Stromal production of prostacyclin confers an antiapoptotic effect to colonic epithelial cells

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 PGF_2α, 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.