ToxSci Advance Access originally published online on March 31, 2004
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Toxicological Sciences 79, 248-257 (2004)
Toxicological Sciences vol. 79 no. 2 © Society of Toxicology; all rights reserved.
Micromolar Concentrations of Sodium Arsenite Induce Cyclooxygenase-2 Expression and Stimulate p42/44 Mitogen-Activated Protein Kinase Phosphorylation in Normal Human Epidermal Keratinocytes
Laboratory of Molecular Toxicology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709
Received January 7, 2004; accepted March 15, 2004
Based on evidence that arsenic modulates proinflammatory events that are involved in skin carcinogenecity, we hypothesized that in normal human epidermal keratinocytes (NHEK) arsenic increases expression of the procarcinogenic enzyme cyclooxygenase-2 (COX-2) and that 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 levels 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.
Key Words: cyclooxygenase; arsenic; PD98059; SB202190; MAP kinase.
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