Inhibition of glycogen synthase kinase-3 beta induces apoptosis and mitotic catastrophe by disrupting centrosome regulation in cancer cells

Sci Rep. 2015 Aug 21;5:13249. doi: 10.1038/srep13249.

Abstract

Glycogen synthase kinase-3 beta (GSK-3β) has been investigated as a therapeutic target for numerous human diseases including cancer because of their diverse cellular functions. Although GSK-3β inhibitors have been investigated as anticancer reagents, precise biological mechanisms remain to be determined. In this study, we investigated the anticancer effects of GSK-3β inhibitors on cancer cell lines and observed centrosome dysregulation which resulted in abnormal mitosis. Mitotic checkpoints sensed the mitotic abnormalities and induced apoptosis. For cells that were inherently resistant to apoptosis, cell death distinct from apoptosis was induced. After GSK-3β inhibitor treatment, these cells exhibited characteristic features of mitotic catastrophe, including distended and multivesiculated nuclei and inappropriate reductions in cyclin B1 expression. This suggested that mitotic catastrophe was an alternative mechanism in cells resistant to apoptosis. Although the role of GSK-3β in centrosomes has not yet been clarified, phosphorylated GSK-3β was localised in centrosomes. From these data, GSK-3β seems to regulate centrosome function. Thus, we propose that centrosome dysregulation is an important mechanism for the anticancer effects of GSK-3β inhibitors and that mitotic catastrophe serves as a safe-guard system to remove cells with any mitotic abnormalities induced by GSK-3β inhibition.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects*
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Centrosome / drug effects
  • Centrosome / metabolism*
  • Chromosomal Instability / drug effects
  • Down-Regulation / drug effects
  • Glycogen Synthase Kinase 3 / antagonists & inhibitors*
  • Glycogen Synthase Kinase 3 / metabolism
  • Glycogen Synthase Kinase 3 beta
  • Humans
  • Mitosis / drug effects*
  • NF-kappa B / metabolism
  • Neoplasms / enzymology*
  • Neoplasms / pathology*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Protein Kinase Inhibitors / pharmacology*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Signal Transduction / drug effects
  • Spindle Apparatus / drug effects
  • Spindle Apparatus / metabolism
  • Thiazoles / pharmacology
  • Urea / analogs & derivatives
  • Urea / pharmacology

Substances

  • NF-kappa B
  • Protein Kinase Inhibitors
  • Thiazoles
  • N-(4-methoxybenzyl)-N'-(5-nitro-1,3-thiazol-2-yl)urea
  • Urea
  • Phosphatidylinositol 3-Kinases
  • GSK3B protein, human
  • Glycogen Synthase Kinase 3 beta
  • Proto-Oncogene Proteins c-akt
  • Glycogen Synthase Kinase 3