Aluminum-maltolate induces apoptosis and necrosis in neuro-2a cells: potential role for p53 signaling.

Abstract

Aluminum maltolate (Al-malt) causes neurodegeneration following in vivo exposure, and apoptosis plays a prominent role. The objective of this study was to define the form of cell death induced by Al-malt and to establish an in vitro model system amenable to mechanistic investigations of Al-malt-induced cell death. Neuro-2a cells, a murine neuroblastoma cell line, were treated with Al-malt for 24 h, following which mode of cell death and alterations in apoptosis-related gene expression were studied. Al-malt concentration-dependently increased cell death. The mode of cell death was a combination of apoptosis and necrosis. Treatment with Al-malt resulted in caspase 3 activation and the externalization of phosphatidyl serine, both indicative of apoptosis. In addition, nuclear condensation and fragmentation were evident. Interestingly, pretreatment with cycloheximide (CHX), a potent protein synthesis inhibitor markedly reduced Al-malt-induced apoptosis, indicating that altered gene expression was critical for this form of cell death. Pretreatment with CHX had no effect on necrosis induced by Al-malt. Analysis of gene expression showed that p53 mRNA was increased following treatment with Al-malt. This increase was accompanied by a marked inhibition of Bcl2 expression and an increase in BAX expression, a pattern of gene expression suggestive of a pro-apoptotic shift. Results show for the first time that p53 is induced by Al in neuron-like cells and suggest that the p53-dependent intrinsic pathway may be responsible for Al-induced apoptosis. Future studies investigating the role of p53 in Al neurotoxicity both in vivo and in vitro are warranted.

• Authors: Victor J Johnson, Sang-Hyun Kim, Raghubir P Sharma
• Journal: Toxicological sciences : an official journal of the Society of Toxicology (Toxicol Sci) Vol. 83 Issue 2 Pg. 329-39 (Feb 2005) ISSN: 1096-6080 [Print] United States
• PMID: 15537749 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Bax protein, mouse
• Organometallic Compounds
• Proto-Oncogene Proteins c-bcl-2
• Pyrones
• RNA, Messenger
• Tumor Suppressor Protein p53
• bcl-2-Associated X Protein
• aluminum maltolate
• Aluminum

Topics

• Aluminum (toxicity)
• Animals
• Apoptosis (drug effects)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Dose-Response Relationship, Drug
• Gene Expression
• Genes, p53
• Mice
• Necrosis (chemically induced)
• Neuroblastoma (drug therapy, metabolism, pathology)
• Organometallic Compounds (toxicity)
• Proto-Oncogene Proteins c-bcl-2 (genetics, metabolism)
• Pyrones (toxicity)
• RNA, Messenger (metabolism)
• Signal Transduction
• Tumor Suppressor Protein p53 (genetics, metabolism)
• bcl-2-Associated X Protein