Role of PPARγ in colon cancer cells

Colorectal cancer (CRC) is the third most commonly diagnosed cancer in Western countries. The treatment of CRC is focused on identifying gene networks involved in regulation of cell growth, differentiation and cell death. PPARs (Peroxisome Proliferator - Activated Receptors) are nuclear hormone receptors. After binding of ligand to receptor, PPAR forms a heterodimeric complex with retinoid X receptor which then binds to PPAR response element on DNA. This interaction is responsible for the regulation of genes involved in glucose and lipid metabolism, differentiation and apoptosis. There are three PPAR isoforms: PPARα, PPAR β/δ and PPARγ. The expression of PPARγ has been described in both normal and many different cancer cell types. In colon tumors, increased PPARγ level was detected. Thus, our interest was focused on the role of PPARγ in regulation of colon tumorigenesis.

First, we compared the expression of PPARγ in 11 human colon cancer cell lines with different grade of malignancy by Western blotting. The highest expression was observed in adenocarcinoma HT-29 cells. Expression of PPARγ was confirmed by immunocytochemistry fluorescent staining. Next, we analyzed the effects of PPARγ synthetic ligands – thiazolidinediones (rosiglitazone, ciglitazone) and compared them with the effects of short chain fatty acid – sodium butyrate (NaBt). Butyrate is produced by gastrointestinal tract by anaerobic fermentation of fiber and can modulate proliferation, differentiation, and apoptosis of colon cancer cells. Rosiglitazone and ciglitazone decreased proliferation of colon cancer cell lines in dose-dependent manner. Interestingly, real-time cell analysis using xCELLigence demonstrated that HCT-116 p21-/- were more sensitive to rosiglitazone/ciglitazone treatment than wild type HCT-116. NaBt treatment dose-dependently reduced proliferation of colon cancer cell lines, too. And finally, the Luciferase assay was performed to analyze PPARγ activation and it detected that rosiglitazone, ciglitazone as well as NaBt activated this receptor. Moreover, NaBt increased PPARγ activity much more intensively than rosiglitazone or ciglitazone in colon cancer cell lines studied.

In conclusion, colon cancer cell lines studied expressed PPARγ with different intensity. Rosiglitazone, ciglitazone as well as NaBt decreased cell proliferation and activated PPARγ. NaBt appeared as more potent activator of PPARγ than rosiglitazone/ciglitazone in colon cancer cell lines.

This work was supported by grant IGA MZ ČR NT/11201-5 and grant Czech Science Foundation No. 7301/11/1730.