Vol. 305, Issue 2, 632-637, May 2003

Activation of Peroxisome Proliferator-Activated Receptor  Does Not Explain the Antiproliferative Activity of the Nonsteroidal Anti-Inflammatory Drug Indomethacin on Human Colorectal Cancer Cells

G. Hawcroft, S. H. Gardner and M. A. Hull

Molecular Medicine Unit, St. James's University Hospital, University of Leeds, Leeds, United Kingdom

The mechanism of the anticolorectal cancer activity of the nonsteroidal anti-inflammatory drug indomethacin is poorly understood. Indomethacin inhibits both cyclooxygenase (COX) isoforms, but it may also act via COX-independent targets. Indomethacin can bind and activate the transcription factor peroxisome proliferator-activated receptor (PPAR) . Moreover, natural and synthetic PPAR ligands can induce growth arrest and apoptosis of human colorectal cancer cells in vitro. Therefore, we tested the hypothesis that the antiproliferative activity of indomethacin on human colorectal cancer cells in vitro is explained by a PPAR-dependent mechanism of action. Human colorectal cancer cell lines SW480 and HCT116 both expressed functional PPAR. Indomethacin directly activated PPAR in both cell lines (HCT116 > SW480). A dominant-negative PPAR strategy was used to demonstrate that endogenous PPAR represses proliferation of HCT116 cells (compatible with tumor suppressor activity) but that the presence of functional PPAR is not necessary for the antiproliferative activity (or reduction in cyclin D1 protein) associated with indomethacin in vitro. In summary, indomethacin (>100 µM) directly activates PPAR in human colorectal cancer cells. However, PPAR activation does not underlie the antineoplastic activity of indomethacin on human colorectal cancer cells in vitro.