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Foreman JE , Sorg JM , McGinnis KS , Rigas B , Williams JL , Clapper ML , Gonzalez FJ , Peters JM
Regulation of Peroxisome Proliferator-Activated Receptor-beta/delta by the APC/beta-CATENIN Pathway and Nonsteroidal Antiinflammatory Drugs
Molecular Carcinogenesis. 2009 Oct;48(10) :942-952
PMID: 19415698 PMCID: PMC2790141 URL: https://www.ncbi.nlm.nih.gov/pubmed/19415698
AbstractStudies indicate that peroxisome proliferator-activated receptor-beta/delta (PPAR beta/delta) can either attenuate or potentiate colon cancer. One hypothesis suggests that PPAR beta/delta is upregulated by the adenomatous polyposis coli (APC)/beta-CATENIN pathway and a related hypothesis suggests that PPAR beta/delta is downregulated by nonsteroidal antiinflammatory drugs (NSAIDs). The present study examined these possibilities using in vivo and in vitro models. While APC/beta-CATENIN-dependent expression of CYCLIN D1 was observed in vivo and in vitro, expression of PPAR beta/delta was not different in colon or intestinal polyps from wild-type or Apc(min) heterozygous mice or in human colon cancer cell lines with mutations in APC and/or beta-CATENIN. No difference in the level of PPAR beta/delta was found in colon from wild-type or Apc(min) heterozygous mice following treatment with NO-donating aspirin (NO-ASA). NSAIDs inhibited cell growth in RKO (wild-type APC) and DLD1 (mutant APC) human colon cancer cell lines but expression of PPAR beta/delta was not downregulated in these cell lines in response to a broad concentration range of celecoxib, indomethacin, NS-398, or nimesulide. However, indomethacin caused an increase in PPAR beta/delta mRNA and protein that was accompanied with increased expression of a known PPAR beta/delta target gene. Interestingly, expression of PPAR alpha was also increased in the human colon cancer cell lines by several NSAIDs at the highest concentration examined. Results from these studies provide additional evidence indicating that PPAR beta/delta is not upregulated by the APC/beta-CATENIN pathway. Further, these studies suggest that increased PPAR beta/delta and/or PPAR alpha by NSAIDs in human colon cancer cell lines could contribute to the mechanisms underlying the chemopreventive effects of NSAIDs. (C) 2009 Wiley-Liss, Inc.
NotesForeman, Jennifer E. Sorg, Joseph M. McGinnis, Kathleen S. Rigas, Basil Williams, Jennie L. Clapper, Margie L. Gonzalez, Frank J. Peters, Jeffrey M. Wiley-liss Hoboken 503af