Activation of Peroxisome Proliferator-Activated Receptor γ Does Not Explain the Antiproliferative Activity of the Nonsteroidal Anti-Inflammatory Drug Indomethacin on Human Colorectal Cancer Cells
- Molecular Medicine Unit, St. James's University Hospital, University of Leeds, Leeds, United Kingdom
- Dr. G. Hawcroft, Molecular Medicine Unit, Clinical Sciences Bldg., St. James's University Hospital, University of Leeds, Leeds LS9 7TF, UK. E-mail:medgha{at}stjames.leeds.ac.uk
Abstract
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) γ. Moreover, natural and synthetic PPARγ 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 PPARγ-dependent mechanism of action. Human colorectal cancer cell lines SW480 and HCT116 both expressed functional PPARγ. Indomethacin directly activated PPARγ in both cell lines (HCT116 > SW480). A dominant-negative PPARγ strategy was used to demonstrate that endogenous PPARγ represses proliferation of HCT116 cells (compatible with tumor suppressor activity) but that the presence of functional PPARγ 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 PPARγ in human colorectal cancer cells. However, PPARγ activation does not underlie the antineoplastic activity of indomethacin on human colorectal cancer cells in vitro.
Footnotes
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This work was funded by Yorkshire Cancer Research and NHS Northern and Yorkshire R&D. The salary of G.H. was obtained from Yorkshire Cancer Research and The West Riding Medical Research Trust. S.H.G. is funded by NHS Northern and Yorkshire R&D. M.A.H. holds a Medical Research Council (UK) Clinician Scientist Fellowship.
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DOI: 10.1124/jpet.103.048769
- Abbreviations:
- NSAID
- nonsteroidal anti-inflammatory drug
- CRC
- colorectal cancer
- COX
- cyclooxygenase
- PPAR
- peroxisome proliferator-activated receptor
- TZD
- thiaziolidinedione
- PG
- prostaglandin
- DMSO
- dimethyl sulfoxide
- PCR
- polymerase chain reaction
- PBS
- phosphate-buffered saline
- PBS/T
- phosphate-buffered saline/Tween 20
- ANOVA
- analysis of variance
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- Received January 6, 2003.
- Accepted January 31, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
