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

Tong-Chuan He1, Timothy A. Chan1, Bert Vogelstein2, and Kenneth W. Kinzler1

 

1 Johns Hopkins Oncology Center and, Johns Hopkins University, Baltimore, Maryland 21231
2 The Howard Hughes Medical Institute, Johns Hopkins University, Baltimore, Maryland 21231

Cell, Vol. 99, 335–345, October, 1999, Copyright 1999 by Cell Press

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Abstract

PPARdelta 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 nonsteroidal 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.

Corresponding author: Kenneth W. Kinzler, (410) 955 8886 (phone), (410) 955 0548 (fax), kinzlke@welchlink.welch.jhu.edu

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