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Differentiation and reversal of malignant changes in colon cancer through PPARγ

Abstract

PPARγ is a nuclear receptor that has a dominant regulatory role in differentiation of cells of the adipose lineage, and has recently been shown to be expressed in the colon. We show here that PPARγ is expressed at high levels in both well- and poorly-differentiated adenocarcinomas, in normal colonic mucosa and in human colon cancer cell lines. Ligand activation of this receptor in colon cancer cells causes a considerable reduction in linear and clonogenic growth, increased expression of carcinoembryonic antigen and the reversal of many gene expression events specifically associated with colon cancer. Transplantable tumors derived from human colon cancer cells show a significant reduction of growth when mice are treated with troglitazone, a PPARγ ligand. These results indicate that the growth and differentiation of colon cancer cells can be modulated through PPARγ.

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Figure 1: PPARγ expression in human colonic tumors and cell lines.
Figure 2: Activation of PPARγ results in growth arrest.
Figure 3: Morphological and biochemical changes associated with PPARγ activation.
Figure 4: Activation of PPARγ leads to reversal of gene expression events associated with colonic malignancy.
Figure 5: PPARγ ligand reduces the growth rate of tumors in nude mice.

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Acknowledgements

We thank I. Summerhayes and P. Thomas for materials and discussion, and P. Lepage and E. Rosen for critically reviewing the manuscript. We also thank A. Levens for assistance in the preparation of this manuscript. This work was supported by grants from the NIH (R37 DK-31405), Novartis, Inc., and a Johnson & Johnson Research Award.

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Correspondence to Bruce M. Spiegelman.

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Sarraf, P., Mueller, E., Jones, D. et al. Differentiation and reversal of malignant changes in colon cancer through PPARγ. Nat Med 4, 1046–1052 (1998). https://doi.org/10.1038/2030

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