Peroxisome proliferator-activated receptors modulate K-Ras-mediated transformation of intestinal epithelial cells.
Peroxisome proliferator-activated receptors modulate K-Ras-mediated transformation of intestinal epithelial cells.
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发表时间：
2002-06
期刊：
影响因子：
11.2
通讯作者：
J. Shao;H. Sheng;R. Dubois
中科院分区：
文献类型：
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作者：
J. Shao;H. Sheng;R. Dubois
过氧化物酶体增殖物激活受体 (PPAR) 的激活对肿瘤细胞产生多种影响。最近的研究表明，在腺瘤性息肉病大肠杆菌肿瘤抑制基因功能丧失后，PPARδ 上调，并且 PPARgamma 核受体的转录激活可导致癌症生长的抑制。在这项研究中，我们阐明了肠上皮细胞 K-Ras 转化后 PPARgamma 和 delta 的调节和功能重要性。在条件性 K-Ras 转化的大鼠肠上皮细胞 (IEC-iK-Ras) 中，PPARδ 的水平和活性显着增加。 PPARδ 上调是由于丝裂原激活蛋白激酶活性增加而发生的，并且受体激活需要通过环加氧酶 2 途径内源性产生前列环素。我们还证明 PPARγ 核受体的激活在 Ras 转化细胞中具有抗肿瘤作用。 PPARgamma 的激活导致细胞周期 G(1) 期延迟，这与磷脂酰肌醇 3'-激酶/Akt 活性的抑制和细胞周期蛋白 D1 表达的减少有关。因此，这两种结构相关的PPAR核受体在肿瘤转化过程中具有不同的作用。 PPARγ 似乎调节分化和信号生长抑制，而 PPARδ 则被致癌 Ras 上调并被环氧合酶 2 衍生的前列腺素激活。
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.