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Activation of Nuclear Factor-B in Human Metastatic Melanoma Cells and the Effect of Oxidative Stress¹

Department of Medicine and the Chao Family Comprehensive Cancer Center, University of California-Irvine, Orange, California 92868

The biological basis for the general pharmacological resistance of human melanoma is unknown. A unique biochemical feature of the melanocyte is the synthesis of melanin, which leads to the generation of hydrogen peroxide and the consumption of reduced glutathione. This activity produces a state of chronic oxidative stress in these cells. We demonstrated previously that the expression of the c-jun family was dysregulated in metastatic melanoma cells compared with normal human melanocytes (D. T. Yamanishi et al., J. Invest. Dermatol., 97: 349–353, l991). In the current investigation, we measured the levels of two major redox response transcription factors, nuclear factor-B (NF-B) and activator protein-1, in metastatic melanoma cells and normal melanocytes and their response to oxidative stress. The basal DNA-binding activity of NF-B as measured by the electrophoretic mobility shift assay in metastatic melanoma cells was increased 4-fold compared with that of normal melanocytes. This level of binding was paralleled by a 1.5- to 4-fold increase in the expression of p50 (NF-B1), p65 (Rel-A), and IB- as measured by Northern blot analysis. In contrast, the expression of p75 (c-rel) was markedly decreased (60%) in melanoma cells compared with normal melanocytes. Following oxidative stress produced by enzyme-generated H₂O₂, free H₂O₂, or incubation with buthionine sulfoximine, NF-B binding activity increased 1.5- to 2.5-fold in melanoma cells (buthionine sulfoximine > H₂O₂), but only slightly in normal melanocytes. In contrast, activator protein-1 binding activity was unaffected or increased in normal melanocytes in response to oxidative stress, but was either unaffected or decreased in melanoma cells. These results suggest that the redox regulation of melanoma cells at the molecular level is fundamentally different from normal melanocytes and may offer a unique avenue for preventive or therapeutic intervention as well as new insights into the pathogenesis of melanocyte transformation.

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