Peroxisome proliferator-activated receptors modulate K-Ras-mediated transformation of intestinal epithelial cells.
Activation of peroxisome proliferator-activated receptors (PPARs) exerts diverse effects on neoplastic cells. Recent work has shown that PPARdelta is up-regulated after loss of adenomatous polyposis coli tumor suppressor gene function and that transcriptional activation of the PPARgamma nuclear receptor can lead to inhibition of carcinoma growth. In this study, we elucidate the regulation and functional importance of PPARgamma 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 PPARdelta were markedly increased. PPARdelta 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 PPARgamma nuclear receptor has antineoplastic effects in Ras-transformed cells. Activation of PPARgamma resulted in a delay in transit through the G(1) 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. PPARgamma appears to modulate differentiation and signal growth inhibition, whereas PPARdelta is up-regulated by oncogenic Ras and activated by cyclooxygenase-2-derived prostaglandins.
Shao
Jinyi
J
Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Sheng
Hongmiao
H
DuBois
Raymond N
RN
D000818:Animals; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D051546:Cyclooxygenase 2; D004790:Enzyme Induction; D011464:Epoprostenol / Q000502:physiology; D011905:Genes, ras / Q000502:physiology*; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000166:cytology / Q000502:physiology*; D007527:Isoenzymes / Q000096:biosynthesis; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis; D020033:Protein Isoforms; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000096:biosynthesis / Q000502:physiology*; D000077154:Rosiglitazone; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000819:agonists / Q000096:biosynthesis / Q000502:physiology*; D018631:ras Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology
D007527:Isoenzymes; D020033:Protein Isoforms; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D000077154:Rosiglitazone; D011464:Epoprostenol; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D020928:Mitogen-Activated Protein Kinases; D018631:ras Proteins