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[Cancer Research 62, 3282-3288, June 1, 2002]
© 2002 American Association for Cancer Research

Molecular Biology and Genetics

Peroxisome Proliferator-activated Receptors Modulate K-Ras-mediated Transformation of Intestinal Epithelial Cells1

Jinyi Shao, Hongmiao Sheng and Raymond N. DuBois2

Departments of Medicine and Cell Biology, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Department of Veterans Affairs Medical Center Nashville, Tennessee 37232

Activation of peroxisome proliferator-activated receptors (PPARs) exerts diverse effects on neoplastic cells. Recent work has shown that PPAR{delta} is up-regulated after loss of adenomatous polyposis coli tumor suppressor gene function and that transcriptional activation of the PPAR{gamma} nuclear receptor can lead to inhibition of carcinoma growth. In this study, we elucidate the regulation and functional importance of PPAR{gamma} and {delta} after K-Ras-transformation of intestinal epithelial cells. In conditionally K-Ras-transformed rat intestinal epithelial cells (IEC-iK-Ras), the level and activity of PPAR{delta} were markedly increased. PPAR{delta} up-regulation occurred due to increased mitogen-activated protein kinase activity and receptor activation required the endogenous production of prostacyclin via the cyclooxygenase-2 pathway. We also demonstrate that activation of the PPAR{gamma} nuclear receptor has antineoplastic effects in Ras-transformed cells. Activation of PPAR{gamma} resulted in a delay in transit through the G1 phase of the cell cycle that was associated with inhibition of phosphatidylinositol 3'-kinase/Akt activity and a reduction of cyclin D1 expression. Therefore, these two PPAR nuclear receptors, which are structurally related, have distinct roles during neoplastic transformation. PPAR{gamma} appears to modulate differentiation and signal growth inhibition, whereas PPAR{delta} is up-regulated by oncogenic Ras and activated by cyclooxygenase-2-derived prostaglandins.




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Copyright © 2002 by the American Association for Cancer Research.