Biochemical and Biophysical Research Communications, Vol.482, No.4, 843-848, 2017
Inhibition of ERK activity enhances the cytotoxic effect of peroxisome proliferator-activated receptor gamma (PPAR gamma) agonists in HeLa cells
In this study, we examined whether the peroxisome proliferator-activated receptor gamma (PPAR gamma) agonists, ciglitazone (CGZ) and troglitazone (TGZ), induce cell death in human cervical cancer HeLa cells. The cells were treated with a range of CGZ or TGZ doses for 24 or 48 h. Low concentrations of CGZ (<= 101 mu M) or TGZ (<= 20 mu M) had no effect on cell viability whereas higher doses induced cell death in a time- and dose dependent manner as evidenced by the detection of activated caspase-3 and PARP cleavage. Treatment with the PPAR gamma antagonist GW9662 followed by PPAR gamma agonists did not increase CGZ- or TGZ-induced cell death, indicating that PPAR gamma agonists induced HeLa cell death independently of PPARy. Moreover, ERK1/2 activation was observed at a CGZ concentration of 25 mu M and a TGZ concentration of 35 both of which induced cell death. To elucidate the role of ERK1/2 activated by the two PPAR gamma agonists, the effect of U0126, an inhibitor of ERK1/2, on PPAR gamma-agonist-induced cell death was examined. Treatment with 10 or 20 mu M U0126 followed by CGZ or TGZ induced the down-regulation of ERK1/2 activity and a decrease in Bcl-2 expression accompanied by the collapse of mitochondrial membrane potential, which in turn significantly enhanced CGZ- or TGZ-induced apoptotic cell death. Our results suggest that PPAR gamma agonists are capable of inducing apoptotic cell death in HeLa cells independently of PPAR gamma and that inhibition of ERK1/2 activity offers a strategy to enhance the cytotoxicity of PPAR gamma agonists in the treatment of cervical cancer. (C) 2016 Elsevier Inc. All rights reserved.