FOXO3 is inhibited by oncogenic PI3K/Akt signaling but can be reactivated by the NSAID sulindac sulfide.
FOXO3 is inhibited by oncogenic PI3K/Akt signaling but can be reactivated by the NSAID sulindac sulfide.
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DOI：
10.1210/jc.2010-2453
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发表时间：
2011-07
期刊：
影响因子：
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通讯作者：
C. Weidinger;K. Krause;K. Mueller;Antje Klagge;D. Fuhrer
中科院分区：
文献类型：
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作者：
C. Weidinger;K. Krause;K. Mueller;Antje Klagge;D. Fuhrer
磷脂酰肌醇3-激酶(PI3K)/Akt通路的过度激活是甲状腺癌发生的关键触发因素。最近来自其他肿瘤实体的研究结果表明，PI3K/ akt驱动的癌变主要涉及肿瘤抑制转录因子叉头盒O (FOXO)-3的失活。然而，人们对FOXO3在甲状腺中的作用知之甚少。目的：研究甲状腺癌基因BRAFV600E、H-RASV12和p110α (H1074R)在体外对PI3K下游靶点FOXO3调控的影响。此外，我们在44例人甲状腺肿瘤中评估了10号染色体上磷酸酶和紧张素同源物缺失（PTEN）的表达对FOXO3转录活性的影响。最后，我们试图通过非甾体抗炎药磺胺酸硫（SS）来调节FOXO3活性。结果我们发现p110α H1074R的过表达通过核排斥导致FOXO3失活。在体内，我们观察到PTEN表达与FOXO3转录激活之间存在直接相关性。在体外，我们发现SS刺激逆转了PI3K/ akt驱动的FOXO3失活，导致其核重新定位，并在良性（frt1 -5）和恶性人甲状腺细胞（fcc -133）中联合诱导抗增殖FOXO靶基因Gadd45α和p27（kip1）和促凋亡FOXO靶基因Bim。与此一致的是，SS促进了甲状腺细胞的细胞周期阻滞和凋亡，这可以通过转染外源性FOXO3来放大。结论：我们的数据表明，促凋亡FOXO3的失调是PI3K/ akt介导的甲状腺癌发生的核心步骤。因此，SS可能是针对PI3K/Akt/FOXO3信号异常的甲状腺肿瘤的一种有吸引力的药理工具。
BACKGROUND Overactivation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway has emerged as a pivotal trigger of thyroid carcinogenesis. Recent findings from other tumor entities revealed that PI3K/Akt-driven carcinogenesis critically involves the inactivation of the tumor-suppressive transcription factor Forkhead box O (FOXO)-3. However, little is known about FOXO3 in the thyroid context. AIMS We sought to investigate the influence of the thyroid oncogenes BRAFV600E, H-RASV12, and p110α (H1074R) on the regulation of the PI3K downstream target FOXO3 in vitro. Furthermore, the impact of the expression of phosphatase and tensin homolog deleted from chromosome 10 (PTEN) on the transcriptional activity of FOXO3 was assessed in a panel of 44 human thyroid tumors. Finally, we tried to modulate FOXO3 activity pharmacologically with help of the nonsteroidal antiinflammatory drug sulindac sulfide (SS). RESULTS We found that the overexpression of p110α H1074R results in the inactivation of FOXO3 via its nuclear exclusion. In vivo, we observed a direct correlation between PTEN expression and the transcriptional activation of FOXO3. In vitro, we found that stimulation with SS reversed PI3K/Akt-driven inactivation of FOXO3, resulting in its nuclear relocation and a combined induction of the antiproliferative FOXO target genes Gadd45α and p27(kip1) and the proapoptotic FOXO target gene Bim in benign (FRTL-5) and malignant human thyrocytes (FTC-133). In agreement with this, SS promoted the cell cycle arrest and apoptosis in thyroid cells, which could be amplified by the transfection of exogenous FOXO3. CONCLUSION Our data suggest that deregulation of proapoptotic FOXO3 represents a central step in PI3K/Akt-mediated thyroid carcinogenesis. Thus, SS might represent an attractive pharmacological tool for targeting thyroid neoplasia with aberrant PI3K/Akt/FOXO3 signaling.