Aurora-A promotes gefitinib resistance via a NF-kappa B signaling pathway in p53 knockdown lung cancer cells?

[[abstract]]Mutations of the p53 tumor suppressor gene are the most common mutations found in human tumors. There is increasing evidence that suggests that p53 status is a determinant of chemosensitivity of tumor cells. We have previously demonstrated that p53 is a crucial regulator in mediating gefitinib-induced cell death, which upregulates apoptosis-related molecules. However, the mechanism of p53 involvement in cellular resistance to gefitinib remains unclear. In this study, we found that human non-small cell lung cancer cells. A549, with wild-type p53 exhibited a low level of Aurora-A expression and were sensitive to treatment with gefitinib. p53-knockdown A549 cells exhibited a high level of Aurora-A expression and were resistant to gefitinib-mediated apoptosis induction. In addition, the silencing of Aurora-A expression using an Aurora-A specific siRNA in p53-knockdown cells sensitized the A549 cancer cells to gefitinib-mediated apoptosis, suggesting a role for Aurora-A in gefitinib resistance. The activation of Aurora-A was accompanied by destabilization of I kappa B alpha and an increase in NF-kappa B transcriptional activity and was correlated with gefitinib resistance. Conversely, knockdown of Aurora-A with a siRNA stabilized I kappa B protein suppressed NF-kappa B activation and reduced gefitinib resistance. Additionally, ectopic expression of an active form of Aurora-A increased the degradation of I kappa B, the activation of NF-kappa B and the enhancement of gefitinib resistance in comparison with parental cells. These results suggest that Aurora-A is potentially involved in promoting gefitinib resistance via the activation of NF-kappa B pathway. Our findings also suggest that p53 not only stimulates apoptosis-related event but also inhibits the drug-resistance ability of Aurora-A, and consequently promotes the gefitinib-induced cellular apoptotic process. (C) 2011 Elsevier Inc. All rights reserved.[[note]]SC