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) delta. In light of the recent finding that
PPARdelta is a target of
beta-catenin transactivation, it is important to determine whether this signaling pathway is operative during the development of
colorectal cancer. Analysis of
PPARdelta mRNA in matched normal and
tumor samples revealed that expression of
PPARdelta, similar to COX-2, is up-regulated in
colorectal carcinomas. In situ hybridization studies demonstrate that
PPARdelta is expressed in normal colon and localized to the epithelial cells at the very
tips of the mucosal glands. In contrast, expression of
PPARdelta mRNA in
colorectal tumors was more widespread with increased levels in transformed epithelial cells. Analysis of
PPARdelta 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
PPARdelta. In addition, the stable PGI(2) analog,
carbaprostacyclin, and a synthetic
PPARdelta agonist induced transactivation of endogenous
PPARdelta in human colon
carcinoma cells. We conclude from these observations that
PPARdelta, similar to COX-2, is aberrantly expressed in
colorectal tumors and that endogenous
PPARdelta is transcriptionally responsive to PGI(2). However, the functional consequence of
PPARdelta activation in colon
carcinogenesis still needs to be determined.