Abstract
Trimethyltin chloride (TMT) has been known as a classic neurotoxicant which can cause serious neuronal degeneration diseases. Nuclear factor κB (NF-κB) and mitogen-activated protein kinases (MAPKs) signaling pathways play pivotal role in the central nerves system. In the present study, the intracellular pathways involved in TMT-induced apoptosis on human neuroblastoma cells SY5Y (SH-SY5Y) were investigated. We observed high level of nuclear NF-κB p65 submit, activated JNK, ERK, and p38 by TMT exposure. In contrast, low level of Bcl-2 and XIAP (two known NF-κB-regulated endogenous anti-apoptotic molecules) was present. To further investigate the role of these pathways and the relationship between them, specific inhibitors were used and the alteration of each pathway was evaluated. Pretreatment with MG132, an inhibitor of proteasome activity, and BAY11-7082, an inhibitor of IκBα phosphorylation, both inhibited NF-κB p65 translocation and significantly promoted apoptosis. NF-κB inhibition also induced down-expression of Bcl-2 and XIAP, exaggerated JNK phosphorylation, and ERK inhibition. SP600125 and U0126, by blocking the phosphorylation of c-Jun and MEK1/2, inhibited JNK and ERK phosphorylation, respectively, and attenuated apoptosis significantly. JNK and ERK inhibition also induced IκBα degradation and NF-κB p65 translocation, leading to expression of Bcl-2 and XIAP. The detrimental role of MG132 and BAY11-7082 appears related to the exaggerated JNK phosphorylation. The SP600125 and U0126 neuroprotection appears related to NF-κB-regulated transcriptional control of Bcl-2 and XIAP. These results suggest that the cross-talk and a balance between NF-κB and MAPKs may be involved in TMT-induced apoptosis on SH-SY5Y cells.
Similar content being viewed by others
References
Baeuerle PA, Henkel T (1994) Function and activation of NF-kappa B in the immune system. Annu Rev Immunol 12:141–179
Bhakar AL, Tannis LL, Zeindler C et al (2002) Constitutive nuclear factor-kappa B activity is required for central neuron survival. J Neurosci 22(19):8466–8475
Bladh LG, Johansson-Haque K, Rafter I, Nilsson S, Okret S (2009) Inhibition of extracellular signal-regulated kinase (ERK) signaling participates in repression of nuclear factor (NF)-kappaB activity by glucocorticoids. Biochim Biophys Acta 1793(3):439–446
Bubici C, Papa S, Pham CG, Zazzeroni F, Franzoso G (2006) The NF-kappaB-mediated control of ROS and JNK signaling. Histol Histopathol 21(1):69–80
Carter AB, Hunninghake GW (2000) A constitutive active MEK – > ERK pathway negatively regulates NF-kappa B-dependent gene expression by modulating TATA-binding protein phosphorylation. J Biol Chem 275(36):27858–27864
Caughlan A, Newhouse K, Namgung U, Xia Z (2004) Chlorpyrifos induces apoptosis in rat cortical neurons that is regulated by a balance between p38 and ERK/JNK MAP kinases. Toxicol Sci 78(1):125–134
Craig R, Larkin A, Mingo AM et al (2000) p38 MAPK and NF-kappa B collaborate to induce interleukin-6 gene expression and release. Evidence for a cytoprotective autocrine signaling pathway in a cardiac myocyte model system. J Biol Chem 275(31):23814–23824
Culmsee C, Siewe J, Junker V et al (2003) Reciprocal inhibition of p53 and nuclear factor-kappaB transcriptional activities determines cell survival or death in neurons. J Neurosci 23(24):8586–8595
Davis RJ (2000) Signal transduction by the JNK group of MAP kinases. Cell 103(2):239–252
Deveraux QL, Reed JC (1999) IAP family proteins–suppressors of apoptosis. Genes Dev 13(3):239–252
Figiel I, Fiedorowicz A (2002) Trimethyltin-evoked neuronal apoptosis and glia response in mixed cultures of rat hippocampal dentate gyrus: a new model for the study of the cell type-specific influence of neurotoxins. Neurotoxicology 23(1):77–86
Figueroa-Masot XA, Hetman M, Higgins MJ, Kokot N, Xia Z (2001) Taxol induces apoptosis in cortical neurons by a mechanism independent of Bcl-2 phosphorylation. J Neurosci 21(13):4657–4667
Florea AM, Splettstoesser F, Dopp E, Rettenmeier AW, Busselberg D (2005) Modulation of intracellular calcium homeostasis by trimethyltin chloride in human tumour cells: neuroblastoma SY5Y and cervix adenocarcinoma HeLa S3. Toxicology 216(1):1–8
Fonger GC, Stroup D, Thomas PL, Wexler P (2000) TOXNET: a computerized collection of toxicological and environmental health information. Toxicol Ind Health 16(1):4–6
Gasso S, Sanfeliu C, Sunol C, Rodriguez-Farre E, Cristofol RM (2000) Trimethyltin and triethyltin differentially induce spontaneous noradrenaline release from rat hippocampal slices. Toxicol Appl Pharmacol 162(3):189–196
Geloso MC, Corvino V, Michetti F (2011) Trimethyltin-induced hippocampal degeneration as a tool to investigate neurodegenerative processes. Neurochem Int
Gomez FD, Apodaca P, Holloway LN, Pannell KH, Whalen MM (2007) Effect of a series of triorganotins on the immune function of human natural killer cells. Environ Toxicol Pharmacol 23(1):18–24
Grilli M, Memo M (1999a) Nuclear factor-kappaB/Rel proteins: a point of convergence of signalling pathways relevant in neuronal function and dysfunction. Biochem Pharmacol 57(1):1–7
Grilli M, Memo M (1999b) Possible role of NF-kappaB and p53 in the glutamate-induced pro-apoptotic neuronal pathway. Cell Death Differ 6(1):22–27
Hayden MS, Ghosh S (2004) Signaling to NF-kappaB. Genes Dev 18(18):2195–2224
Hetman M, Xia Z (2000) Signaling pathways mediating anti-apoptotic action of neurotrophins. Acta Neurobiol Exp (Wars) 60(4):531–545
Hlinak Z, Krejci I, Hynie S, Klenerova V (2008) Dipeptide “alaptide” prevented impairments in spontaneous behavior produced with trimethyltin in male rats. Neuro Endocrinol Lett 29(6):917–923
Jenkins SM, Barone S (2004) The neurotoxicant trimethyltin induces apoptosis via caspase activation, p38 protein kinase, and oxidative stress in PC12 cells. Toxicol Lett 147(1):63–72
Jiang Q, Gu Z, Zhang G, Jing G (2000) Diphosphorylation and involvement of extracellular signal-regulated kinases (ERK1/2) in glutamate-induced apoptotic-like death in cultured rat cortical neurons. Brain Res 857(1–2):71–77
Johnson GL, Lapadat R (2002) Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science 298(5600):1911–1922
Kassed CA, Butler TL, Patton GW et al (2004) Injury-induced NF-kappaB activation in the hippocampus: implications for neuronal survival. FASEB J 18(6):723–724
Kim JK, Bae H, Kim MJ et al (2009) Inhibitory effect of Poncirus trifoliate on acetylcholinesterase and attenuating activity against trimethyltin-induced learning and memory impairment. Biosci Biotechnol Biochem 73(5):1105–1112
Kolch W (2005) Coordinating ERK/MAPK signalling through scaffolds and inhibitors. Nat Rev Mol Cell Biol 6(11):827–837
Kucharczak J, Simmons MJ, Fan Y, Gelinas C (2003) To be, or not to be: nF-kappaB is the answer–role of Rel/NF-kappaB in the regulation of apoptosis. Oncogene 22(56):8961–8982
Lezoualc’h F, Sagara Y, Holsboer F, Behl C (1998) High constitutive NF-kappaB activity mediates resistance to oxidative stress in neuronal cells. J Neurosci 18(9):3224–3232
Lin H, Chen C, Li X, Chen BD (2002) Activation of the MEK/MAPK pathway is involved in bryostatin1-induced monocytic differentiation and up-regulation of X-linked inhibitor of apoptosis protein. Exp Cell Res 272(2):192–198
Lu K, Liang CL, Liliang PC et al (2010a) Inhibition of extracellular signal-regulated kinases 1/2 provides neuroprotection in spinal cord ischemia/reperfusion injury in rats: relationship with the nuclear factor-kappaB-regulated anti-apoptotic mechanisms. J Neurochem 114(1):237–246
Lu K, Liang CL, Liliang PC et al (2010b) Inhibition of extracellular signal-regulated kinases 1/2 provides neuroprotection in spinal cord ischemia/reperfusion injury in rats: relationship with the nuclear factor-kappaB-regulated anti-apoptotic mechanisms. J Neurochem 114(1):237–246
Mattson MP, Culmsee C, Yu Z, Camandola S (2000) Roles of nuclear factor kappaB in neuronal survival and plasticity. J Neurochem 74(2):443–456
Mendoza MC, Er EE, Blenis J (2011) The Ras-ERK and PI3 K-mTOR pathways: cross-talk and compensation. Trends Biochem Sci 36(6):320–328
Morita M, Imai H, Liu Y et al (2008) FK506-protective effects against trimethyltin neurotoxicity in rats: hippocampal expression analyses reveal the involvement of periarterial osteopontin. Neuroscience 153(4):1135–1145
Mundy WR, Freudenrich TM (2006) Apoptosis of cerebellar granule cells induced by organotin compounds found in drinking water: involvement of MAP kinases. Neurotoxicology 27(1):71–81
Namgung U, Xia Z (2000) Arsenite-induced apoptosis in cortical neurons is mediated by c-Jun N-terminal protein kinase 3 and p38 mitogen-activated protein kinase. J Neurosci 20(17):6442–6451
Nurmi A, Lindsberg PJ, Koistinaho M et al (2004) Nuclear factor-kappaB contributes to infarction after permanent focal ischemia. Stroke 35(4):987–991
Pahl HL (1999) Activators and target genes of Rel/NF-kappaB transcription factors. Oncogene 18(49):6853–6866
Park J, Kim I, Oh YJ, Lee K, Han PL, Choi EJ (1997) Activation of c-Jun N-terminal kinase antagonizes an anti-apoptotic action of Bcl-2. J Biol Chem 272(27):16725–16728
Pennypacker KR, Kassed CA, Eidizadeh S, Saporta S, Sanberg PR, Willing AE (2001) NF-kappaB p50 is increased in neurons surviving hippocampal injury. Exp Neurol 172(2):307–319
Piacentini R, Gangitano C, Ceccariglia S et al (2008) Dysregulation of intracellular calcium homeostasis is responsible for neuronal death in an experimental model of selective hippocampal degeneration induced by trimethyltin. J Neurochem 105(6):2109–2121
Piccioli P, Porcile C, Stanzione S et al (2001) Inhibition of nuclear factor-kappaB activation induces apoptosis in cerebellar granule cells. J Neurosci Res 66(6):1064–1073
Porcile C, Piccioli P, Stanzione S et al (2002) Proteasome inhibitors induce cerebellar granule cell death: inhibition of nuclear factor-kB activation. Ann N Y Acad Sci 973:402–413
Reali C, Scintu F, Pillai R, Donato R, Michetti F, Sogos V (2005) S100b counteracts effects of the neurotoxicant trimethyltin on astrocytes and microglia. J Neurosci Res 81(5):677–686
Ryan KM, Ernst MK, Rice NR, Vousden KH (2000) Role of NF-kappaB in p53-mediated programmed cell death. Nature 404(6780):892–897
Shuto M, Seko K, Kuramoto N et al (2009) Activation of c-Jun N-terminal kinase cascades is involved in part of the neuronal degeneration induced by trimethyltin in cortical neurons of mice. J Pharmacol Sci 109(1):60–70
Stehlik C, de Martin R, Kumabashiri I, Schmid JA, Binder BR, Lipp J (1998) Nuclear factor (NF)-kappaB-regulated X-chromosome-linked iap gene expression protects endothelial cells from tumor necrosis factor alpha-induced apoptosis. J Exp Med 188(1):211–216
Tang X, Yang X, Lai G et al (2010) Mechanism underlying hypokalemia induced by trimethyltin chloride: inhibition of H +/K + -ATPase in renal intercalated cells. Toxicology 271(1–2):45–50
White E (1996) Life, death, and the pursuit of apoptosis. Genes Dev 10(1):1–15
Xiao YQ, Malcolm K, Worthen GS et al (2002) Cross-talk between ERK and p38 MAPK mediates selective suppression of pro-inflammatory cytokines by transforming growth factor-beta. J Biol Chem 277(17):14884–14893
Zhang W, Stanimirovic D (2002) Current and future therapeutic strategies to target inflammation in stroke. Curr Drug Targets Inflamm Allergy 1(2):151–166
Zhang W, Potrovita I, Tarabin V et al (2005) Neuronal activation of NF-kappaB contributes to cell death in cerebral ischemia. J Cereb Blood Flow Metab 25(1):30–40
Conflict of interest
The authors declare that they have no conflict of interest.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Qing, Y., Liang, Y., Du, Q. et al. Apoptosis induced by Trimethyltin chloride in human neuroblastoma cells SY5Y is regulated by a balance and cross-talk between NF-κB and MAPKs signaling pathways. Arch Toxicol 87, 1273–1285 (2013). https://doi.org/10.1007/s00204-013-1021-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00204-013-1021-9