PPARgamma agonists inhibit growth and expansion of CD133+ brain tumour stem cells

Br J Cancer. 2008 Dec 16;99(12):2044-53. doi: 10.1038/sj.bjc.6604786. Epub 2008 Nov 18.

Abstract

Brain tumour stem cells (BTSCs) are a small population of cells that has self-renewal, transplantation, multidrug resistance and recurrence properties, thus remain novel therapeutic target for brain tumour. Recent studies have shown that peroxisome proliferator-activated receptor gamma (PPARgamma) agonists induce growth arrest and apoptosis in glioblastoma cells, but their effects on BTSCs are largely unknown. In this study, we generated gliospheres with more than 50% CD133+ BTSC by culturing U87MG and T98G human glioblastoma cells with epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF). In vitro treatment with PPARgamma agonist, 15-Deoxy-Delta(12,14)-Prostaglandin J(2) (15d-PGJ2) or all-trans retinoic acid resulted in a reversible inhibition of gliosphere formation in culture. Peroxisome proliferator-activated receptor gamma agonists inhibited the proliferation and expansion of glioma and gliosphere cells in a dose-dependent manner. Peroxisome proliferator-activated receptor gamma agonists also induced cell cycle arrest and apoptosis in association with the inhibition of EGF/bFGF signalling through Tyk2-Stat3 pathway and expression of PPARgamma in gliosphere cells. These findings demonstrate that PPARgamma agonists regulate growth and expansion of BTSCs and extend their use to target BTSCs in the treatment of brain tumour.

MeSH terms

  • AC133 Antigen
  • Antigens, CD / metabolism*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cytoprotection / drug effects
  • Epidermal Growth Factor / pharmacology
  • Fibroblast Growth Factor 2 / pharmacology
  • Glycoproteins / metabolism*
  • Humans
  • Janus Kinases / metabolism
  • Neoplastic Stem Cells / metabolism*
  • Neoplastic Stem Cells / pathology*
  • PPAR gamma / agonists*
  • PPAR gamma / metabolism
  • Peptides / metabolism*
  • Prostaglandin D2 / analogs & derivatives*
  • Prostaglandin D2 / pharmacology
  • STAT Transcription Factors / metabolism
  • Signal Transduction / drug effects
  • Tretinoin / pharmacology*

Substances

  • 15-deoxyprostaglandin J2
  • AC133 Antigen
  • Antigens, CD
  • Glycoproteins
  • PPAR gamma
  • PROM1 protein, human
  • Peptides
  • STAT Transcription Factors
  • Fibroblast Growth Factor 2
  • Tretinoin
  • Epidermal Growth Factor
  • Janus Kinases
  • Prostaglandin D2