Aurora kinase inhibition downregulates NF-kappaB and sensitises human tumour cells to chemotherapeutic agents

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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. We have demonstrated that Aurora-A activates NF-kappaB via IkappaBalpha phosphorylation and degradation. Aurora-A depletion using siRNA led to NF-kappaB inhibition. NF-kappaB downregulation enhances the efficacy of cisplatin-induced apoptosis and reverses acquired cisplatin resistance in A2780CP cells. A549 human lung adenocarcinoma cells are resistant to cytotoxic effects of both Adriamycin and VP-16. We found that in A549 cells treated with a small molecule inhibitor towards Aurora kinases enhances the efficacy of cytotoxic drugs via NF-kappaB regulation. This study provides evidence for a potential mechanism of chemoresistance and may be useful for the enhancement of certain chemotherapeutics regimens.