Aurora-A down-regulates IkappaBalpha via Akt activation and interacts with insulin-like growth factor-1 induced phosphatidylinositol 3-kinase pathway for cancer cell survival

Mol Cancer. 2009 Nov 5;8:95. doi: 10.1186/1476-4598-8-95.

Abstract

Background: The mitotic Aurora-A kinase exerts crucial functions in maintaining mitotic fidelity. As a bona fide oncoprotein, Aurora-A aberrant overexpression leads to oncogenic transformation. Yet, the mechanisms by which Aurora-A enhances cancer cell survival remain to be elucidated.

Results: Here, we found that Aurora-A overexpression was closely correlated with clinic stage and lymph node metastasis in tongue carcinoma. Aurora-A inhibitory VX-680 suppressed proliferation, induced apoptosis and markedly reduced migration in cancer cells. We further showed that insulin-like growth factor-1, a PI3K physiological activator, reversed VX-680-decreased cell survival and motility. Conversely, wortmannin, a PI3K inhibitor, combined with VX-680 showed a synergistic effect on inducing apoptosis and suppressing migration. In addition, Aurora-A inhibition suppressed Akt activation, and VX-680-induced apoptosis was attenuated by Myr-Akt overexpression, revealing a cross-talk between Aurora-A and PI3K pathway interacting at Akt activation. Significantly, we showed that suppression of Aurora-A decreased phosphorylated Akt and was associated with increased IkappaBalpha expression. By contrast, Aurora-A overexpression upregulated Akt activity and downregulated IkappaBalpha, these changes were accompanied by nuclear translocation of nuclear factor-kappaB and increased expression of its target gene Bcl-xL. Lastly, Aurora-A overexpression induced IkappaBalpha reduction was abrogated by suppression of Akt either chemically or genetically.

Conclusion: Taken together, our data established that Aurora-A, via activating Akt, stimulated nuclear factor-kappaB signaling pathway to promote cancer cell survival, and promised a novel combined chemotherapy targeting both Aurora-A and PI3K in cancer treatment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • Aurora Kinases
  • Carcinoma, Squamous Cell / enzymology
  • Carcinoma, Squamous Cell / pathology
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Dose-Response Relationship, Drug
  • Down-Regulation / drug effects
  • Down-Regulation / genetics*
  • Enzyme Activation / drug effects
  • Humans
  • I-kappa B Proteins / metabolism*
  • Insulin-Like Growth Factor I / metabolism*
  • Lymphatic Metastasis / pathology
  • NF-KappaB Inhibitor alpha
  • Neoplasm Staging
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphorylation / drug effects
  • Piperazines / pharmacology
  • Protein Binding / drug effects
  • Protein Subunits / metabolism
  • Protein Transport / drug effects
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Signal Transduction / drug effects
  • Tongue Neoplasms / enzymology
  • Tongue Neoplasms / pathology*
  • Transcription Factor RelA / metabolism

Substances

  • I-kappa B Proteins
  • NFKBIA protein, human
  • Piperazines
  • Protein Subunits
  • Transcription Factor RelA
  • NF-KappaB Inhibitor alpha
  • VX680
  • Insulin-Like Growth Factor I
  • Phosphatidylinositol 3-Kinases
  • Aurora Kinases
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt