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Acetaminophen Induces Human Neuroblastoma Cell Death through NFKB Activation
Neuroblastoma resistance to apoptosis may contribute to the aggressive behavior of this tumor. Therefore, it would be relevant to activate endogenous cellular death mechanisms as a way to improve neuroblastoma therapy. We used the neuroblastoma SH-SY5Y cell line as a model to study the mechanisms in...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3500330/ https://www.ncbi.nlm.nih.gov/pubmed/23166834 http://dx.doi.org/10.1371/journal.pone.0050160 |
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author | Posadas, Inmaculada Santos, Pablo Ceña, Valentín |
author_facet | Posadas, Inmaculada Santos, Pablo Ceña, Valentín |
author_sort | Posadas, Inmaculada |
collection | PubMed |
description | Neuroblastoma resistance to apoptosis may contribute to the aggressive behavior of this tumor. Therefore, it would be relevant to activate endogenous cellular death mechanisms as a way to improve neuroblastoma therapy. We used the neuroblastoma SH-SY5Y cell line as a model to study the mechanisms involved in acetaminophen (AAP)-mediated toxicity by measuring CYP2E1 enzymatic activity, NFkB p65 subunit activation and translocation to the nucleus, Bax accumulation into the mitochondria, cytochrome c release and caspase activation. AAP activates the intrinsic death pathway in the SH-SY5Y human neuroblastoma cell line. AAP metabolism is partially responsible for this activation, because blockade of the cytochrome CYP2E1 significantly reduced but did not totally prevent, AAP-induced SH-SY5Y cell death. AAP also induced NFkB p65 activation by phosphorylation and its translocation to the nucleus, where NFkB p65 increased IL-1β production. This increase contributed to neuroblastoma cell death through a mechanism involving Bax accumulation into the mitochondria, cytochrome c release and caspase3 activation. Blockade of NFkB translocation to the nucleus by the peptide SN50 prevented AAP-mediated cell death and IL-1β production. Moreover, overexpression of the antiapoptotic protein Bcl-x(L) did not decrease AAP-mediated IL-1β production, but prevented both AAP and IL-1β-mediated cell death. We also confirmed the AAP toxic actions on SK-N-MC neuroepithelioma and U87MG glioblastoma cell lines. The results presented here suggest that AAP activates the intrinsic death pathway in neuroblastoma cells through a mechanism involving NFkB and IL-1β. |
format | Online Article Text |
id | pubmed-3500330 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-35003302012-11-19 Acetaminophen Induces Human Neuroblastoma Cell Death through NFKB Activation Posadas, Inmaculada Santos, Pablo Ceña, Valentín PLoS One Research Article Neuroblastoma resistance to apoptosis may contribute to the aggressive behavior of this tumor. Therefore, it would be relevant to activate endogenous cellular death mechanisms as a way to improve neuroblastoma therapy. We used the neuroblastoma SH-SY5Y cell line as a model to study the mechanisms involved in acetaminophen (AAP)-mediated toxicity by measuring CYP2E1 enzymatic activity, NFkB p65 subunit activation and translocation to the nucleus, Bax accumulation into the mitochondria, cytochrome c release and caspase activation. AAP activates the intrinsic death pathway in the SH-SY5Y human neuroblastoma cell line. AAP metabolism is partially responsible for this activation, because blockade of the cytochrome CYP2E1 significantly reduced but did not totally prevent, AAP-induced SH-SY5Y cell death. AAP also induced NFkB p65 activation by phosphorylation and its translocation to the nucleus, where NFkB p65 increased IL-1β production. This increase contributed to neuroblastoma cell death through a mechanism involving Bax accumulation into the mitochondria, cytochrome c release and caspase3 activation. Blockade of NFkB translocation to the nucleus by the peptide SN50 prevented AAP-mediated cell death and IL-1β production. Moreover, overexpression of the antiapoptotic protein Bcl-x(L) did not decrease AAP-mediated IL-1β production, but prevented both AAP and IL-1β-mediated cell death. We also confirmed the AAP toxic actions on SK-N-MC neuroepithelioma and U87MG glioblastoma cell lines. The results presented here suggest that AAP activates the intrinsic death pathway in neuroblastoma cells through a mechanism involving NFkB and IL-1β. Public Library of Science 2012-11-16 /pmc/articles/PMC3500330/ /pubmed/23166834 http://dx.doi.org/10.1371/journal.pone.0050160 Text en © 2012 Posadas et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Posadas, Inmaculada Santos, Pablo Ceña, Valentín Acetaminophen Induces Human Neuroblastoma Cell Death through NFKB Activation |
title | Acetaminophen Induces Human Neuroblastoma Cell Death through NFKB Activation |
title_full | Acetaminophen Induces Human Neuroblastoma Cell Death through NFKB Activation |
title_fullStr | Acetaminophen Induces Human Neuroblastoma Cell Death through NFKB Activation |
title_full_unstemmed | Acetaminophen Induces Human Neuroblastoma Cell Death through NFKB Activation |
title_short | Acetaminophen Induces Human Neuroblastoma Cell Death through NFKB Activation |
title_sort | acetaminophen induces human neuroblastoma cell death through nfkb activation |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3500330/ https://www.ncbi.nlm.nih.gov/pubmed/23166834 http://dx.doi.org/10.1371/journal.pone.0050160 |
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