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M109145200v1
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Papers In Press, published online ahead of print May 7, 2002
J. Biol. Chem, 10.1074/jbc.M109145200
Submitted on September 21, 2001
Revised on May 7, 2002
Accepted on May 7, 2002

N-acetyl-cysteine and celecoxib lessen cadmium cytotoxicity which is associated with cyclooxygenase-2 up-regulation

Maria E. Figueiredo-Pereira, Zongmin Li, Marlon Jansen, and Patricia Rockwell

Biological Sciences, Hunter College of CUNY, New York, NY 10021

Corresponding Author: pereira{at}genectr.hunter.cuny.edu

In many neurodegenerative disorders, aggregates of ubiquitinated proteins are detected in neuronal inclusions but their role in neurodegeneration remains to be defined. To identify intracellular mechanisms associated with the appearance of ubiquitin-protein aggregates, mouse neuronal HT4 cells were treated with cadmium. This heavy metal is a potent cell poison that mediates oxidative stress and disrupts the ubiquitin/proteasome pathway. In the current studies, the following intracellular events were found to be also induced by cadmium: (i) a specific rise in cyclooxygenase-2 (COX-2) gene expression but not cyclooxygenase-1, (ii) an increase in the extracellular levels of the pro-inflammatory prostaglandin PGE2, a product of COX-2 and (iii) production of 4-hydroxy-2-nonenal-protein adducts, which result from lipid peroxidation. In addition, cadmium treatment led to the accumulation of high molecular weight ubiquitin-COX-2 conjugates and perturbed COX-2 glycosylation. The thiol reducing anti-oxidant N-acetyl-cysteine, and, to a lesser extent, the COX-2 inhibitor Celecoxib attenuated the loss of cell viability induced by cadmium demonstrating that oxidative stress and COX-2 activation contribute to cadmium cytotoxicity. These findings establish that disruption of the ubiquitin/proteasome pathway is not the only event triggered by cadmium. This oxidative stressor also activates COX-2 function. Both events could be triggered by formation of 4-hydroxy-2-nonenal as a result of cadmium-induced lipid peroxidation. Pro-inflammatory responses stimulated by oxidative stressors that mimic the cadmium effects may, therefore, be important initiators of the neurodegenerative process and exacerbate its progress.


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