Aurora-A, a negative prognostic marker, increases migration and decreases radiosensitivity in cancer cells

Cancer Res. 2007 Nov 1;67(21):10436-44. doi: 10.1158/0008-5472.CAN-07-1379.

Abstract

Centrosomal Aurora-A (Aur-A) kinase ensures proper spindle assembly and accurate chromosome segregation in mitosis. Overexpression of Aur-A leads to centrosome amplification, aberrant spindle, and consequent genetic instability. In the present study, Aur-A was found to be overexpressed in laryngeal squamous cell carcinoma (LSCC). Moreover, Aur-A expression was adversely correlated with median survival, and further identified as a potential independent factor for disease prognosis. Suppression of Aurora kinase activity chemically or genetically led to LSCC Hep2 cell cycle arrest and apoptotic cell death. Importantly, we found that Aur-A increases cell migration and this novel function was correlated with Akt1 activation. The enhanced cell migration induced by Aur-A overexpression could be abrogated by either small-molecule Akt1 inhibitor or short interfering RNA. VX-680, a selective Aurora kinase inhibitor, decreased Akt1 phosphorylation at Ser(473) and inhibited cell migration, but failed to do so in constitutive active Akt1 (myr-Akt1)-overexpressed cells. Moreover, our data suggested that overexpression of Aur-A kinase might also contribute to radioresistance of LSCC. Inhibiting Aur-A by VX-680 induced expression of p53 and potently sensitized cells to radiotherapy, leading to significant cell death. Ectopic overexpression of Aur-A, however, reduced p53 level and rendered cells more resistant to irradiation. Taken together, we showed that Aur-A kinase, a negative prognostic marker, promotes migration and reduces radiosensitivity in laryngeal cancer cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • Aurora Kinases
  • Carcinoma, Squamous Cell / mortality*
  • Carcinoma, Squamous Cell / pathology
  • Carcinoma, Squamous Cell / radiotherapy
  • Cell Line, Tumor
  • Cell Movement
  • Humans
  • Laryngeal Neoplasms / mortality*
  • Laryngeal Neoplasms / pathology
  • Laryngeal Neoplasms / radiotherapy
  • Piperazines / pharmacology
  • Prognosis
  • Protein Serine-Threonine Kinases / analysis
  • Protein Serine-Threonine Kinases / antagonists & inhibitors
  • Protein Serine-Threonine Kinases / physiology*
  • Proto-Oncogene Proteins c-akt / physiology
  • RNA, Small Interfering / pharmacology
  • Radiation Tolerance*
  • Survival Rate
  • Tumor Suppressor Protein p53 / physiology

Substances

  • Piperazines
  • RNA, Small Interfering
  • Tumor Suppressor Protein p53
  • tozasertib
  • AKT1 protein, human
  • Aurora Kinases
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt