Characteristics of the peroxisome proliferator activated receptor γ (PPARγ) ligand induced apoptosis in colon cancer cells

Background: Involvement of peroxisome proliferator activated receptor gamma (PPARgamma) in the growth response of colon cancer cells has been suggested, Aims: To investigate the characteristics of PPARgamma induced apoptosis in colon cancer cells. Methods: The effects of ligands for each of the PPAR subtypes (alpha, delta, and gamma) on DNA synthesis and cell viability were examined in HT-29 colon cancer cells. Modulation of apoptosis related gene expression by PPARgamma ligands was screened with cDNA arrays, and the results were confirmed by quantitative reverse transcription-polymerose chain reaction (RT-PCR) analysis. Results: PPARalpha, PPAR5, and PPARgamma were all expressed in HT-29 cells. PPARgamma ligands, 1 5-deoxy-Delta(12,14-) prostaglandin J(2) (15d-PGJ(2)) and troglitazone (TGZ), suppressed DNA synthesis of HT-29 cells whereas 1 ligands for PPARdelta and PPARdelta 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 cospase 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 gadd 753 expression by 15d-PGJ(2) and TGZ. PPARgamma induced apoptosis was antagonised by the presence of serum in the culture medium, and interaction between PPARgamma 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)beta-catenin and/orAPC/gamma-catenin pathway, activation of PPARgamma signalling appears to compensate for deregulated c-myc expression caused by mutated APC. The present results suggest the potential usefulness of PPARgamma ligands for chemoprevention and treatment of colon cancers.