PPARγ agonists regulate the expression of stemness and differentiation genes in brain tumour stem cells

Abstract

Background:Brain tumour stem cells (BTSCs) are a small population of cancer cells that exhibit self-renewal, multi-drug resistance, and recurrence properties. We have shown earlier that peroxisome proliferator-activated receptor gamma (PPARγ) agonists inhibit the expansion of BTSCs in T98G and U87MG glioma. In this study, we analysed the influence of PPARγ agonists on the expression of stemness and differentiation genes in BTSCs.Methods:The BTSCs were isolated from T98G and DB29 glioma cells, and cultured in neurobasal medium with epidermal growth factor+basic fibroblast growth factor. Proliferation was measured by WST-1 (4-[3-(4-iodophenyl)-2-(4-nitrophenyl)-2 H-5-tetrazolio]-1,3-benzene disulphonate) and 3H thymidine uptake assays, and gene expression was analysed by quantitative reverse--transcription PCR and Taqman array. The expression of CD133, SRY box 2, and nanog homeobox (Nanog) was also evaluated by western blotting, immunostaining, and flow cytometry.Results:We found that PPARγ agonists, ciglitazone and 15-deoxy-Δ12,14-ProstaglandinJ2, inhibited cell viability and proliferation of T98G- and DB29-BTSCs. The PPARγ agonists reduced the expansion of CD133+ BTSCs and altered the expression of stemness and differentiation genes. They also inhibited Sox2 while enhancing Nanog expression in BTSCs.Conclusion:These findings highlight that PPARγ agonists inhibit BTSC proliferation in association with altered expression of Sox2, Nanog, and other stemness genes. Therefore, targeting stemness genes in BTSCs could be a novel strategy in the treatment of glioblastoma.

Lycopene modulates growth and survival associated genes in prostate cancer

“…Earlier studies have also shown that PPARγ agonists exert anti-tumor effects in many tumors including prostate cancer [28][29][30][31][32]. We demonstrated earlier that PPARγ agonists inhibit the growth and expansion of brain tumor stem cells by modulating stemness and differentiation genes in glioma [28,29]. In this study we found that PPARγ agonists 15d-PGJ2, Ciglitazone and Pioglitazone induced a dose-dependent decrease in proliferation of PC-3 cells.…”

“…PPARγ modulates lipid metabolism and glucose homeostasis and selective PPARγ agonists have been used as prescription drugs for type 2 diabetes. Earlier studies have also shown that PPARγ agonists exert anti-tumor effects in many tumors including prostate cancer [28][29][30][31][32]. We demonstrated earlier that PPARγ agonists inhibit the growth and expansion of brain tumor stem cells by modulating stemness and differentiation genes in glioma [28,29].…”

“…We have shown earlier that PPARγ agonists inhibit the growth and survival of brain tumor stem cells, while other studies demonstrated inhibition of prostate cancer cells [28,29,32]. In this study we examined the potentiating effect of lycopene on PPARγ agonists in PC-3 cells.…”

“…PPARγ agonists also modulate lipid metabolism and glucose homeostasis and have been used as prescription drugs for type 2 diabetes. We and others have shown earlier that PPARγ agonists induce growth-arrest and apoptosis in different types of tumors [28][29][30]. Other studies have also demonstrated that PPARγ agonists induce growtharrest by modulating the expression and activation of PPARγ in prostate cancer [30,31].…”

Inhibition of Oxidative Stress-Elicited AKT Activation Facilitates PPARγ Agonist-Mediated Inhibition of Stem Cell Character and Tumor Growth of Liver Cancer Cells

“…PPARγ blocks carcinogenesis and the invasive and metastatic potentials of HCC [23], [24], indicating that the application of PPARγ agonists may be a therapeutic prospect for HCC treatment. Interestingly, PPARγ agonists have been recently implicated in driving ET-743-mediated differentiation of myxoid round cell liposarcoma [15] and the inhibition of TICs in brain cancer [25].…”