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-α) can induce apoptosis but also supports cell survival pathways. Among the possible anti-apoptotic mechanisms of TNF-α is the activation of the transcription factor NF-KB. Since reactive oxygen species (ROS) are assumed to contribute to TNF-α mediated cytotoxicity but can also facilitate NF-KB activation this study investigates the relationship between TNF-α treatment, NF-KB activation and the expression of the anti-oxidative enzyme catalase. TNF-α 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 H 2 O 2 , caused a transient nuclear p65 translocation upon TNF-α treatment as compared to the sustained NF-KB activation in wild type cells. This was due to a lack of sufficient H 2 O 2 to co-stimulate NF-KB activation as demonstrated by the observation that addition of exogenous H 2 O 2 led to a second increase of NF-KB activity. The rapid decline of nuclear translocation of NF-KB in the catalase overexpressing cells resulted in a slower increase of NF-KB mediated reporter gene expression. These results indicate that TNF-α mediated downregulation of catalase expression and accordingly sufficient H 2 O 2 is required for appropriate function of the NF-KB dependent survival pathway.