PPAR.DELTA. LINKS APC TO CHEMOPREVENTIVE DRUGS

摘要

PPAR.delta. was identified as a target of APC suppression through the analys is of global gene expression profiles in human colorectal cancer cells. PPAR.delta. expression is elevated in primary colorectal cancers and significantly repressed by APC in colorectal cancer cells. This repression i s mediated by two Tcf-4-responsive elements in the PPAR.delta. promotor. Reporters containing PPAR.delta.-responsive elements are repressed by sulindac, a non-steroidal anti-inflammatory (NSAID) agent which can reduce t he size and number of colon tumors in humans and animals with APC mutations. Furthermore, sulindac is able to specifically disrupt the ability of PPAR.delta. to bind its cognate recognition sequences. These findings sugges t a model wherein NSAIDs inhibit tumorigenesis through post-transcriptional modification of a gene that is normally regulated by APC. This novel molecul ar target for NSAIDs can be used to develop more effective chemopreventive agen ts for colorectal tumors.