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COLORECTAL CANCER |
(PPAR) ligand induced apoptosis in colon cancer cells
Department of Gastroenterology, Dokkyo University School of Medicine, Mibu, Tochigi 321-0293, Japan
Correspondence to:
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 
(PPAR) in the growth response of colon cancer cells has been suggested.
Aims: To investigate the characteristics of PPAR induced apoptosis in colon cancer cells.
Methods: The effects of ligands for each of the PPAR subtypes (
, 
, and ) on DNA synthesis and cell viability were examined in HT-29 colon cancer cells. Modulation of apoptosis related gene expression by PPAR ligands was screened with cDNA arrays, and the results were confirmed by quantitative reverse transcription-polymerase chain reaction (RT-PCR) analysis.
Results: PPAR, PPAR, and PPAR were all expressed in HT-29 cells. PPAR ligands, 15-deoxy-12,14-prostaglandin J2 (15d-PGJ2) and troglitazone (TGZ), suppressed DNA synthesis of HT-29 cells whereas ligands for PPAR and PPAR 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. PPAR induced apoptosis was antagonised by the presence of serum in the culture medium, and interaction between PPAR 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)/ß-catenin and/or APC/-catenin pathway, activation of PPAR signalling appears to compensate for deregulated c-myc expression caused by mutated APC. The present results suggest the potential usefulness of PPAR ligands for chemoprevention and treatment of colon cancers.
Keywords: peroxisome proliferator activated receptor; apoptosis; colon cancer
Abbreviations: PPAR, peroxisome proliferator activated receptor; RT-PCR, reverse transcription-polymerase chain reaction; 15d-PGJ2, 15-deoxy-12,14- 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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