PPARdelta is an APC-regulated target of nonsteroidal anti-inflammatory drugs.
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Journal: 1999/November - Cell
ISSN: 0092-8674
PUBMED: 10555149
Abstract:
PPARB was identified as a target of APC through the analysis of global gene expression profiles in human colorectal cancer (CRC) cells. PPARdelta expression was elevated in CRCs and repressed by APC in CRC cells. This repression was mediated by beta-catenin/Tcf-4-responsive elements in the PPARdelta promotor. The ability of PPARs to bind eicosanoids suggested that PPARdelta might be a target of chemopreventive non-steroidal anti-inflammatory drugs (NSAIDs). Reporters containing PPARdelta-responsive elements were repressed by the NSAID sulindac. Furthermore, sulindac was able to disrupt the ability of PPARdelta to bind its recognition sequences. These findings suggest that NSAIDs inhibit tumorigenesis through inhibition of PPARdelta, the gene for which is normally regulated by APC.
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Cell 99(3): 335-345
PMID: 10555149

PPARδ Is an APC-Regulated Target of Nonsteroidal Anti-Inflammatory Drugs

Johns Hopkins Oncology Center, Johns Hopkins University, Baltimore, Maryland 21231
The Howard Hughes Medical Institute, Johns Hopkins University, Baltimore, Maryland 21231
To whom correspondence should be addressed (ude.uhj.hclew.knilhclew@eklznik)
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Summary

PPAR δ was identified as a target of APC through the analysis of global gene expression profiles in human colorectal cancer (CRC) cells. PPARδ expression was elevated in CRCs and repressed by APC in CRC cells. This repression was mediated by β-catenin/Tcf-4-responsive elements in the PPARδ promotor. The ability of PPARs to bind eicosanoids suggested that PPARδ might be a target of chemopreventive non-steroidal anti-inflammatory drugs (NSAIDs). Reporters containing PPARδ-responsive elements were repressed by the NSAID sulindac. Furthermore, sulindac was able to disrupt the ability of PPARδ to bind its recognition sequences. These findings suggest that NSAIDs inhibit tumorigenesis through inhibition of PPARδ, the gene for which is normally regulated by APC.

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