Thiazolidinedione, a peroxisome proliferator-activated receptor-gamma ligand, inhibits growth and metastasis of HT-29 human colon cancer cells through differentiation-promoting effects

Int J Oncol. 2004 Sep;25(3):631-9.


Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) ligands inhibit the growth of PPAR-gamma expressing cancer cells through terminal differentiation. However, there are few studies examining the effect of a PPAR-gamma ligand on metastatic potential of cancer cells in an animal model and the underlying molecular mechanisms. We have recently developed a rectal cancer xenograft animal model in which anti-tumor and anti-metastatic efficacy of agents can be evaluated. This study was designed to examine whether a representative PPAR-gamma ligand, thiazolidinedione (TZD), could inhibit growth and metastasis of PPAR-gamma positive HT-29 human colon cancer cells through the induction of terminal differentiation. TZD caused G1 arrest in association with a marked increase in p21Waf-1, Drg-1, and E-cadherin expression. In untreated cancer cells, fluorescence immunostaining demonstrated beta-catenin in the nucleus and/or cytoplasm; in TZD-treated cancer cells, beta-catenin localization shifted to the plasma membrane, in association with increased E-cadherin at this site and reduced tyrosine phosphorylation of beta-catenin. In addition, TZD completely inhibited lymph node and lung metastases in the xenograft animal model, and TZD inhibited growth of primary xenografts by 40%. These results suggest that TZD can function as a cytostatic anti-cancer agent to inhibit growth and metastasis of HT-29 colon cancer cells through differentiation-promoting effects. These effects involve not only modulation of the E-cadherin/beta-catenin system, but also up-regulation of Drg-1 gene expression.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use*
  • Cadherins / analysis
  • Cadherins / genetics
  • Cadherins / metabolism
  • Cell Cycle / drug effects
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism
  • Cell Differentiation
  • Cell Membrane / chemistry
  • Cell Membrane / metabolism
  • Cell Membrane / ultrastructure
  • Colonic Neoplasms / drug therapy*
  • Colonic Neoplasms / pathology
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cytoskeletal Proteins / analysis
  • Cytoskeletal Proteins / metabolism
  • HT29 Cells
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Intracellular Space / chemistry
  • Intracellular Space / metabolism
  • Ligands
  • Lymph Nodes / pathology
  • Mice
  • Neoplasm Metastasis
  • Neoplasm Transplantation
  • PPAR gamma / agonists*
  • Retinoblastoma Protein / metabolism
  • Thiazolidinediones / pharmacology
  • Thiazolidinediones / therapeutic use*
  • Trans-Activators / analysis
  • Trans-Activators / metabolism
  • Xenograft Model Antitumor Assays
  • beta Catenin


  • Antineoplastic Agents
  • CDKN1A protein, human
  • CTNNB1 protein, human
  • CTNNB1 protein, mouse
  • Cadherins
  • Cdkn1a protein, mouse
  • Cell Cycle Proteins
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cytoskeletal Proteins
  • Intracellular Signaling Peptides and Proteins
  • Ligands
  • N-myc downstream-regulated gene 1 protein
  • PPAR gamma
  • Retinoblastoma Protein
  • Thiazolidinediones
  • Trans-Activators
  • beta Catenin
  • 2,4-thiazolidinedione