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‐κB. Since reactive oxygen species (ROS) are assumed to contribute to TNF‐α mediated cytotoxicity but can also facilitate NF‐κB activation this study investigates the relationship between TNF‐α treatment, NF‐κB 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‐κB activation in wild type cells. This was due to a lack of sufficient H 2 O 2 to co‐stimulate NF‐κB activation as demonstrated by the observation that addition of exogenous H 2 O 2 led to a second increase of NF‐κB activity. The rapid decline of nuclear translocation of NF‐κB in the catalase overexpressing cells resulted in a slower increase of NF‐κB 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‐κB dependent survival pathway. J. Cell. Biochem. 103: 1497–1511, 2008. © 2007 Wiley‐Liss, Inc.