaye KF, Taylor RE (2005) Nicotine blocks ethanol-induced apoptosis in primary cultures of rat cerebral cortical and cerebellar granule cells. Neurotox Res 7:319–322
Garrido R, Malecki A, Hennig B, Toborek M (2000) Nicotine attenuates arachidonic acid-induced neurotoxicity in cultured spinal cord neurons. Brain Res 861:59–68
Garrido R, Mattson MP, Hennig B, Toborek M (2001) Nicotine protects against arachidonic-acid-induced caspase activation, cytochrome c release and apoptosis of cultured spinal cord neurons. J Neurochem 76:1395–1403
Fucile S, Renzi M, Lauro C, Limatola C, Ciotti T, Eusebi F (2004) Nicotinic cholinergic stimulation promotes survival and reduces motility of cultured rat cerebellar granule cells. Neuroscience 127:53–61
Garrido R, Springer JE, Hennig B, Toborek M (2003) Nicotine attenuates arachidonic acid-induced apoptosis of spinal cord neurons by preventing depletion of neurotrophic factors. J Neurotrauma 20:1201–1213
Garrido R, King-Pospisil K, Son KW, Hennig B, Toborek M (2003) Nicotine upregulates nerve growth factor expression and prevents apoptosis of cultured spinal cord neurons. Neurosci. Res. 47:349–355
Wright SC, Zhong J, Zheng H, Larrick JW (1993) Nicotine inhibition of apoptosis suggests a role in tumor promotion. FASEB J 7:1045–1051
Jin Z, Gao F, Flagg T, Deng X (2004) Nicotine induces multi-site phosphorylation of Bad in association with suppression of apoptosis. J Biol Chem 279:23837–23844
Mai H, May WS, Gao F, Jin Z, Deng X (2003) A functional role for nicotine in Bcl2 phosphorylation and suppression of apoptosis. J Biol Chem 278:1886–1891
Heusch WL, Maneckjee R (1998) Signalling pathways involved in nicotine regulation of apoptosis of human lung cancer cells. Carcinogenesis 19:551–556
Dutu T, Michiels S, Fouret P, Penault-Llorca F, Validire P, Benhamou S, Taranchon E, Morat L, Grunenwald D, Le Chevalier T, Sabatier L, Soria JC (2005) Differential expression of biomarkers in lung adenocarcinoma: a comparative study between smokers and never-smokers. Ann Oncol 16:1906–1914
Tsurutani J, Castillo SS, Brognard J, Granville CA, Zhang C, Gills JJ, Sayyah J, Dennis PA (2005) Tobacco components stimulate Akt-dependent proliferation and NFkappaB-dependent survival in lung cancer cells. Carcinogenesis 26:1182–1195
Xin M, Deng X (2005) Nicotine inactivation of the proapoptotic function of Bax through phosphorylation. J Biol Chem 280:10781–10789
Xin M, Deng X (2006) Protein phosphatase 2A enhances Bax’s proapoptotic function through dephosphorylation. J Biol Chem 281:18859–18867
Onoda N, Nehmi A, Weiner D, Mujumdar S, Christen R, Los G (2001) Nicotine affects the signaling of the death pathway, reducing the response of head and neck cancer cell lines to DNA damaging agents. Head Neck 23:860–870
Dasgupta P, Kinkade R, Joshi B, Decook C, Haura E, Chellappan S (2006) Nicotine inhibits apoptosis induced by chemotherapeutic drugs by up-regulating XIAP and survivin. Proc Natl Acad Sci USA 103:6332–6337
Maneckjee R, Minna JD (1994) Opioids induce while nicotine suppresses apoptosis in human lung cancer cells. Cell Growth Differ 5:1033–1040
Zhang T, Lu H, Shang X, Tian Y, Zheng C, Wang S, Cheng H, Zhou R (2006) Nicotine prevents the apoptosis induced by menadione in human lung cancer cells. Biochem Biophys Res Commun 342:928–934
Argentin G, Cicchetti R (2006) Evidence for the role of nitric oxide in antiapoptotic and genotoxic effect of nicotine on human gingival fibroblasts. Apoptosis 11:1887–1897
Argentin G, Cicchetti R (2004) Genotoxic and antiapoptotic effect of nicotine on human gingival fibroblasts. Toxicol Sci 79:75–81
Aoshiba K, Nagai A, Yasui S, Konno K (1996) Nicotine prolongs neutrophil survival by suppressing apoptosis. J Lab Clin Med 127:186–194
Sugano N, Minegishi T, Kawamoto K, Ito K (2001) Nicotine inhibits UV-induced activation of the apoptotic pathway. Toxicol Lett 125:61–65
De Rosa MJ, Esandi Mdel C, Garelli A, Rayes D, Bouzat C (2005) Relationship between alpha 7 nAChR and apoptosis in human lymphocytes. J Neuroimmunol 160:154–161
Hakki A, Pennypacker K, Eidizadeh S, Friedman H, Pross S (2001) Nicotine inhibition of apoptosis in murine immune cells. Exp Biol Med (Maywood) 226:947–953
Hakki A, Friedman H, Pross S (2002) Nicotine modulation of apoptosis in human coronary artery endothelial cells. Int Immunopharmacol 2:1403–1409
Berger F, Gage FH, Vijayaraghavan S (1998) Nicotinic receptor-induced apoptotic cell death of hippocampal progenitor cells. J Neurosci 18:6871–6881
Roy TS, Andrews JE, Seidler FJ, Slotkin TA (1998) Nicotine evokes cell death in embryonic rat brain during neurulation. J Pharmacol Exp Ther 287:1136–1144
Zhao Z, Reece EA (2005) Nicotine-induced embryonic malformations mediated by apoptosis from increasing intracellular calcium and oxidative stress. Birth Defects Res B Dev Reprod Toxicol 74:383–391
Yamamura M, Amano Y, Sakagami H, Yamanaka Y, Nishimoto Y, Yoshida H, Yamaguchi M, Ohata H, Momose K, Takeda M (1998) Calcium mobilization during nicotine-induced cell death in human glioma and glioblastoma cell lines. Anticancer Res 18:2499–2502
Kim KH, Joo KJ, Park HJ, Kwon CH, Jang MH, Kim CJ (2005) Nicotine induces apoptosis in TM3 mouse Leydig cells. Fertil Steril 83(Suppl 1):1093–1099
Arredondo J, Nguyen VT, Chernyavsky AI, Bercovich D, Orr-Urtreger A, Kummer W, Lips K, Vetter DE, Grando SA (2002) Central role of alpha7 nicotinic receptor in differentiation of the stratified squamous epithelium. J Cell Biol 159:325–336
Arredondo J, Hall LL, Ndoye A, Nguyen VT, Chernyavsky AI, Bercovich D, Orr-Urtreger A, Beaudet AL, Grando SA (2003) Central role of fibroblast alpha3 nicotinic acetylcholine receptor in mediating cutaneous effects of nicotine. Lab Invest 83:207–225
Arredondo J, Chernyavsky AI, Marubio LM, Beaudet AL, Jolkovsky DL, Pinkerton KE, Grando SA (2005) Receptor-mediated tobacco toxicity: regulation of gene expression through alpha3beta2 nicotinic receptor in oral epithelial cells. Am J Pathol 166:597–613
Villablanca AC (1998) Nicotine stimulates DNA synthesis and proliferation in vascular endothelial cells in vitro. J Appl Physiol 84:2089–2098
Crowley-Weber CL, Dvorakova K, Crowley C, Bernstein H, Bernstein C, Garewal H, Payne CM (2003) Nicotine increases oxidative stress, activates NF-kappaB and GRP78, induces apoptosis and sensitizes cells to genotoxic/xenobiotic stresses by a multiple stress inducer, deoxycholate: relevance to colon carcinogenesis. Chem Biol Interact 145:53–66
Wu YP, Kita K, Suzuki N (2002) Involvement of human heat shock protein 90 alpha in nicotine-induced apoptosis. Int J Cancer 100:37–42
Isogai E, Ishijima S, Sonoda T, Kita K, Suzuki H, Hasegawa R, Yamamori H, Takakubo Y, Suzuki N (1998) Protease activation following UV irradiation is linked to hypomutability in human cells selected for resistance to combination of UV and antipain. Mutat Res 403:215–222
Ramage L, Jones AC, Whelan CJ (2006) Induction of apoptosis with tobacco smoke and related products in A549 lung epithelial cells in vitro. J Inflamm (Lond) 3:3
Yang YM, Liu GT (2004) Damaging effect of cigarette smoke extract on primary cultured human umbilical vein endothelial cells and its mechanism. Biomed Environ Sci 17:121–134
Galitovsky V, Chowdhury P, Zharov VP (2004) Photothermal detection of nicotine-induced apoptotic effects in pancreatic cancer cells. Life Sci 75:2677–2687
Zharov VP, Galitovsky V, Chowdhury P (2005) Nanocluster model of photothermal assay: application for high-sensitive monitoring of nicotine-induced changes in metabolism, apoptosis, and necrosis at a cellular level. J Biomed Opt 10:44011
Lee HJ, Guo HY, Lee SK, Jeon BH, Jun CD, Lee SK, Park MH, Kim EC (2005) Effects of nicotine on proliferation, cell cycle, and differentiation in immortalized and malignant oral keratinocytes. J Oral Pathol Med 34:436–443
Gimonet D, Grailhe R, Coninx P, Antonicelli F, Haye B, Liautaud-Roger F (2003) Functional role of nicotinic acetylcholine receptors in apoptosis in HL-60 cell line. Eur J Pharmacol 482:25–29
Yoshida H, Sakagami H, Yamanaka Y, Amano Y, Yamaguchi M, Yamamura M, Fukuchi K, Gomi K, Ohata H, Momose K, Takeda M (1998) Induction of DNA fragmentation by nicotine in human myelogenous leukemic cell lines. Anticancer Res 18:2507–2511
Mariggio MA, Guida L, Laforgia A, Santacroce R, Curci E, Montemurro P, Fumarulo R (2001) Nicotine effects on polymorphonuclear cell apoptosis and lipopolysaccharide-induced monocyte functions. A possible role in periodontal disease? J Periodontal Res 36:32–39
Zhang S, Day IN, Ye S (2001) Microarray analysis of nicotine-induced changes in gene expression in endothelial cells. Physiol Genomics 5:187–192
Hu D, Cao K, Peterson-Wakeman R, Wang R (2002) Altered profile of gene expression in rat hearts induced by chronic nicotine consumption. Biochem Biophys Res Commun 297:729–736
Dunckley T, Lukas RJ (2003) Nicotine modulates the expression of a diverse set of genes in the neuronal SH-SY5Y cell line. J Biol Chem 278:15633–15640
Wuenschell C, Kunimi M, Castillo C, Marjoram P (2004) Nicotine-responsive genes in cultured embryonic mouse lung buds: interaction of nicotine and superoxide dismutase. Pharmacol Res 50:341–350
Konu O, Xu X, Ma JZ, Kane J, Wang J, Shi SJ, Li MD (2004) Application of a customized pathway-focused microarray for gene expression profiling of cellular homeostasis upon exposure to nicotine in PC12 cells. Brain Res Mol Brain Res 121:102–113
Belluardo N, Olsson PA, Mudo’ G, Sommer WH, Amato G, Fuxe K (2005) Transcription factor gene expression profiling after acute intermittent nicotine treatment in the rat cerebral cortex. Neuroscience 133:787–796
Ghiani CA, Lelievre V, Beltran-Parrazal L, Sforza DM, Malvar J, Smith DJ, Charles AC, Ferchmin PA, Vellis J (2006) Gene expression is differentially regulated by neurotransmitters in embryonic neuronal cortical culture. J Neurochem 97(Suppl 1):35–43
Lee CG, Cho SJ, Kang MJ, Chapoval SP, Lee PJ, Noble PW, Yehualaeshet T, Lu B, Flavell RA, Milbrandt J, Homer RJ, Elias JA (2004) Early growth response gene 1-mediated apoptosis is essential for transforming growth factor beta1-induced pulmonary fibrosis. J Exp Med 200:377–389
Nonaka D, Fabbri A, Roz L, Mariani L, Vecchione A, Moore GW, Tavecchio L, Croce CM, Sozzi G (2005) Reduced FEZ1/LZTS1 expression and outcome prediction in lung cancer. Cancer Res 65:1207–1212
Ono K, Uzawa K, Nakatsuru M, Shiiba M, Mochida Y, Tada A, Bukawa H, Miyakawa A, Yokoe H, Tanzawa H (2003) Down-regulation of FEZ1/LZTS1 gene with frequent loss of heterozygosity in oral squamous cell carcinomas. Int J Oncol 23:297–302
Sova P, Feng Q, Geiss G, Wood T, Strauss R, Rudolf V, Lieber A, Kiviat N (2006) Discovery of novel methylation biomarkers in cervical carcinoma by global demethylation and microarray analysis. Cancer Epidemiol Biomarkers Prev 15:114–123
Ruault M, Brun ME, Ventura M, Roizes G, De Sario A (2002) MLL3, a new human member of the TRX/MLL gene family, maps to 7q36, a chromosome region frequently deleted in myeloid leukaemia. Gene 284:73–81
Yeom M, Shim I, Lee HJ, Hahm DH (2005) Proteomic analysis of nicotine-associated protein expression in the striatum of repeated nicotine-treated rats. Biochem Biophys Res Commun 326:321–328
Hwang YY, Li MD (2006) Proteins differentially expressed in response to nicotine in five rat brain regions: Identification using a 2-DE/MS-based proteomics approach. Proteomics 6:3138–3153
Bai L, Merchant JL (2003) Transcription factor ZBP-89 is required for STAT1 constitutive expression. Nucl Acids Res 31:7264–7270
Bai L, Yoon SO, King PD, Merchant JL (2004) ZBP-89-induced apoptosis is p53-independent and requires JNK. Cell Death Differ. 11:663–673
Wilber A, Lu M, Schneider MC (2002) Deoxyribonuclease I-like III is an inducible macrophage barrier to liposomal transfection. Mol Ther 6:35–42
Yakovlev AG, Wang G, Stoica BA, Simbulan-Rosenthal CM, Yoshihara K, Smulson ME (1999) Role of DNAS1L3 in Ca2+- and Mg2+-dependent cleavage of DNA into oligonucleosomal and high molecular mass fragments. Nucl Acids Res 27:1999–2005
Stegh AH, Schickling O, Ehret A, Scaffidi C, Peterhansel C, Hofmann TG, Grummt I, Krammer PH, Peter ME (1998) DEDD, a novel death effector domain-containing protein, targeted to the nucleolus. EMBO J 17:5974–5986
Tibbetts MD, Zheng L, Lenardo MJ (2003) The death effector domain protein family: regulators of cellular homeostasis. Nat Immunol 4:404–409
Lee JC, Schickling O, Stegh AH, Oshima RG, Dinsdale D, Cohen GM, Peter ME (2002) DEDD regulates degradation of intermediate filaments during apoptosis. J Cell Biol 158:1051–1066
Yu R, Wu M, Lin S, Talbot P (2006) Cigarette Smoke Toxicants Alter Growth and Survival of Cultured Mammalian Cells. Toxicol Sci 93:82–95
Cooke JP (2007) Angiogenesis and the role of the endothelial nicotinic acetylcholine receptor. Life Sci 80:2347–2351
Cooke JP, Bitterman H (2004) Nicotine and angiogenesis: a new paradigm for tobacco-related diseases. Ann Med 36:33–40