Requirement of Erk, but Not JNK, for Arsenite-induced Cell Transformation

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 M) induces cell transformation. Interestingly, arsenite induces Erk phosphorylation and increased Erk activity at doses ranging from 0.8 to 200 M, while higher doses (more than 50 M) are required for activation of JNK. Arseniteinduced 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 MEK 1/2 . 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.Arsenite is introduced into the environment during energy production based on coal, oil shale, and geothermal sources. Once in the environment, arsenite represents a potential health hazard of unknown magnitude. Arsenite is associated with increased risks of human cancer of the skin, respiratory tract, hematopoietic system, and urinary bladder (1-4). Epidemiological investigations indicated that long-term arsenic exposure results in promotion of carcinogenesis, especially in lung and skin via inhalation and ingestion (5). Many cases of skin cancer have been documented in people exposed to arsenite through medical or other occupational exposures. It has been reported that high arsenic levels in drinking water (0.35-1.14 mg/liter) increased risks of cancer of skin, bladder, kidney, lung, and colon (1, 2, 5, 6). Hence, arsenite is a well documented human carcinogen (5, 7).Previously, several hypotheses have been proposed to describe the mechanism of arsenite-induced carcinogenesis (8 -14). It has been suggested that arsenic induces chromosome aberration and sister chromatid exchange which may be involved in arsenite-induced carcinogenesis (11,12). Recently, Zhao et al. (13) reported that arsenic may act as a carcinogen by inducing DNA hypomethylation, which in turn facilitates aberrant gene expression. Additionally, it was found that arsenite is a potent stimulator of extracellular signal-regulated protein kinase (Erk) 1 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). However, the role of JNK activation by arsenite in cell transformation or tumor promotion is unclear. We have established cell culture conditions for studying arsenite-induced cell tr...

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