Activation of the peroxisome proliferator-activated receptor gamma promotes the development of colon tumors in C57BL/6J-APCMin/+ mice.
The development of colorectal cancer, one of the most frequent cancers, is influenced by prostaglandins and fatty acids. Decreased prostaglandin production, seen in mice with mutations in the cyclooxygenase 2 gene or in animals and humans treated with cyclooxygenase inhibitors, prevents or attenuates colon cancer development. There is also a strong correlation between the intake of fatty acids from animal origin and colon cancer. Therefore, the peroxisome proliferator-activated receptor gamma (PPARgamma), a downstream transcriptional mediator for prostaglandins and fatty acids which is highly expressed in the colon may be involved in this process. Activation of PPARgamma by two different synthetic agonists increased the frequency and size of colon tumors in C57BL/6J-APCMin/+ mice, an animal model susceptible to intestinal neoplasia. Tumor frequency was only increased in the colon, and did not change in the small intestine, coinciding with the colon-restricted expression of PPARgamma. Treatment with PPARgamma agonists increased beta-catenin levels both in the colon of C57BL/61-APCMin/+ mice and in HT-29 colon carcinoma cells. Genetic abnormalities in the Wnt/wingless/APC pathway, which enhance the transcriptional activity of the beta-catenin-T-cell factor/lymphoid enhancer factor 1 transcription complex, often underly the development of colon tumors. Our data indicate that PPARgamma activation modifies the development of colon tumors in C57BL/61-APCMin/+ mice.
Lefebvre
A M
AM
LBRE, U.325 INSERM, Département d'Athérosclérose, Institut Pasteur, Lille, France.
Chen
I
I
Desreumaux
P
P
Najib
J
J
Fruchart
J C
JC
Geboes
K
K
Briggs
M
M
Heyman
R
R
Auwerx
J
J
D000230:Adenocarcinoma / Q000473:pathology / Q000503:physiopathology*; D000818:Animals; D002839:Chromans / Q000494:pharmacology; D015179:Colorectal Neoplasms / Q000473:pathology / Q000503:physiopathology*; D051546:Cyclooxygenase 2; D003598:Cytoskeletal Proteins / Q000378:metabolism; D019073:HT29 Cells; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D000077154:Rosiglitazone; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones; D015534:Trans-Activators; D014157:Transcription Factors / Q000502:physiology*; D000077288:Troglitazone; D051176:beta Catenin
C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; D002839:Chromans; D003598:Cytoskeletal Proteins; D007527:Isoenzymes; D008565:Membrane Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D015534:Trans-Activators; D014157:Transcription Factors; D051176:beta Catenin; D000077154:Rosiglitazone; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D000077288:Troglitazone