The mechanism whereby cyclooxygenase-2 and its prostaglandin (PG) products are involved in colonic carcinogenesis is not fully understood. Prostacyclin (PGI2) is a major PG with antiapoptotic activity and is produced in the gastrointestinal tract. We reported previously that a human colorectal cancer (CRC) cell line, HCA-7, produces significant levels of PGE2, PGD2, thromboxane, and PGF2α, but not PGI2. We now report that human colonic fibroblast cell lines produce significant amounts of PGI2 and that fibroblast lines derived from normal-appearing colonic mucosa of hereditary nonpolyposis CRC individuals produce 50-fold more PGI2 than normal fibroblast lines derived from individuals with nonhereditary CRC. Coculture of HCA-7 cells with hereditary nonpolyposis CRC fibroblasts, but not normal fibroblasts, markedly reduced butyrate-induced apoptosis of HCA-7 cells. This antiapoptotic effect was inhibited by the cyclooxygenase-2 inhibitor rofecoxib and was restored by the stable PGI2 analogue carbaprostacyclin. PGI2 binds either G protein-coupled cell surface PGI2 receptor or the nuclear peroxisome proliferator-activated receptor (PPAR) δ. PPAR δ likely mediates this antiapoptotic effect because HCA-7 cells express this receptor, and another PPAR δ agonist, docosahexaenoic acid, mimics the effect. We propose a novel mechanism by which stromal production of PGI2 promotes survival of colonocytes through PPAR δ activation. This mechanism may have relevance to maintenance of cells in the normal crypt and to clonal expansion of mutant colonocytes during tumorigenesis.
|Original language||English (US)|
|Number of pages||4|
|State||Published - Apr 15 2003|
ASJC Scopus subject areas
- Cancer Research