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Characteristics of the peroxisome proliferator activated receptor γ (PPARγ) ligand induced apoptosis in colon cancer cells
  1. T Shimada,
  2. K Kojima,
  3. K Yoshiura,
  4. H Hiraishi,
  5. A Terano
  1. Department of Gastroenterology, Dokkyo University School of Medicine, Mibu, Tochigi 321-0293, Japan
  1. Correspondence to:
    Dr T Shimada, Department of Gastroenterology, Dokkyo University School of Medicine, 880 Kita-kobayashi, Mibu, Tochigi 321-0293, Japan;
    tshimada{at}dokkyomed.ac.jp

Abstract

Background: Involvement of peroxisome proliferator activated receptor γ (PPARγ) in the growth response of colon cancer cells has been suggested.

Aims: To investigate the characteristics of PPARγ induced apoptosis in colon cancer cells.

Methods: The effects of ligands for each of the PPAR subtypes (α, δ, and γ) on DNA synthesis and cell viability were examined in HT-29 colon cancer cells. Modulation of apoptosis related gene expression by PPARγ ligands was screened with cDNA arrays, and the results were confirmed by quantitative reverse transcription-polymerase chain reaction (RT-PCR) analysis.

Results: PPARα, PPARδ, and PPARγ were all expressed in HT-29 cells. PPARγ ligands, 15-deoxy-δ12,14-prostaglandin J2 (15d-PGJ2) and troglitazone (TGZ), suppressed DNA synthesis of HT-29 cells whereas ligands for PPARα and PPARδ had no significant effects. Both 15d-PGJ2 and TGZ induced HT-29 cell death in a dose dependent manner which was associated with an increase in fragmented DNA and was sensitive to a caspase inhibitor. Among several genes selected by cDNA array screening, quantitative RT-PCR analysis confirmed downregulation of c-myc expression and upregulation of c-jun and gadd153 expression by 15d-PGJ2 and TGZ. PPARγ induced apoptosis was antagonised by the presence of serum in the culture medium, and interaction between PPARγ signalling and cell survival signalling through the phosphatidylinositol 3-kinase pathway was suggested.

Conclusions: As c-myc is an important target gene of the adenomatous polyposis coli (APC)/β-catenin and/or APC/γ-catenin pathway, activation of PPARγ signalling appears to compensate for deregulated c-myc expression caused by mutated APC. The present results suggest the potential usefulness of PPARγ ligands for chemoprevention and treatment of colon cancers.

  • peroxisome proliferator activated receptor
  • apoptosis
  • colon cancer
  • PPAR, peroxisome proliferator activated receptor
  • RT-PCR, reverse transcription-polymerase chain reaction
  • 15d-PGJ2, 15-deoxy-δ12,14- prostaglandin J2
  • TGZ, troglitazone
  • APC, adenomatous polyposis coli
  • RXR, retinoid X receptor
  • cPGI, carbaprostacyclin
  • AT-RA, all-trans retinoic acid
  • 9c-RA, 9-cis-retinoic acid
  • FBS, fetal bovine serum
  • CHX, cycloheximide
  • RAR, retinoid A receptor
  • COX-2, cyclooxygenase 2
  • PI3-kinase, phosphatidylinositol 3-kinase
  • Tcf/Lef, T cell factor/lymphoid enhancer factor
  • PBS, phosphate buffered saline
  • BrdU, bromodeoxyuridine
  • MAP, mitogen activated protein

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