Characteristics of the peroxisome proliferator activated receptor gamma (PPARgamma) ligand induced apoptosis in colon cancer cells.

Abstract

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-polymerase chain reaction (RT-PCR) analysis.

RESULTS:

PPARalpha, PPARdelta, and PPARgamma were all expressed in HT-29 cells. PPARgamma ligands, 15-deoxy-delta(12,)(14)-prostaglandin J2 (15d-PGJ2) and troglitazone (TGZ), suppressed DNA synthesis of HT-29 cells whereas ligands for PPARalpha 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 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. 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/or APC/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.

• Authors: T Shimada, K Kojima, K Yoshiura, H Hiraishi, A Terano
• Journal: Gut (Gut) Vol. 50 Issue 5 Pg. 658-64 (May 2002) ISSN: 0017-5749 [Print] England
• PMID: 11950812 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 15-deoxy-delta(12,14)-prostaglandin J2
• Chromans
• DNA, Complementary
• DNA, Neoplasm
• Ligands
• Neoplasm Proteins
• Receptors, Cytoplasmic and Nuclear
• Thiazoles
• Thiazolidinediones
• Transcription Factors
• Troglitazone
• Prostaglandin D2

Topics

• Apoptosis (drug effects)
• Cell Division
• Cell Survival (drug effects)
• Chromans (pharmacology)
• Colonic Neoplasms (metabolism, pathology)
• DNA, Complementary (genetics)
• DNA, Neoplasm (biosynthesis)
• Dose-Response Relationship, Drug
• Gene Expression Regulation, Neoplastic
• HT29 Cells
• Humans
• Ligands
• Neoplasm Proteins (metabolism)
• Oligonucleotide Array Sequence Analysis
• Polymerase Chain Reaction (methods)
• Prostaglandin D2 (analogs & derivatives, pharmacology)
• Receptors, Cytoplasmic and Nuclear (metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Signal Transduction
• Thiazoles (pharmacology)
• Thiazolidinediones
• Transcription Factors (metabolism)
• Troglitazone