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-δ^12,14-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.