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Doublecortin induces mitotic microtubule catastrophe and inhibits glioma cell invasion

Manoranjan Santra1, Sutapa Santra, Cindi Roberts

  • 1Department of Neurology, Henry Ford Health System, Detroit, Michigan, USA.

Journal of Neurochemistry
|December 20, 2008
PubMed

Insights

Doublecortin (DCX) protein inhibits glioma cell mitosis and invasion by disrupting microtubule spindles and actin filaments. This anti-glioma effect is mediated through a neurabin II dependent pathway involving protein phosphatase-1.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Cancer Research

Background:

  • Doublecortin (DCX) is a microtubule-binding protein typically found in neuronal cells.
  • DCX expression is often absent in glioma cells, suggesting a potential role in glioma suppression.
  • Previous studies indicate DCX can induce cell cycle arrest and suppress tumor xenografts.

Purpose of the Study:

  • To investigate the hypothesis that DCX inhibits glioma U87 cell mitosis and invasion.
  • To elucidate the molecular mechanisms by which DCX affects glioma cell behavior.

Main Methods:

  • U87 glioma cells were engineered to synthesize DCX.
  • Mitotic spindle catastrophe and actin filament depolymerization were analyzed.
  • Interactions between DCX, neurabin II, protein phosphatase-1 (PP1), and kinesin-13 were examined.
  • Glioma cell invasion assays were performed.

Main Results:

  • DCX synthesis in U87 cells induced mitotic microtubule (MT) spindle catastrophe via a neurabin II dependent pathway.
  • Phosphorylated DCX localized in the cytosol, disrupting the nuclear interaction of kinesin-13 and PP1, leading to active kinesin-13.
  • Activated kinesin-13 caused MT spindle catastrophe, arresting mitosis.
  • Phosphorylated DCX induced actin filament depolymerization and down-regulated matrix metalloproteinases-2 and -9, inhibiting cell invasion.

Conclusions:

  • DCX inhibits glioma U87 cell mitosis through MT spindle catastrophe.
  • DCX suppresses glioma cell invasion by inducing actin depolymerization.
  • The anti-glioma effects are mediated by the DCX-neurabin II-PP1 complex in the cytosol, inhibiting PP1 activity.

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