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

colon cancer cells totally devoid of COX activity are PPARd was identified as a target of APC through the growth inhibited as effectively as cells producing COX analysis of global gene expression profiles in human (Hanif et al., 1996; Elder et al., 1997). Likewise, COX-1 colorectal cancer (CRC) cells. PPARd expression was and COX-2 null mouse embryo fibroblast cells remain elevated in CRCs and repressed by APC in CRC sensitive to the antiproliferative and antineoplastic efcells. This repression was mediated by b-catenin/Tcffects of NSAIDs (Zhang et al., 1999). In those colon 4-responsive elements in the PPARd promotor. The cancer cells producing COX, COX-produced prostaability of PPARs to bind eicosanoids suggested that glandins cannot rescue cells from NSAID-associated PPARd might be a target of chemopreventive nongrowth arrest in vivo or in vitro (Narisawa et al., 1984; steroidal anti-inflammatory drugs (NSAIDs). Reporters Hanif et al., 1996; Chan et al., 1998). The concentration containing PPARd-responsive elements were repressed of NSAIDs that inhibit growth is 10 to 100 times higher by the NSAID sulindac. Furthermore, sulindac was able than that required to inhibit COX activity, suggesting the to disrupt the ability of PPARd to bind its recognition existence of additional cellular targets (Hanif et al., 1996; sequences. These findings suggest that NSAIDs inhibit Ahnen, 1998; Charalambous et al., 1998; Simmons et tumorigenesis through inhibition of PPARd, the gene al., 1999). Finally, many studies have demonstrated that for which is normally regulated by APC. the COX-2 protein is elevated in the neoplastic epithelial