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

N. Shane Cutler, Ramona Graves-Deal, Bonnie J. LaFleur, Zhenqiang Gao, Bruce M. Boman, Robert H. Whitehead, Erin Terry, Jason D. Morrow, Robert J. Coffey

Research output: Contribution to journalArticlepeer-review

69 Scopus citations

Abstract

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, 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 languageEnglish (US)
Pages (from-to)1748-1751
Number of pages4
JournalCancer Research
Volume63
Issue number8
StatePublished - Apr 15 2003
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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