Activation of peroxisome proliferator-activated receptor gamma by troglitazone inhibits cell growth through the increase of p27KiP1 in human. Pancreatic carcinoma cells

Cancer Res. 2000 Oct 1;60(19):5558-64.


In the present study, we examine whether human pancreatic carcinoma cells express peroxisome proliferator-activated receptor gamma (PPARgamma) and the effect of PPARgamma activation by its selective ligand on cellular growth in pancreatic cancer cells. Immunohistochemical study of resected human pancreata using a polyclonal PPARgamma antibody revealed that PPARgamma protein expression in the nuclei of carcinoma cells was observed in 9 of 10 pancreatic adenocarcinomas. In contrast, normal pancreatic duct epithelial cells in the samples expressed no PPARgamma. Reverse transcription-PCR and Northern blot analysis demonstrated that all four tested human pancreatic cancer cell lines, PK-1, PK-8, PK-9, and MIA Paca-2, expressed PPARgamma mRNA. Luciferase assay in PK-1 cells showed that troglitazone, a selective ligand for PPARgamma, transactivated the transcription of a peroxisome proliferator response element-driven promoter in a dose-dependent fashion. Troglitazone inhibited the growth of all four pancreatic carcinoma cell lines in a dose-dependent manner. Cell cycle analysis by flow cytometry demonstrated that troglitazone induced G1 arrest in PK-1 cells. To examine the role of cyclin-dependent kinase inhibitors in the G1 arrest by troglitazone, we determined p27KiP1, p21CiP1/Waf1, or p18Ink4c protein expression by Western blot analysis in troglitazone-treated PK-1 cells. Troglitazone increased p27Kip1 but not p21Cip1/Waf1 or p18Inkc protein levels in time- and dose-dependent manners. To clarify the functional importance of p27Kip1 in the cell growth inhibition by troglitazone. All these results suggest that PPARgamma could be considered as a possible target molecule for treatment in human pancreatic carcinomas.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / drug therapy
  • Adenocarcinoma / metabolism
  • Adenocarcinoma / pathology*
  • Antineoplastic Agents / pharmacology*
  • Blotting, Northern
  • Cell Cycle Proteins*
  • Cell Division / drug effects
  • Chromans / pharmacology*
  • Cyclin-Dependent Kinase Inhibitor p27
  • G1 Phase / drug effects
  • Growth Inhibitors / pharmacology
  • Humans
  • Immunohistochemistry
  • Luciferases / genetics
  • Luciferases / metabolism
  • Microtubule-Associated Proteins / biosynthesis*
  • Microtubule-Associated Proteins / genetics
  • Oligonucleotides, Antisense / genetics
  • Oligonucleotides, Antisense / pharmacology
  • Pancreatic Neoplasms / drug therapy
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / pathology*
  • Peroxisome Proliferators
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / genetics
  • Receptors, Cytoplasmic and Nuclear / biosynthesis
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Receptors, Cytoplasmic and Nuclear / physiology*
  • Response Elements / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Thiazoles / pharmacology*
  • Thiazolidinediones*
  • Transcription Factors / biosynthesis
  • Transcription Factors / genetics
  • Transcription Factors / physiology*
  • Troglitazone
  • Tumor Cells, Cultured
  • Tumor Suppressor Proteins*


  • Antineoplastic Agents
  • Cell Cycle Proteins
  • Chromans
  • Growth Inhibitors
  • Microtubule-Associated Proteins
  • Oligonucleotides, Antisense
  • Peroxisome Proliferators
  • RNA, Messenger
  • Receptors, Cytoplasmic and Nuclear
  • Thiazoles
  • Thiazolidinediones
  • Transcription Factors
  • Tumor Suppressor Proteins
  • Cyclin-Dependent Kinase Inhibitor p27
  • Luciferases
  • Troglitazone