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PPARgamma ligands inhibit cholangiocarcinoma cell growth through p53-dependent GADD45 and p21 pathway

Chang Han1, A Jake Demetris, George K Michalopoulos

  • 1Department of Pathology, Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

Hepatology (Baltimore, Md.)
|June 28, 2003
PubMed

Insights

PPARgamma ligands inhibit cholangiocarcinoma growth by inducing cell cycle arrest and upregulating p53. This p53-dependent mechanism highlights PPARgamma ligands as potential therapeutics for cholangiocarcinoma.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Peroxisome proliferator-activated receptor-gamma (PPARgamma) ligands are known to inhibit growth and induce differentiation in various human cancers.
  • The role of PPARgamma ligands in regulating the growth of human cholangiocarcinoma cells has not been previously established.

Purpose of the Study:

  • To investigate the biological functions of PPARgamma ligands in human cholangiocarcinoma cell growth.
  • To elucidate the molecular mechanisms underlying PPARgamma ligand-mediated growth regulation in cholangiocarcinoma.

Main Methods:

  • Western blot analysis to confirm PPARgamma expression in cholangiocarcinoma cell lines.
  • Reporter assays to assess PPARgamma functionality.
  • Cell proliferation assays, flow cytometry for cell cycle analysis.
  • Western blot to measure protein expression (p53, GADD45, p21) and kinase activity (Cdc2).
  • Dominant-negative p53 inhibition experiments.

Main Results:

  • PPARgamma is expressed and functional in human cholangiocarcinoma cells.
  • PPARgamma ligands (15d-PGJ(2), troglitazone) dose-dependently inhibit cell growth and induce G2/M cell cycle arrest.
  • Ligand treatment elevates p53 expression and its downstream targets GADD45 and p21.
  • p53 inhibition abrogates the growth inhibitory and cell cycle arrest effects of PPARgamma ligands.
  • PPARgamma ligands do not directly inhibit Cdc2 activity.

Conclusions:

  • PPARgamma ligands inhibit cholangiocarcinoma cell growth through a novel p53-dependent pathway.
  • The mechanism involves G2/M cell cycle arrest mediated by p53 activation.
  • PPARgamma ligands demonstrate potential as a therapeutic strategy for human cholangiocarcinoma.

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