TY - JOUR
T1 - APC-dependent suppression of colon carcinogenesis by PPARγ
AU - Girnun, Geoffrey D.
AU - Smith, Wendy M.
AU - Drori, Stavit
AU - Sarraf, Pasha
AU - Mueller, Elisabetta
AU - Eng, Charis
AU - Nambiar, Prashant
AU - Rosenberg, Daniel W.
AU - Bronson, Roderick T.
AU - Edelmann, Winfried
AU - Kucherlapati, Raju
AU - Gonzalez, Frank J.
AU - Spiegelman, Bruce M.
PY - 2002/10/15
Y1 - 2002/10/15
N2 - 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.
AB - 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.
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U2 - 10.1073/pnas.162480299
DO - 10.1073/pnas.162480299
M3 - Article
C2 - 12370429
AN - SCOPUS:0037109043
SN - 0027-8424
VL - 99
SP - 13771
EP - 13776
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 21
ER -
