Aurora-A regulation of nuclear factor-κB signaling by phosphorylation of IκBα

The Aurora-A/STK15 gene encodes a kinase that is frequently amplified in cancer. Overexpression of Aurora-A in mammalian cells leads to centrosome amplification, genetic instability, and transformation. In this study, we show that Aurora-A activates nuclear factor-kappa B (NF-kappa B) via I kappa B alpha phosphorylation. Inhibition of endogenous Aurora-A reduces tumor necrosis factor alpha (TNF alpha)-induced I kappa B alpha degradation. We analyzed primary human breast cancers, and 13.6% of samples showed Aurora-A gene amplification, all of which exhibited nuclear localization of NF-kappa B. We propose that this subgroup of patients with breast cancer might benefit from inhibiting Aurora-A. We also show that down-regulation of NF-kappa B via Aurora-A depletion can enhance cisplatin-dependent apoptosis. These data define a new role for Aurora-A in regulating I kappa B alpha that is critical for the activation of NF-kappa B-directed gene expression and may be partially responsible for the oncogenic effect of Aurora-A when the gene is amplified and overexpressed in human tumors.