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

Biochem Biophys Res Commun. 2011 Feb 11;405(2):168-72. doi: 10.1016/j.bbrc.2011.01.001. Epub 2011 Jan 7.


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 IκBα and an increase in NF-κB transcriptional activity and was correlated with gefitinib resistance. Conversely, knockdown of Aurora-A with a siRNA stabilized IκB protein suppressed NF-κB activation and reduced gefitinib resistance. Additionally, ectopic expression of an active form of Aurora-A increased the degradation of IκB, the activation of NF-κB 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-κB 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.

MeSH terms

  • Active Transport, Cell Nucleus
  • Antineoplastic Agents / pharmacology*
  • Aurora Kinases
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm*
  • Gefitinib
  • Gene Expression Regulation, Neoplastic
  • Gene Knockdown Techniques
  • Humans
  • I-kappa B Proteins / genetics
  • I-kappa B Proteins / metabolism
  • Lung Neoplasms / enzymology*
  • Lung Neoplasms / genetics
  • Mutation
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / genetics
  • NF-kappa B / metabolism*
  • Protein Serine-Threonine Kinases / metabolism*
  • Quinazolines / pharmacology*
  • Transcriptional Activation
  • Tumor Suppressor Protein p53 / genetics


  • Antineoplastic Agents
  • I-kappa B Proteins
  • NF-kappa B
  • NFKBIA protein, human
  • Quinazolines
  • Tumor Suppressor Protein p53
  • NF-KappaB Inhibitor alpha
  • Aurora Kinases
  • Protein Serine-Threonine Kinases
  • Gefitinib