Aurora-A kinase regulates NF-kappaB activity: lessons from combination studies.
The Aurora-A/STK15 gene encodes a kinase that is frequently amplified in cancer. However, it is not clear what role this plays in the development of cancer since little is known about its biochemical targets. We have showed that Aurora-A induces phosphorylation of IkappaBa, thereby mediating its degradation. Loss of IkappaBa leads to activation of NF-kappaB target gene transcription. We analysed primary human breast cancers and 13.6% of samples showed Aurora-A gene amplification all of which exhibited nuclear localisation of NF-kappaB. We propose that this subgroup of breast cancer patients might benefit from inhibiting Aurora-A. Further analysis of different human tumour cell types for their NF-kappaB activity have showed that there is an association between cell resistance to chemotherapeutic agents and NF-kappaB activation. A549 human lung adenocarcinoma cells and SKOV3 human ovarian cancer cells have high levels of NF-kappaB and are resistant to cytotoxic agents such as adriamycin and VP-16 (etoposide). We also found that in A549 and SKOV3 cells treated with a small molecule inhibitor towards Aurora kinases, the NF-kappaB activity was downregulated and the efficacy of cytotoxic drugs was enhanced. In addition, the transcriptional targets Bcl-XL and Bcl-2 were downregulated. These findings have important implications for cancer chemotherapy. Aurora-A-inhibition enhances the efficacy of chemotherapeutic agents and reverses acquired resistance resulting from the activation of NF-kappaB. Consequently, preventing NF-kappaB activation by inhibition of Aurora-A, may provide a valuable enhancement to specific chemotherapeutic regimens.
Linardopoulos
Spiros
S
Breakthrough Breast Cancer Research Center, London, and Institute for Cancer Research, Sutton, UK. spiros.linardopoulos@icr.ac.uk
D000230:Adenocarcinoma / Q000201:enzymology / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D064096:Aurora Kinase A; D064127:Aurora Kinases; D001943:Breast Neoplasms / Q000201:enzymology / Q000378:metabolism; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D008175:Lung Neoplasms / Q000201:enzymology / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000201:enzymology / Q000378:metabolism; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051020:bcl-X Protein / Q000378:metabolism
D000970:Antineoplastic Agents; C494811:BCL2L1 protein, human; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; C576917:AURKA protein, human; D064096:Aurora Kinase A; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; D051550:I-kappa B Kinase