PI3K/AKT/mTOR-dependent stabilization of oncogenic far-upstream element binding proteins in hepatocellular carcinoma cells.
PI3K/AKT/mTOR-dependent stabilization of oncogenic far-upstream element binding proteins in hepatocellular carcinoma cells.
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PI3K/AKT/MTOR依赖性稳定肝细胞癌细胞中的致癌远面元件结合蛋白。
DOI：
10.1002/hep.28357
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发表时间：
2016-03
期刊：
影响因子：
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通讯作者：
Breuhahn K
中科院分区：
文献类型：
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作者：
Samarin J;Laketa V;Malz M;Roessler S;Stein I;Horwitz E;Singer S;Dimou E;Cigliano A;Bissinger M;Falk CS;Chen X;Dooley S;Pikarsky E;Calvisi DF;Schultz C;Schirmacher P;Breuhahn K
远上游元件结合蛋白（FBP）家族的转录因子代表细胞通路枢纽，它们在肝癌（肝细胞癌[HCC]）中的过表达刺激肿瘤细胞增殖并与不良预后相关。在这里，我们确定癌基因的FBP在肝癌细胞中过表达的模式。使用扰动的方法（激酶抑制剂，小干扰RNA）和一种新的系统雷帕霉素依赖性激活AKT亚型，我们证明了磷脂酰肌醇-4，5-二磷酸3-激酶/AKT途径的活性参与肝癌细胞核FBP 1和FBP 2的富集。在人HCC组织中，磷酸化AKT与核FBP 1/2积累和增殖标记物KI 67的表达显著相关。雷帕霉素（mTOR）抑制或阻断其下游效应子真核翻译起始因子4 E活性的机制靶点同样降低了FBP 1/2浓度。mTORC 1抑制剂雷帕霉素减少了AKT质粒流体动力学基因递送后肝脏肿瘤中的FBP富集。此外，多激酶抑制剂索拉非尼显著降低了HCC细胞和多药耐药2缺陷小鼠中的FBP水平，这些小鼠由于严重炎症而发生HCC。两种FBP 1/2信使RNA都是高度稳定的，其中FBP 2比FBP 1更稳定。重要的是，磷脂酰肌醇-4，5-二磷酸3-激酶/AKT/mTOR信号传导的抑制以半胱天冬酶-3/-7依赖性方式显著降低FBP 1/2蛋白的稳定性。这些数据提供了对肝癌中FBP蛋白富集的转录非依赖性机制的深入了解;进一步的研究将不得不显示磷脂酰肌醇-4，5-二磷酸3-激酶/AKT/mTOR通路活性与半胱天冬酶介导的FBP稳定之间的这种先前未知的相互作用是否允许在FBP阳性HCC中建立干预策略。
Transcription factors of the far-upstream element-binding protein (FBP) family represent cellular pathway hubs, and their overexpression in liver cancer (hepatocellular carcinoma [HCC]) stimulates tumor cell proliferation and correlates with poor prognosis. Here we determine the mode of oncogenic FBP overexpression in HCC cells. Using perturbation approaches (kinase inhibitors, small interfering RNAs) and a novel system for rapalog-dependent activation of AKT isoforms, we demonstrate that activity of the phosphatidylinositol-4,5-biphosphate 3-kinase/AKT pathway is involved in the enrichment of nuclear FBP1 and FBP2 in liver cancer cells. In human HCC tissues, phospho-AKT significantly correlates with nuclear FBP1/2 accumulation and expression of the proliferation marker KI67. Mechanistic target of rapamycin (mTOR) inhibition or blockade of its downstream effector eukaryotic translation initiation factor 4E activity equally reduced FBP1/2 concentrations. The mTORC1 inhibitor rapamycin diminishes FBP enrichment in liver tumors after hydrodynamic gene delivery of AKT plasmids. In addition, the multikinase inhibitor sorafenib significantly reduces FBP levels in HCC cells and in multidrug resistance 2-deficient mice that develop HCC due to severe inflammation. Both FBP1/2 messenger RNAs are highly stable, with FBP2 being more stable than FBP1. Importantly, inhibition of phosphatidylinositol-4,5-biphosphate 3-kinase/AKT/mTOR signaling significantly diminishes FBP1/2 protein stability in a caspase-3/-7-dependent manner. These data provide insight into a transcription-independent mechanism of FBP protein enrichment in liver cancer; further studies will have to show whether this previously unknown interaction between phosphatidylinositol-4,5-biphosphate 3-kinase/AKT/mTOR pathway activity and caspase-mediated FBP stabilization allows the establishment of interventional strategies in FBP-positive HCCs.