Inhibition of sonic hedgehog and PI3K/Akt/mTOR pathways cooperate in suppressing survival, self-renewal and tumorigenic potential of glioblastoma-initiating cells

Mol Cell Biochem. 2019 Apr;454(1-2):11-23. doi: 10.1007/s11010-018-3448-z. Epub 2018 Sep 24.


Since PI3K/Akt/mTOR and sonic hedgehog (SHH) signaling pathways are highly activated in glioblastoma-initiating cells (GICs), we examined the effects of inhibiting these pathways on GIC characteristics and tumor growth in mice. NVP-LDE-225 (inhibitor of Smoothened) inhibited the expression of Gli1, Gli2, Smoothened, Patched1, and Patched2, and induced the expression of SuFu, whereas NVP-BEZ-235 (dual inhibitor of PI3K and mTOR) inhibited the expression of p-PI3K, p-Akt, p-mTOR, and p-p70S6K. NVP-LDE-225 co-operated with NVP-BEZ-235 in inhibiting the self-renewal capacity of GICs, expression of pluripotency maintaining factors (Nanog, c-Myc, Oct4, and Sox2), Musashi1, cyclin D1, and Bcl-2, and transcription and expression of Gli, and in inducing the expression of cleaved caspase-3, cleaved PARP and Bim. Additionally, NVP-LDE-225 co-operated with NVP-BEZ-235 in inhibiting epithelial-mesenchymal transition. Finally, the combination of NVP-LDE-225 and NVP-BEZ-235 was superior in inhibiting tumor growth, regulating the expression of pluripotency promoting factors, stem cell markers, cell cycle, and cell proliferation, and modulating EMT compared to single agent alone. In conclusion, the combined inhibition of PI3K/Akt/mTOR and SHH pathways was superior to single pathway inhibition in suppressing glioblastoma growth by targeting GICs.

Keywords: Akt; Glioblastoma; Glioblastoma-initiating cells; NVP-BEZ-235; NVP-LDE-225; PI3K; Sonic hedgehog; mTOR.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Biphenyl Compounds / pharmacology*
  • Cell Proliferation*
  • Glioblastoma / drug therapy
  • Glioblastoma / metabolism
  • Glioblastoma / physiopathology
  • Hedgehog Proteins / metabolism
  • Humans
  • Imidazoles / pharmacology*
  • Mice
  • Mice, SCID
  • Neoplastic Stem Cells / drug effects*
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / physiology
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors
  • Proto-Oncogene Proteins c-akt / metabolism
  • Pyridines / pharmacology*
  • Quinolines / pharmacology*
  • Signal Transduction / drug effects*
  • Smoothened Receptor / antagonists & inhibitors
  • Smoothened Receptor / metabolism
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • TOR Serine-Threonine Kinases / metabolism


  • Antineoplastic Agents
  • Biphenyl Compounds
  • Hedgehog Proteins
  • Imidazoles
  • Phosphoinositide-3 Kinase Inhibitors
  • Pyridines
  • Quinolines
  • SHH protein, human
  • SMO protein, human
  • Smoothened Receptor
  • sonidegib
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • dactolisib