ToxSci Advance Access published online on March 31, 2004
Toxicological Sciences, doi:10.1093/toxsci/kfh132
Toxicological Sciences © Society of Toxicology 2004; all rights reserved
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1 Laboratory of Molecular Toxicology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, 27709, USA
* To whom correspondence should be addressed. E-mail: germolec{at}niehs.nih.gov.
Based on evidence that arsenic modulates pro-inflammatory events that are involved in skin carcinogenecity, it was hypothesized that in normal human epidermal keratinocytes (NHEK) arsenic: 1) increases expression of the procarcinogenic enzyme cyclooxygenase-2 (COX-2); and 2) this occurs via specific mitogen and stress signaling pathways. To test this hypothesis, NHEK were exposed to sodium arsenite and COX-2 expression, prostaglandin E2 (PGE2) secretion, mitogen-activated protein kinase (MAPK) phosphorylation, and DNA synthesis were quantified. Inhibitors of p42/44 and p38 MAPKs were used to evaluate the contribution of mitogen and stress signaling to the modulation of COX-2. Our results demonstrate that arsenite (0.005-5 µM) elevates COX-2 expression, PGE2 secretion (2.5-5 µM), and DNA synthesis (1-5 µM). Arsenite stimulated p42/44 but not p38 MAPK phosphorylation (2.5 µM), responses different than those produced by epidermal growth factor. Inhibition of mitogen-activated protein kinase kinase (MAPKK) and p38 MAPK using PD98059 (20 µM) and SB202190 (5 µM), respectively, attenuated the elevation of COX-2 protein induced by arsenite whereas physiological concentrations of three COX-2 inhibitors (e.g., NS-398, piroxicam, and aspirin) reduced arsenite-stimulated DNA synthesis. These data indicate that arsenite elevates COX-2 in NHEK at the transcriptional and translational level as well as increases PGE2 secretion. Compounds that inhibit COX-2 expression and activity may be useful in the scientific study, prevention, and treatment of arsenic skin carcinogenesis, and deserve further investigation.
© 2004 Toxicological Sciences © Society of Toxicology 2004; all rights reserved.
Environmental Toxicology
Micromolar Concentrations of Sodium Arsenite Induce Cyclooxygenase-2 Expression and Stimulate p42/44 Mitogen-Activated Protein Kinase Phosphorylation in Normal Human Epidermal Keratinocytes
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