Rottlerin inhibits cell growth and invasion via down-regulation of Cdc20 in glioma cells

Oncotarget. 2016 Oct 25;7(43):69770-69782. doi: 10.18632/oncotarget.11974.

Abstract

Rottlerin, isolated from a medicinal plant Mallotus phillippinensis, has been demonstrated to inhibit cellular growth and induce cytoxicity in glioblastoma cell lines through inhibition of calmodulin-dependent protein kinase III. Emerging evidence suggests that rottlerin exerts its antitumor activity as a protein kinase C inhibitor. Although further studies revealed that rottlerin regulated multiple signaling pathways to suppress tumor cell growth, the exact molecular insight on rottlerin-mediated tumor inhibition is not fully elucidated. In the current study, we determine the function of rottlerin on glioma cell growth, apoptosis, cell cycle, migration and invasion. We found that rottlerin inhibited cell growth, migration, invasion, but induced apoptosis and cell cycle arrest. Mechanistically, the expression of Cdc20 oncoprotein was measured by the RT-PCR and Western blot analysis in glioma cells treated with rottlerin. We observed that rottlerin significantly inhibited the expression of Cdc20 in glioma cells, implying that Cdc20 could be a novel target of rottlerin. In line with this, over-expression of Cdc20 decreased rottlerin-induced cell growth inhibition and apoptosis, whereas down-regulation of Cdc20 by its shRNA promotes rottlerin-induced anti-tumor activity. Our findings indicted that rottlerin could exert its tumor suppressive function by inhibiting Cdc20 pathway which is constitutively active in glioma cells. Therefore, down-regulation of Cdc20 by rottlerin could be a promising therapeutic strategy for the treatment of glioma.

Keywords: Cdc20; glioma; growth; invasion; rottlerin.

MeSH terms

  • Acetophenones / pharmacology*
  • Apoptosis / drug effects
  • Benzopyrans / pharmacology*
  • Brain Neoplasms / drug therapy*
  • Brain Neoplasms / pathology
  • Cdc20 Proteins / antagonists & inhibitors
  • Cdc20 Proteins / physiology
  • Cell Cycle Checkpoints / drug effects
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Down-Regulation
  • Glioma / drug therapy*
  • Glioma / pathology
  • Humans
  • Neoplasm Invasiveness
  • RNA, Small Interfering / genetics

Substances

  • Acetophenones
  • Benzopyrans
  • Cdc20 Proteins
  • RNA, Small Interfering
  • CDC20 protein, human
  • rottlerin