Journal
PLOS ONE
Volume 7, Issue 11, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0050160
Keywords
-
Categories
Funding
- Programa Ramon y Cajal from Ministerio de Educacion y Ciencia (Spain)
- Universidad de Castilla-La Mancha-Caja Castilla-La Mancha
- Junta de Comunidades de Castilla-la Mancha [PAI07-0063, PI-2007/47]
- Fondo de Investigaciones Sanitarias [PI081434]
- Ministerio de Ciencia e Innovacion [BFU2011-30161-C02-01]
- Consejeria de Educacion, Junta de Comunidades de Castilla-La Mancha [PII1I09-0163-002, POII10-0274-182]
Ask authors/readers for more resources
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-1 beta 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-1 beta production. Moreover, overexpression of the antiapoptotic protein Bcl-x(L) did not decrease AAP-mediated IL-1 beta production, but prevented both AAP and IL-1 beta-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-1 beta.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available