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

Jinyi Shao, Hongmiao Sheng, Raymond N. DuBois

Research output: Contribution to journalArticle

87 Citations (Scopus)

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
Externally publishedYes

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Peroxisome Proliferator-Activated Receptors
Epithelial Cells
Cytoplasmic and Nuclear Receptors
Cyclooxygenase 2
Phosphatidylinositol 3-Kinase
Adenomatous Polyposis Coli
Cyclin D1
G1 Phase
Epoprostenol
Growth
Mitogen-Activated Protein Kinases
Tumor Suppressor Genes
Antineoplastic Agents
Transcriptional Activation
Prostaglandins
Cell Cycle
Up-Regulation

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Peroxisome proliferator-activated receptors modulate K-Ras-mediated transformation of intestinal epithelial cells. / Shao, Jinyi; Sheng, Hongmiao; DuBois, Raymond N.

In: Cancer Research, Vol. 62, No. 11, 01.06.2002, p. 3282-3288.

Research output: Contribution to journalArticle

Shao, Jinyi ; Sheng, Hongmiao ; DuBois, Raymond N. / Peroxisome proliferator-activated receptors modulate K-Ras-mediated transformation of intestinal epithelial cells. In: Cancer Research. 2002 ; Vol. 62, No. 11. pp. 3282-3288.
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