Inhibition of ERK activity enhances the cytotoxic effect of peroxisome proliferator-activated receptor γ (PPARγ) agonists in HeLa cells

Biochem Biophys Res Commun. 2017 Jan 22;482(4):843-848. doi: 10.1016/j.bbrc.2016.11.122. Epub 2016 Nov 23.

Abstract

In this study, we examined whether the peroxisome proliferator-activated receptor γ (PPARγ) 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 (≤10 μM) or TGZ (≤20 μM) 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 PPARγ antagonist GW9662 followed by PPARγ agonists did not increase CGZ- or TGZ-induced cell death, indicating that PPARγ agonists induced HeLa cell death independently of PPARγ. Moreover, ERK1/2 activation was observed at a CGZ concentration of 25 μM and a TGZ concentration of 35 μM, both of which induced cell death. To elucidate the role of ERK1/2 activated by the two PPARγ agonists, the effect of U0126, an inhibitor of ERK1/2, on PPARγ-agonist-induced cell death was examined. Treatment with 10 or 20 μM 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 PPARγ agonists are capable of inducing apoptotic cell death in HeLa cells independently of PPARγ and that inhibition of ERK1/2 activity offers a strategy to enhance the cytotoxicity of PPARγ agonists in the treatment of cervical cancer.

Keywords: Apoptosis; Cervical cancer; Ciglitazone; PPARγ; Troglitazone.

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Butadienes / pharmacology
  • Caspase 3 / metabolism
  • Cell Survival / drug effects
  • Cervix Uteri / cytology
  • Cervix Uteri / drug effects
  • Cervix Uteri / metabolism
  • Chromans / pharmacology*
  • Drug Synergism
  • Enzyme Inhibitors / pharmacology
  • Female
  • HeLa Cells
  • Humans
  • Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors*
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / antagonists & inhibitors*
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Nitriles / pharmacology
  • PPAR gamma / agonists*
  • PPAR gamma / metabolism
  • Thiazolidinediones / pharmacology*
  • Troglitazone
  • Uterine Cervical Neoplasms / drug therapy*
  • Uterine Cervical Neoplasms / metabolism

Substances

  • Antineoplastic Agents
  • Butadienes
  • Chromans
  • Enzyme Inhibitors
  • Nitriles
  • PPAR gamma
  • Thiazolidinediones
  • U 0126
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Caspase 3
  • Troglitazone
  • ciglitazone