Micromolar concentrations of sodium arsenite induce cyclooxygenase-2 expression and stimulate p42/44 mitogen-activated protein kinase phosphorylation in normal human epidermal keratinocytes.
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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微摩尔浓度的亚砷酸钠可诱导正常人表皮角质形成细胞中环氧合酶-2 的表达并刺激 p42/44 丝裂原激活的蛋白激酶磷酸化。
DOI：
10.1093/toxsci/kfh132
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发表时间：
2004
期刊：
影响因子：
--
通讯作者：
Germolec,DR
中科院分区：
文献类型：
--
作者：
Trouba,KJ;Germolec,DR
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, PGE2secretion (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 PGE2secretion. 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.
