Skip to main content

Advertisement

SpringerLink
Log in

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

  • Molecular Toxicology
  • Published:
Archives of Toxicology Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

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

    Article  PubMed  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • Davis RJ (2000) Signal transduction by the JNK group of MAP kinases. Cell 103(2):239–252

    Article  PubMed  CAS  Google Scholar 

  • Deveraux QL, Reed JC (1999) IAP family proteins–suppressors of apoptosis. Genes Dev 13(3):239–252

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Hayden MS, Ghosh S (2004) Signaling to NF-kappaB. Genes Dev 18(18):2195–2224

    Article  PubMed  CAS  Google Scholar 

  • Hetman M, Xia Z (2000) Signaling pathways mediating anti-apoptotic action of neurotrophins. Acta Neurobiol Exp (Wars) 60(4):531–545

    CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Johnson GL, Lapadat R (2002) Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science 298(5600):1911–1922

    Article  PubMed  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Kolch W (2005) Coordinating ERK/MAPK signalling through scaffolds and inhibitors. Nat Rev Mol Cell Biol 6(11):827–837

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    PubMed  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • Nurmi A, Lindsberg PJ, Koistinaho M et al (2004) Nuclear factor-kappaB contributes to infarction after permanent focal ischemia. Stroke 35(4):987–991

    Article  PubMed  Google Scholar 

  • Pahl HL (1999) Activators and target genes of Rel/NF-kappaB transcription factors. Oncogene 18(49):6853–6866

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Ryan KM, Ernst MK, Rice NR, Vousden KH (2000) Role of NF-kappaB in p53-mediated programmed cell death. Nature 404(6780):892–897

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • White E (1996) Life, death, and the pursuit of apoptosis. Genes Dev 10(1):1–15

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Zhang W, Stanimirovic D (2002) Current and future therapeutic strategies to target inflammation in stroke. Curr Drug Targets Inflamm Allergy 1(2):151–166

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

Download references

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Toxicology, MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13# Hangkong Road, Wuhan, 430030, People’s Republic of China

    Yan Qing, Yanfang Liang, Qingqing Du, Pan Fan, Hangong Xu, Yiping Xu & Nian Shi

Authors
  1. Yan Qing
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yanfang Liang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Qingqing Du
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Pan Fan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hangong Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yiping Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Nian Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Nian Shi.

Rights and permissions

Reprints 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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00204-013-1021-9

Keywords

Search

Navigation