Cell division cycle 25A (Cdc25A), a dual specificity protein phosphatase, exhibits anti-apoptotic activity, but the underlying molecular mechanisms are poorly characterized. Here we report that Cdc25A inhibits cisplatin-induced apoptotic cell death by stimulating nuclear factor-kappa B (NF-kappa B) activity. In HEK-293 cells, Cdc25A decreased protein level of inhibitor subunit kappa B alpha (I kappa-B alpha) in association with increased serine 32-phosphorylation, followed by stimulation of transcriptional activity of NF-kappa B. Inhibition of NF-kappa B activity by chemical inhibitor or overexpression of I kappa-B alpha in Cdc25A-elevated cancer cells resistant to cisplatin improved their sensitivity to cisplatin-induced apoptosis. Our data show for the first time that Cdc25A has an important physiological role in NF-kappa B activity regulation and it may be an important survival mechanism of cancer cells. (C) 2012 Elsevier Inc. All rights reserved.