There is evidence from both genetic and pharmacologic studies to suggest that the cyclooxygenase-2 (COX-2) enzyme plays a causal role in the development of colorectal cancer. However, little is known about the identity or role of the eicosanoid receptor pathways activated by COX-derived prostaglandins (PG). We previously have reported that COX-2-derived prostacyclin promotes embryo implantation in the mouse uterus via activation of the nuclear hormone receptor peroxisome proliferator-activated receptor (PPAR) ␦. In light of the recent finding that PPAR␦ is a target of ␤-catenin transactivation, it is important to determine whether this signaling pathway is operative during the development of colorectal cancer. Analysis of PPAR␦ mRNA in matched normal and tumor samples revealed that expression of PPAR␦, similar to COX-2, is up-regulated in colorectal carcinomas. In situ hybridization studies demonstrate that PPAR␦ is expressed in normal colon and localized to the epithelial cells at the very tips of the mucosal glands. In contrast, expression of PPAR␦ mRNA in colorectal tumors was more widespread with increased levels in transformed epithelial cells. Analysis of PPAR␦ and COX-2 mRNA in serial sections suggested they were colocalized to the same region within a tumor. Finally, transient transfection assays established that endogenously synthesized prostacyclin (PGI 2) could serve as a ligand for PPAR␦. In addition, the stable PGI2 analog, carbaprostacyclin, and a synthetic PPAR␦ agonist induced transactivation of endogenous PPAR␦ in human colon carcinoma cells. We conclude from these observations that PPAR␦, similar to COX-2, is aberrantly expressed in colorectal tumors and that endogenous PPAR␦ is transcriptionally responsive to PGI 2. However, the functional consequence of PPAR␦ activation in colon carcinogenesis still needs to be determined.

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