title: Aurora-A promotes gefitinib resistance via a NF-κB 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 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.
authors.affiliation: Institute of Medical and Molecular Toxicology, Chung Shan Medical University, Department of Medical Oncology and Chest Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan, ROC.
authors.forename: Chun Chi
authors.initials: CC
authors.lastname: Wu
authors.forename: Chang-Tze Ricky
authors.initials: CT
authors.lastname: Yu
authors.forename: Gee-Chen
authors.initials: GC
authors.lastname: Chang
authors.forename: Jin-Mei
authors.initials: JM
authors.lastname: Lai
authors.forename: Shih-Lan
authors.initials: SL
authors.lastname: Hsu
mesh_terms: D021581:Active Transport, Cell Nucleus; D000970:Antineoplastic Agents / Q000494:pharmacology*; D064127:Aurora Kinases; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D000077156:Gefitinib; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism; D008175:Lung Neoplasms / Q000201:enzymology* / Q000235:genetics; D009154:Mutation; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011799:Quinazolines / Q000494:pharmacology*; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D011799:Quinazolines; D016159:Tumor Suppressor Protein p53; D000072000:NF-KappaB Inhibitor alpha; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; D000077156:Gefitinib