NF-kappaB activation prevents apoptotic oxidative stress via an increase of both thioredoxin and MnSOD levels in TNFalpha-treated Ewing sarcoma cells

• Published in: FEBS letters 2004-12, Vol.578 (1-2), p.111-115
• Main Authors: Djavaheri-Mergny, Mojgan, Javelaud, Delphine, Wietzerbin, Juana, Besançon, Françoise
• Format: Article
• Language: English
• Subjects: Adolescent; Antioxidants - metabolism; Apoptosis - physiology; Caspase 3; Caspases - metabolism; Child; Enzyme Activation; Humans; JNK Mitogen-Activated Protein Kinases - metabolism; Lipid Peroxidation; NF-kappa B - metabolism; Oxidative Stress; Reactive Oxygen Species - metabolism; Sarcoma, Ewing - metabolism; Superoxide Dismutase - metabolism; Thioredoxins - metabolism; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 0014-5793

Repression of activation of c-Jun N-terminal kinase (JNK) participates in the anti-apoptotic effect of nuclear factor-kappaB (NF-kappaB) in TNFalpha-treated Ewing sarcoma cells. As oxidative stress is one of the most prominent activators of JNK, we investigated the relationship between TNFalpha-induced NF-kappaB activation and the control of oxidative stress. Inhibition of NF-kappaB activation resulted in an increase in TNFalpha-induced ROS production, lipid peroxidation and protein oxidation. Those ROS and lipid peroxides were both involved in TNFalpha-induced apoptosis, whereas only ROS elevation triggered sustained JNK activation. TNFalpha increased the level of two antioxidant enzymes, thioredoxin and manganese superoxide dismutase by an NF-kappaB-dependent mechanism. Inhibition of expression or activity of these enzymes sensitized cells to TNFalpha-induced apoptosis, indicating their functional role in protection from cell death. Thus, agents that inhibit activities of these enzymes may prove helpful in the treatment of Ewing tumors.