Cucurbitacin B induces inhibitory effects via CIP2A/PP2A/Akt pathway in glioblastoma multiforme

Mol Carcinog. 2018 Jun;57(6):687-699. doi: 10.1002/mc.22789. Epub 2018 Feb 26.

Abstract

Cancerous inhibitor of protein phosphatase 2A (CIP2A) is a human oncoprotein that is overexpressed in multiple types of tumors and promotes the proliferation and transformation of cancer cells. However, whether CIP2A can be a new drug target for human glioblastoma multiforme (GBM) is largely unclear. In the present study, we demonstrated that the overexpression of CIP2A promotes invasive behavior in GBM, and a natural compound, cucurbitacin B (CuB), shows an anti-proliferative and anti-invasion effect in GBM cell lines. CuB effectively induces apoptosis, downregulates CIP2A expression and its downstream signaling molecule, phospho-Akt, and upregulates protein phosphatase 2A (PP2A) activity. Overexpression of CIP2A reduced CuB-inhibited growth and invasion in GBM cells. Silencing CIP2A enhanced CuB-induced invasion inhibition and apoptosis in GBM. CuB combined with cisplatin synergistically inhibited GBM cells. CuB also inhibited tumor growth in murine models. Western blot results further revealed that CuB downregulates CIP2A, and phospho-Akt in vivo. In summary, inhibition of CIP2A determines the effects of CuB-induced invasive behavior inhibition and apoptosis in GBM cells. These characteristics render CuB as a promising candidate drug for further development and for designing new effective CIP2A inhibitors.

Keywords: CIP2A; apoptosis; cucurbitacin B; glioblastoma; invasive behavior.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cisplatin / pharmacology
  • Down-Regulation / drug effects
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Glioblastoma / drug therapy*
  • Glioblastoma / metabolism
  • Humans
  • Male
  • Mice
  • Mice, Nude
  • Neoplasm Invasiveness / pathology
  • Protein Phosphatase 2 / metabolism*
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Signal Transduction / drug effects*
  • Triterpenes / pharmacology*
  • Up-Regulation / drug effects

Substances

  • Triterpenes
  • cucurbitacin B
  • Proto-Oncogene Proteins c-akt
  • Protein Phosphatase 2
  • Cisplatin