Peroxisome proliferator-activated receptor expression and activation in normal human colonic epithelial cells and tubular adenomas

Abstract

Objective Peroxisome proliferator-activated receptor (PPAR) ligands, widely used in type 2 diabetes treatment, have variably been shown to promote or prevent colon tumor formation in animal models and cell lines, but their role in normal human colon is unknown. The aim of this study was to determine PPARδ expression and function in normal human colonic epithelial cells and tubular adenomas.

Material and methods Short-term cultures of normal human colonic epithelial cells were established from biopsies obtained in 42 patients with normal colonoscopy. PPAR and adipophilin mRNA expression was assessed by real-time RT-PCR. PPARs were activated by ligands for PPARα (Wy-14643), PPARδ (GW-501516) and PPARγ (rosiglitazone or troglitazone). Cell viability was measured using the methyltetrazoleum assay, proliferation by thymidine incorporation, and DNA profiles by flow cytometry. PPAR mRNA levels in tubular adenomas or metaplastic polyps (n=12) were compared with those in controls.

Results PPARα and γ were consistently expressed in normal colonocytes while no PPAR expression could be detected. PPARγ activation induced a 7.5-fold increase in adipophilin expression (a PPAR-activated gene). PPARγ activation had no effect on viability or DNA profiles, but led to a 25% significant decrease in cell proliferation. Finally, a selective and significant 2.5-fold decrease in PPARα expression was observed in tubular adenomas, but not in metaplastic polyps, compared to controls.

Conclusions Our findings support the view that PPARγ ligands act as anti-proliferative agents rather than as promoters of tumorigenesis in normal human colon. Moreover, they raise interest in investigation of PPARα as a therapeutic target to prevent adenoma formation.

• Adenomatous polyps
• antidiabetic agents
• colorectal cancer
• peroxisome proliferator-activated receptors
• transcriptional regulatory element