Peroxisome proliferator-activated receptors modulate K-Ras-mediated transformation of intestinal epithelial cells

Jinyi Shao, Hongmiao Sheng, Raymond N. DuBois

    Research output: Contribution to journalArticlepeer-review

    89 Scopus citations

    Abstract

    Activation of peroxisome proliferator-activated receptors (PPARs) exerts diverse effects on neoplastic cells. Recent work has shown that PPARδ is up-regulated after loss of adenomatous polyposis coli tumor suppressor gene function and that transcriptional activation of the PPARγ nuclear receptor can lead to inhibition of carcinoma growth. In this study, we elucidate the regulation and functional importance of PPARγ and δ 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 PPARδ were markedly increased. PPARδ 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 PPARγ nuclear receptor has antineoplastic effects in Ras-transformed cells. Activation of PPARγ 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. PPARγ appears to modulate differentiation and signal growth inhibition, whereas PPARδ is up-regulated by oncogenic Ras and activated by cyclooxygenase-2-derived prostaglandins.

    Original languageEnglish (US)
    Pages (from-to)3282-3288
    Number of pages7
    JournalCancer Research
    Volume62
    Issue number11
    StatePublished - Jun 1 2002

    ASJC Scopus subject areas

    • Oncology
    • Cancer Research

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