Abstract

Background and aims: The activation of the peroxisome proliferator-activated receptor γ (PPARγ) that forms heterodimers with retinoid X receptors (RXRs) elicits an antineoplastic effect on colorectal cancer. It was previously reported that the accumulation of the non-functional phosphorylated form of RXRα (p-RXRα) interfered with its signalling and promoted the growth of hepatoma cells. In this study the effects of p-RXRα on the ability of RXRα and PPARγ ligands to inhibit growth in colon cancer cells was examined.

Methods: The effects of the combination of the PPARγ ligand ciglitazone and the RXRα lignad 9-cis-retinoic acid (RA) on inhibition of cell growth in Caco2 human colon cancer cells which express high levels of p-RXRα protein were examined

Results: The RXRα protein was phospholylated and also accumulated in human colon cancer tissue samples as well as human colon cancer cell lines. When the phosphorylation of RXRα was inhibited by the MEK inhibitor PD98059 or by transfection with a point-mutated RXRα, which mimicked the unphosphorylated form, the combination of 9-cisRA and ciglitazone synergistically inhibited the cell growth and induced apoptosis. The combined treatment with these agents also caused a decrease in the expression levels of both cyclo-oxygenase-2 (COX-2) and c-Jun proteins and mRNAs. Reporter assays indicated that this combination induced the transcriptional activity of the peroxisome proliferator-responsive element promoter and also inhibited that of the AP-1 promoter.

Conclusion: A malfunction of RXRα due to phosphorylation is associated with colorectal cancer. Therefore, the inhibition of phosphorylation of RXRα and the activation of the RXR–PPARγ heterodimer by their respective ligands may be useful in the chemoprevention and/or treatment of colorectal cancer.