Catalase overexpression impairs TNF-α induced NF-κB activation and sensitizes MCF-7 cells against TNF-α

The pleiotropic cytokine tumor necrosis factor alpha (TNF-alpha) can induce apoptosis but also supports cell survival pathways. Among the possible anti-apoptotic mechanisms of TNF-alpha is the activation of the transcription factor NF-kappa B. Since reactive oxygen species (ROS) are assumed to contribute to TNF-alpha mediated cytotoxicity but can also facilitate NF-kappa B activation this study investigates the relationship between TNF-alpha treatment, NF-kappa B activation and the expression of the anti-oxidative enzyme catalase. TNF-alpha treatment caused downregulation of catalase expression in MCF-7, Caco-2 and Hct-116 cancer cell lines. Overexpression of catalase in MCF-7 cells, resulting in lower intracellular ROS levels upon challenge with H2O2, caused a transient nuclear p65 translocation upon TNF-alpha treatment as compared to the sustained NF-kappa B activation in wild type cells. This was due to a lack of sufficient H2O2 to co-stimulate NF-kappa B activation as demonstrated by the observation that addition of exogenous H2O2 led to a second increase of NF-kappa B activity. The rapid decline of nuclear translocation of NF-kappa B in the catalase overexpressing cells resulted in a slower increase of NF-kappa B mediated reporter gene expression. These results indicate that TNF-alpha mediated downregulation of catalase expression and accordingly sufficient H2O2 is required for appropriate function of the NF-kappa B dependent survival pathway.