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

• Published in: Gut 2002-05, Vol.50 (5), p.658-664
• Main Authors: Shimada, T, Kojima, K, Yoshiura, K, Hiraishi, H, Terano, A
• Format: Article
• Language: English
• Subjects: 14- prostaglandin J2; 15-deoxy-δ12; 15d-PGJ2; 9-cis-retinoic acid; 9c-RA; adenomatous polyposis coli; all-trans retinoic acid; APC; apoptosis; Apoptosis - drug effects; AT-RA; Biological and medical sciences; BrdU; bromodeoxyuridine; carbaprostacyclin; Cell Division; Cell Survival - drug effects; Chromans - pharmacology; CHX; colon cancer; Colonic Neoplasms - metabolism; Colonic Neoplasms - pathology; Colorectal Cancer; COX-2; cPGI; cycloheximide; cyclooxygenase 2; DNA, Complementary - genetics; DNA, Neoplasm - biosynthesis; Dose-Response Relationship, Drug; FBS; fetal bovine serum; Gastroenterology. Liver. Pancreas. Abdomen; Gene Expression Regulation, Neoplastic; HT29 Cells; Humans; Ligands; Medical sciences; mitogen activated protein; Neoplasm Proteins - metabolism; Oligonucleotide Array Sequence Analysis; PBS; peroxisome proliferator activated receptor; phosphate buffered saline; phosphatidylinositol 3-kinase; PI3-kinase; Polymerase Chain Reaction - methods; PPAR; Prostaglandin D2 - analogs & derivatives; Prostaglandin D2 - pharmacology; RAR; Receptors, Cytoplasmic and Nuclear - metabolism; retinoid A receptor; retinoid X receptor; Reverse Transcriptase Polymerase Chain Reaction; reverse transcription-polymerase chain reaction; RT-PCR; RXR; Signal Transduction; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; T cell factor/lymphoid enhancer factor; Tcf/Lef; TGZ; Thiazoles - pharmacology; Thiazolidinediones; Transcription Factors - metabolism; Troglitazone; Tumors
• ISSN: 0017-5749; 1468-3288; 1458-3288
• DOI: 10.1136/gut.50.5.658

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.