APC-dependent suppression of colon carcinogenesis by PPARγ

Geoffrey D. Girnun, Wendy M. Smith, Stavit Drori, Pasha Sarraf, Elisabetta Mueller, Charis Eng, Prashant Nambiar, Daniel W. Rosenberg, Roderick T. Bronson, Winfried Edelmann, Raju Kucherlapati, Frank J. Gonzalez, Bruce M. Spiegelman

Research output: Contribution to journalArticlepeer-review

246 Scopus citations


Activation of PPARγ by synthetic ligands, such as thiazolidinediones, stimulates adipogenesis and improves insulin sensitivity. Although thiazolidinediones represent a major therapy for type 2 diabetes, conflicting studies showing that these agents can increase or decrease colonic tumors in mice have raised concerns about the role of PPARγ in colon cancer. To analyze critically the role of this receptor, we have used mice heterozygous for Pparγ with both chemical and genetic models of this malignancy. Heterozygous loss of PPARγ causes an increase in β-catenin levels and a greater incidence of colon cancer when animals are treated with azoxymethane. However, mice with preexisting damage to Apc, a regulator of β-catenin, develop tumors in a manner insensitive to the status of PPARγ. These data show that PPARγ can suppress β-catenin levels and colon carcinogenesis but only before damage to the APC/β-catenin pathway. This finding suggests a potentially important use for PPARγ ligands as chemopreventative agents in colon cancer.

Original languageEnglish (US)
Pages (from-to)13771-13776
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number21
StatePublished - Oct 15 2002

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