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

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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Figure 1: Effect of BRL-49,653 and troglitazone treatment on tumor number and size in the intestinal tract of C57BL/6J-APCMin/+ mice.
Figure 2: Expression of PPARγβ-catenin, COX-2 and β-actin in the intestinal tract of C57BL/6J-APCMin/+ mice.
Figure 3: Histological and histochemical analysis of colon tumors in C57BL/6J-APCMin/+ mice.
Figure 4: Effect of BRL-49,653 treatment on β-catenin and COX-2 expression in the colon.

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Acknowledgements

We acknowledge J.-F. Colombel, R. Evans, M. Leibowitz, D. Moller, B. Paulweber, J. Olefsky, E. Saez, A. Saltiel, P. Tontonoz, and members of the Auwerx lab for discussions and suggestions. Support of grants from Association pour la Recherche contre le Cancer (ARC), from INSERM, from Institut Pasteur de Lille, and from Ligand Pharmaceuticals is acknowledged. J. A. is a research director from CNRS.

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Correspondence to Johan Auwerx.

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Lefebvre, AM., Chen, I., Desreumaux, P. et al. Activation of the peroxisome proliferator-activated receptor γ promotes the development of colon tumors in C57BL/6J-APCMin/+ mice. Nat Med 4, 1053–1057 (1998). https://doi.org/10.1038/2036

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