TITLE

THE ROLE OF PPAR[sub γ] IN THE ANTI-COLORECTAL CANCER ACTIVITY OF INDOMETHACIN

AUTHOR(S)
Hawcroft, G.; Gardner, S.H.; Hull, M.A.
PUB. DATE
April 2003
SOURCE
Gut;Apr2003 Supplement 1, Vol. 52, pA51
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
ABSTRACT
We have previously shown that indomethacin inhibits proliferation and induces apoptosis of several human colorectal cancer (CRC) cell lines in vitro. The anti-proliferative effects of indomethacin (100-600 µM) were associated with a decrease in express on of β-katenin and the β-catenin/TCF target gene cyclin D1 (CD1), in a COX-2independent manner. However, mutation of the TCF-binding site in the CD1 promoter did not abolish down-regulation of CD1 by indomethac n implying that other cis- and/or trans-acting elements must also mediate the effects of indomethac n on CD1 express on. It has previously been demonstrated that indomethacin can activate peroxisome proliferator-act voted receptor γ (PPARγ) in adipocytes and that growth arrest by PPARγ ligands can occur via PPARγ-dependent repression of CD1. Therefore the aim of this study was to investigate whether growth arrest and down-regulation of CD1 expression Dy indomethacin occurs via a mechanism involving PPARγ activation in human CRC cells. SW480 and HCT116 human CRC cells expressed PPAR7 mRNA and protein. PPARγ function was tested using the thiazolidinedione (TZD) PPARγ ligand troglitazone (10-50 µM) and a PPAR response element-luciferase (PPRE-tk-luc) reporter gene. Both SW480 and HCT116 cells contained functional PPARγ that was also activated by indomethacin (HCT116 > SW480). The functional relevance of PPARγ activation for the anti-proliferative effects of indomethacin was tested by transient transfection of dominant-negative PPARγ (dnPPARγ) in HCT116 cells, dnPPARγ inhibited TZD-induced PPRE-tk-luc activity. However, dnPPARγ expression did not inhibit indomethacin-induced down-regulation of CD1. Despite the fact that indomethacin directly activates PPARγ in human CRC cells, PPARγ activation does not explain the antiproliferative activity of indomethacin (including down-regulation of CD1) in human...
ACCESSION #
9747615

 

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