Aurora kinase inhibition downregulates NF-kappaB and sensitises tumour cells to chemotherapeutic agents

Biochem Biophys Res Commun. 2007 Jan 5;352(1):220-5. doi: 10.1016/j.bbrc.2006.11.004. Epub 2006 Nov 10.

Abstract

We have identified that Aurora-A activates NF-kappaB via IkappaBalpha phosphorylation. Here, we analysed different human tumour cell types for their NF-kappaB activity. We found 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. This study provides evidence for a potential mechanism of chemoresistance and may be useful for the enhancement of certain chemotherapeutics regimens.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Aurora Kinases
  • Cell Line, Tumor
  • Down-Regulation / drug effects*
  • Humans
  • NF-kappa B / metabolism*
  • Piperazines / pharmacology*
  • Protein Kinase Inhibitors / pharmacology*
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein-Serine-Threonine Kinases / metabolism*

Substances

  • Antineoplastic Agents
  • NF-kappa B
  • Piperazines
  • Protein Kinase Inhibitors
  • VX680
  • Aurora Kinases
  • Protein-Serine-Threonine Kinases