Chromium induces a persistent activation of mitogen-activated protein kinases by a redox-sensitive mechanism in H4 rat hepatoma cells
| Autor: | G, Kim, E J, Yurkow |
|---|---|
| Rok vydání: | 1996 |
| Předmět: |
Chromium
Mitogen-Activated Protein Kinase 1 Mitogen-Activated Protein Kinase 3 Protein-Tyrosine Kinases Peroxides Rats Enzyme Activation Liver Neoplasms Experimental Calcium-Calmodulin-Dependent Protein Kinases Tumor Cells Cultured Animals Tetradecanoylphorbol Acetate Mitogen-Activated Protein Kinases Oxidation-Reduction Protein Kinase C |
| Zdroj: | Cancer research. 56(9) |
| ISSN: | 0008-5472 |
| Popis: | Chromium is an important industrial metal, an environmental pollutant, and a human carcinogen. To investigate the mechanisms of chromium-induced carcinogenesis, activation of mitogen-activated protein (MAP) kinases ERK1 and ERK2 was examined in rat hepatoma cells following exposure to hexavalent chromium (Cr(VI)). Cr(VI) was found to activate both forms of MAP kinase in a dose- and time-dependent manner. In contrast to the protein kinase C (PKC) agonist, phorbol 12-myristate 13-acetate, which induced a transient activation of MAP kinases, Cr(VI) caused persistent activation of these enzymes. Furthermore, unlike phorbol 12-myristate 13-acetate, the ability of chromium to activate MAP kinases was found to be independent of PKC since chromium-induced MAP kinase activation occurred in PKC-depleted cells. Stimulation of ERK1 and ERK2 was associated with the ability of Cr(VI) to increase cellular peroxide levels as determined using the H2O2-sensitive fluorescent probe 2',7'-dichlorofluorescein diacetate and flow cytometry. Furthermore, the activation of these kinases by chromium was enhanced in cells treated with the glutathione-depleting agent, L-buthionine-[S,R]-sulfoximine, and attenuated in cells pretreated with an agent that elevates cellular levels of glutathione (i.e., N-acetyl-L-cysteine). The ability of chromium to modulate MAP kinase activity in this manner suggests a mechanism of chromium-induced carcinogenesis that involves the persistent stimulation of cellular regulatory pathways. |
| Databáze: | OpenAIRE |
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