Abstract
Trivalent arsenic (arsenite, As3+) is a human carcinogen, which is associated with cancers of skin, lung, liver, and bladder. However, the mechanism by which arsenite causes cancer is not well understood. In this study, we found that exposure of Cl 41 cells, a well characterized mouse epidermal cell model for tumor promotion, to a low concentration of arsenite (<25 microM) induces cell transformation. Interestingly, arsenite induces Erk phosphorylation and increased Erk activity at doses ranging from 0.8 to 200 microM, while higher doses (more than 50 microM) are required for activation of JNK. Arsenite-induced Erk activation was markedly inhibited by introduction of dominant negative Erk2 into cells, while expression of dominant negative Erk2 did not show inhibition of JNK and MEK1/2. Furthermore, arsenite-induced cell transformation was blocked in cells expressing the dominant negative Erk2. In contrast, overexpression of dominant negative JNK1 was shown to increase cell transformation even though it inhibits arsenite-induced JNK activation. Our results not only show that arsenite induces Erk activation, but also for the first time demonstrates that activation of Erk, but not JNK, by arsenite is required for its effects on cell transformation.
Highlights
Arsenite is introduced into the environment during energy production based on coal, oil shale, and geothermal sources
Department of Biochemistry and Molecular Biology, University of Massachusetts Medical School [17, 18]; fetal bovine serum (FBS) and Eagle’s minimal essential medium (MEM) were from Biowhittaker; LipofectAMINE was from Life Technologies, Inc.; TPA was from Sigma; rabbit polyclonal IgG against PKC␣ was from Santa Cruz Biotechnology; EGF was from Collaborative Research; luciferase assay substrate was from Promega; and PhosphoPlus MAPK antibody kit, phospho-MEK1/2 antibody, and p44/42 mitogen-activated protein (MAP) kinase assay kit were from New England Biolabs
Cell transformation can only be observed in cells exposed to low concentration (25 M) of arsenite, while no cell transformation colonies were observed at high concentrations of arsenite (50 –100 M) (Fig. 1A)
Summary
Arsenite is introduced into the environment during energy production based on coal, oil shale, and geothermal sources. Arsenite is associated with increased risks of human cancer of the skin, respiratory tract, hematopoietic system, and urinary bladder [1,2,3,4]. It was found that arsenite is a potent stimulator of extracellular signal-regulated protein kinase (Erk) and AP-1 transactivational activity and an efficient inducer of c-fos and c-jun gene expression [10, 14]. Induction of c-jun and c-fos by arsenite is associated with activation of JNK [10]. The role of JNK activation by arsenite in cell transformation or tumor promotion is unclear. Our data have shown that activation of Erk, but not JNK, is required for cell transformation induced by arsenite
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