PPARgamma agonists inhibit growth and expansion of CD133+ brain tumour stem cells
1Neuroscience Research Laboratory, Methodist Research Institute at Clarian Health, Indianapolis, IN, USA.
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.
Insights
Peroxisome proliferator-activated receptor gamma (PPARgamma) agonists inhibit brain tumour stem cell growth and expansion. These findings highlight PPARgamma agonists as a potential therapeutic strategy for targeting brain tumours.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Brain tumour stem cells (BTSCs) drive glioblastoma growth and recurrence.
- Peroxisome proliferator-activated receptor gamma (PPARgamma) agonists show promise against glioblastoma cells.
- The effect of PPARgamma agonists on BTSCs remains largely unknown.
Purpose of the Study:
- To investigate the effects of PPARgamma agonists on brain tumour stem cells.
- To determine if PPARgamma agonists can inhibit BTSC proliferation and expansion.
- To elucidate the molecular mechanisms underlying PPARgamma agonist action on BTSCs.
Main Methods:
- Generation of gliospheres enriched in CD133+ BTSCs from U87MG and T98G cells.
- In vitro treatment of gliospheres with PPARgamma agonists (15d-PGJ2, all-trans retinoic acid).
- Assessment of gliosphere formation, cell proliferation, cell cycle, apoptosis, and signaling pathway inhibition (Tyk2-Stat3).
Main Results:
- PPARgamma agonists reversibly inhibited gliosphere formation.
- PPARgamma agonists dose-dependently inhibited glioma and gliosphere cell proliferation and expansion.
- PPARgamma agonists induced cell cycle arrest and apoptosis, linked to inhibition of EGF/bFGF signaling via Tyk2-Stat3 and PPARgamma expression.
Conclusions:
- PPARgamma agonists effectively regulate the growth and expansion of brain tumour stem cells.
- PPARgamma agonists demonstrate potential as a therapeutic approach for brain tumours by targeting BTSCs.
- Targeting PPARgamma offers a novel strategy for glioblastoma treatment.
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