Cell death is induced by ciglitazone, a peroxisome proliferator-activated receptor γ (PPARγ) agonist, independently of PPARγ in human glioma cells

Peroxisome proliferator-activated receptor gamma (PPAR gamma) regulates multiple signaling pathways, and its agonists induce apoptosis in various cancer cells. However, their role in cell death is unclear. In this study, the relationship between ciglitazone (CGZ) and PPAR gamma in CGZ-induced cell death was examined. At concentrations of greater than 30 mu M. CGZ, a synthetic PPAR gamma agonist, activated caspase-3 and induced apoptosis in T98G cells. Treatment of T98G cells with less than 30 mu M CGZ effectively induced cell death after pretreatment with 30 mu M of the PPAR gamma antagonist GW9662, although GW9662 alone did not induce cell death. This cell death was also observed when cells were co-treated with CGZ and GW9662, but was not observed when cells were treated with CGZ prior to GW9662. In cells in which PPAR gamma was down-regulated cells by siRNA, lower concentrations of CGZ (<30 mu M) were sufficient to induce cell death, although higher concentrations of CGZ (>= 30 mu M) were required to induce cell death in control T98G cells, indicating that CGZ effectively induces cell death in T98G cells independently of PPAR gamma. Treatment with GW9662 followed by CGZ resulted in a down-regulation of Akt activity and the loss of mitochondrial membrane potential (MMP), which was accompanied by a decrease in Bcl-2 expression and an increase in Bid cleavage. These data suggest that CGZ is capable of inducing apoptotic cell death independently of PPAR gamma in glioma cells, by down-regulating Akt activity and inducing MMP collapse. (C) 2011 Elsevier Inc. All rights reserved.