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.

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 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

Substances

  • 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