Tumor suppressor and anti-inflammatory actions of PPARγ agonists are mediated via upregulation of PTEN
Tumor suppressor and anti-inflammatory actions of PPARγ agonists are mediated via upregulation of PTEN
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DOI：
10.1016/s0960-9822(01)00225-1
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发表时间：
2001-05-15
期刊：
影响因子：
9.2
通讯作者：
Macphee, CH
中科院分区：
文献类型：
--
作者：
Patel, L;Pass, I;Macphee, CH
PTEN肿瘤抑制基因通过拮抗磷脂酰肌醇3-激酶（PI 3-激酶）介导的信号级联反应调节多种细胞功能，包括细胞迁移、存活和增殖。然而，调控PTEN表达的机制尚不清楚。配体激活的核受体过氧化物酶体增殖体激活受体γ (PPAR γ)[2]已被证明可调节多种细胞类型的分化和/或细胞生长[3,4,5]，这导致PPAR γ与PTEN[1,6]一样可作为肿瘤抑制因子，PPAR γ也参与抗炎反应[7,8]，尽管这些作用的下游介质尚未明确定义。在这里，我们发现PPAR γ通过其选择性配体罗格列酮激活，上调了人类巨噬细胞、Caco2结直肠癌细胞和MCF7乳腺癌细胞中的PTEN表达，这种上调与PI 3-激酶活性降低相关，这是通过降低蛋白激酶b的磷酸化来测量的。反义介导的PPAR γ表达中断阻止了通常伴随单核细胞分化的PTEN的上调，并减少了巨噬细胞凋亡的比例，而电泳迁移率转移实验显示PPAR γ能够结合PTEN上游基因组序列中的两个应答元件。我们的研究结果表明PPAR γ通过调节炎症和肿瘤来源细胞中的PTEN表达来调节PI 3-激酶信号传导。
The PTEN tumor suppressor gene modulates several cellular functions, including cell migration, survival, and proliferation [1] by antagonizing phosphatidylinositol 3-kinase (PI 3-kinase)mediated signaling cascades. Mechanisms by which the expression of PTEN is regulated are, however, unclear. The ligand-activated nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR gamma) [2] has been shown to regulate differentiation and/or cell growth in a number of cell types [3, 4, 5], which has led to the suggestion that PPAR gamma, like PTEN [1, 6], could act as a tumor suppressor, PPAR gamma has also been implicated in antiinflammatory responses [7, 8], although downstream mediators of these effects are not well defined. Here, we show that the activation of PPAR gamma by its selective ligand, rosiglitazone, upregulates PTEN expression in human macrophages, Caco2 colorectal cancer cells, and MCF7 breast cancer cells, This upregulation correlated with decreased PI 3-kinase activity as measured by reduced phosphorylation of protein kinase B. One consequence of this was that rosiglitazone treatment reduced the proliferation rate of Caco2 and MCF7 cells, Antisense-mediated disruption of PPAR gamma expression prevented the upregulation of PTEN that normally accompanies monocyte differentiation and reduced the proportion of macrophages undergoing apoptosis, while electrophoretic mobility shift assays showed that PPAR gamma is able to bind two response elements in the genomic sequence upstream of PTEN, Our results demonstrate a role for PPAR gamma in regulating PI 3-kinase signaling by modulating PTEN expression in inflammatory and tumor-derived cells.