Activation of the phosphatidylinositol 3′-kinase/AKT pathway in neuroblastoma and its regulation by thioredoxin 1
Activation of the phosphatidylinositol 3′-kinase/AKT pathway in neuroblastoma and its regulation by thioredoxin 1
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DOI：
10.1016/j.humpath.2011.01.019
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发表时间：
2011-11-01
期刊：
影响因子：
3.3
通讯作者：
Vassal, Gilles
中科院分区：
文献类型：
--
作者：
Sartelet, Herve;Rougemont, Anne-Laure;Vassal, Gilles
神经母细胞瘤是一种生存率低的小儿恶性肿瘤。磷脂酰肌醇3 '-激酶/AKT途径是包括细胞凋亡在内的细胞过程的重要调节因子。硫氧还蛋白1是一种肿瘤抑制磷酸酶和张力蛋白同系物的抑制剂，在许多肿瘤中过表达。本研究的目的是探讨硫氧还蛋白1对磷脂酰肌醇3 '-激酶/AKT通路的激活和调节，以确定潜在的治疗靶点。使用抗磷脂酰肌醇3 '-激酶、AKT、活化AKT、磷酸酶和张力蛋白同系物、磷酸化磷酸酶和张力蛋白同系物、硫氧还蛋白1、表皮生长因子受体、血管内皮生长因子及其受体的抗体，对来自101名患者的肿瘤样品的组织微阵列进行免疫组织化学分析（血管内皮生长因子1和血管内皮生长受体2），血小板衍生生长因子受体，胰岛素样生长因子1受体，神经营养酪氨酸激酶受体2型，磷酸化的70-kd S6蛋白激酶、4 E-结合蛋白1和磷酸化的哺乳动物雷帕霉素靶标。使用3种神经母细胞瘤细胞系，我们研究了AKT特异性抑制剂（LY 294002，RAD 001）和硫氧还蛋白1单独或组合的细胞活力。我们发现激活的AKT和AKT分别在97%和98%的神经母细胞瘤中表达，尽管与硫氧还蛋白1相关的磷酸酶和张力蛋白同源物高表达。转移瘤中AKT表达高于原发瘤。胰岛素样生长因子1受体、2型酪氨酸激酶受体、血管内皮生长受体1和下游磷酸化70 kd S6蛋白激酶与激活的AKT相关。LY 294002和RAD 001显著降低AKT活性和细胞活力，并诱导G（1）细胞周期停滞。硫氧还蛋白1降低AKT抑制剂和阿霉素的细胞毒性，上调AKT活化，并诱导细胞生长。因此，血管内皮生长受体1、酪氨酸激酶受体2型、胰岛素样生长因子1受体和硫氧还蛋白1出现为优先致力于磷脂酰肌醇3 '-激酶/AKT途径活化，如在神经母细胞瘤中观察到的。硫氧还蛋白1是治疗干预的潜在靶点。(C)2011 Elsevier Inc. All rights reserved.
Neuroblastoma is a malignant pediatric tumor with poor survival. The phosphatidylinositol 3'-kinase/AKT pathway is a crucial regulator of cellular processes including apoptosis. Thioredoxin 1, an inhibitor of tumor-suppressor phosphatase and tensin homolog, is overexpressed in many tumors. The objective of this study was to explore phosphatidylinositol 3'-kinase/AKT pathway activation and regulation by thioredoxin 1 to identify potential therapeutic targets. Immunohistochemical analysis was done on tissue microarrays from tumor samples of 101 patients, using antibodies against phosphatidylinositol 3'-kinase, AKT, activated AKT, phosphatase and tensin homolog, phosphorylated phosphatase and tensin homolog, thioredoxin 1, epidermal growth factor receptor, vascular endothelial growth factor and receptors (vascular endothelial growth factor 1 and vascular endothelial growth receptor 2), platelet-derived growth factor receptors, insulin-like growth factor 1 receptor, neurotrophic tyrosine kinase receptor type 2, phosphorylated 70-kd S6 protein kinase, 4E-binding protein 1, and phosphorylated mammalian target of rapamycin. Using 3 neuroblastoma cell lines, we investigated cell viability with AKT-specific inhibitors (LY294002, RAD001) and thioredoxin 1 alone or in combination. We found activated AKT and AKT expressed in 97% and 98%, respectively, of neuroblastomas, despite a high expression of phosphatase and tensin homolog correlated with thioredoxin 1. AKT expression was greater in metastatic than primary tumors. Insulin-like growth factor 1 receptor, tyrosine kinase receptor type 2, vascular endothelial growth receptor 1, and downstream phosphorylated 70-kd S6 protein kinase were correlated with activated AKT. LY294002 and RAD001 significantly reduced AKT activity and cell viability and induced a G(1) cell cycle arrest. Thioredoxin 1 decreased cytotoxicity of AKT inhibitors and doxorubicin, up-regulated AKT activation, and induced cell growth. Thus, vascular endothelial growth receptor 1, tyrosine kinase receptor type 2, insulin-like growth factor 1 receptor, and thioredoxin 1 emerged as preferentially committed to phosphatidylinositol 3'-kinase/AKT pathway activation as observed in neuroblastoma. Thioredoxin 1 is a potential target for therapeutic intervention. (C) 2011 Elsevier Inc. All rights reserved.