Activation of the peroxisome proliferator-activated receptor γ promotes the development of colon tumors in C57BL/6J-APCMin/+ mice

AM Lefebvre, I Chen, P Desreumaux, J Najib… - Nature medicine, 1998 - nature.com
AM Lefebvre, I Chen, P Desreumaux, J Najib, JC Fruchart, K Geboes, M Briggs, R Heyman…
Nature medicine, 1998nature.com
The development of colorectal cancer, one of the most frequent cancers, is influenced by
prostaglandins and fatty acids 1. 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 2, 3, 4. There
is also a strong correlation between the intake of fatty acids from animal origin and colon
cancer 5, 6. Therefore, the peroxisome proliferator-activated receptor γ (PPARγ; ref. 7), a …
Abstract
The development of colorectal cancer, one of the most frequent cancers, is influenced by prostaglandins and fatty acids 1. 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 2, 3, 4. There is also a strong correlation between the intake of fatty acids from animal origin and colon cancer 5, 6. Therefore, the peroxisome proliferator-activated receptor γ (PPARγ; ref. 7), a downstream transcriptional mediator for prostaglandins and fatty acids which is highly expressed in the colon 8, 9, may be involved in this process. Activation of PPARγ by two different synthetic agonists increased the frequency and size of colon tumors in C57BL/6J-APC Min/+ 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 PPARγ. Treatment with PPARγ agonists increased β-catenin levels both in the colon of C57BL/6J-APC Min/+ mice and in HT-29 colon carcinoma cells. Genetic abnormalities in the Wnt/wingless/APC pathway, which enhance the transcriptional activity of the β-catenin-T-cell factor/lymphoid enhancer factor 1 transcription complex, often underly the development of colon tumors. Our data indicate that PPARγ activation modifies the development of colon tumors in C57BL/6J-APC Min/+ mice.
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