In:
Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 97, No. 24 ( 2000-11-21), p. 13275-13280
Abstract:
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) δ. In light of the recent finding that PPARδ is a target of β-catenin transactivation, it is
important to determine whether this signaling pathway is operative during the development of colorectal cancer. Analysis of PPARδ mRNA
in matched normal and tumor samples revealed that expression of PPARδ, similar to COX-2, is up-regulated in colorectal carcinomas. In situ hybridization studies demonstrate that PPARδ
is expressed in normal colon and localized to the epithelial cells at the very tips of the mucosal glands. In contrast, expression of PPARδ
mRNA in colorectal tumors was more widespread with increased levels in transformed epithelial cells. Analysis of PPARδ 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 PPARδ. In addition, the stable PGI 2 analog, carbaprostacyclin, and a synthetic PPARδ
agonist induced transactivation of endogenous PPARδ in human colon carcinoma cells. We conclude from these observations that
PPARδ, similar to COX-2, is aberrantly expressed in colorectal tumors and that endogenous PPARδ is transcriptionally responsive to PGI 2 . However, the functional consequence of PPARδ
activation in colon carcinogenesis still needs to be determined.
Type of Medium:
Online Resource
ISSN:
0027-8424
,
1091-6490
DOI:
10.1073/pnas.97.24.13275
Language:
English
Publisher:
Proceedings of the National Academy of Sciences
Publication Date:
2000
detail.hit.zdb_id:
209104-5
detail.hit.zdb_id:
1461794-8
SSG:
11
SSG:
12
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