Small-Molecule Inhibitors of Phosphatidylinositol 3-Kinase/Akt Signaling Inhibit Wnt/β-Catenin Pathway Cross-Talk and Suppress Medulloblastoma Growth
Small-Molecule Inhibitors of Phosphatidylinositol 3-Kinase/Akt Signaling Inhibit Wnt/β-Catenin Pathway Cross-Talk and Suppress Medulloblastoma Growth
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DOI：
10.1158/0008-5472.can-09-0578
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发表时间：
2010-01-01
期刊：
影响因子：
11.2
通讯作者：
Johnsen, John Inge
中科院分区：
文献类型：
--
作者：
Baryawno, Ninib;Sveinbjornsson, Baldur;Johnsen, John Inge
β-连环蛋白和受体激酶通路的激活经常发生在髓母细胞瘤中，这是最常见的儿科恶性脑肿瘤。在这项研究中，我们表明 β-连环蛋白和磷脂酰肌醇 3-激酶 (PI3K)/Akt 信号通路之间的分子串扰对于维持髓母细胞瘤病理生理学至关重要。通过免疫组织化学在所有检查的原发性髓母细胞瘤中检测到磷酸肌醇依赖性蛋白激酶 1 (PDK1)、Akt 和糖原合酶激酶 3 beta (GSK-3 beta) 的组成型激活 (n = 41)。针对 PI3K/Akt 信号通路的小分子抑制剂通过抑制 GSK-3 beta 活性来影响 β-catenin 信号传导，导致 β-catenin 保留在细胞质中并减少其靶基因 cyclin D1 和 c-Myc 的表达。 PDK1抑制剂OSU03012诱导髓母细胞瘤细胞线粒体依赖性凋亡，并以协同或相加的方式增强化疗药物的细胞毒作用。在体内，OSU03012 以剂量依赖性方式抑制已建立的髓母细胞瘤异种移植肿瘤的生长，并增强雷帕霉素抑制剂 CCI-779 的哺乳动物靶点的抗肿瘤作用。这些发现证明了髓母细胞瘤中 PI3K/Akt 和 β-catenin 通路之间的串扰的重要性，并使 PI3K/Akt 信号通路作为治疗该疾病的治疗靶点合理化。癌症研究； 70(1)； 266-76。 (C) 2010 AACR。
Activation of the beta-catenin and receptor kinase pathways occurs often in medulloblastoma, the most common pediatric malignant brain tumor. In this study, we show that molecular cross-talk between the beta-catenin and phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathways is crucial to sustain medulloblastoma pathophysiology. Constitutive activation of phosphoinositide-dependent protein kinase 1 (PDK1), Akt, and glycogen synthase kinase 3 beta (GSK-3 beta) was detected by immunohistochemistry in all primary medulloblastomas examined (n = 41). Small-molecule inhibitors targeting the PI3K/Akt signaling pathway affected beta-catenin signaling by inhibition of GSK-3 beta activity, resulting in cytoplasmic retention of beta-catenin and reduced expression of its target genes cyclin D1 and c-Myc. The PDK1 inhibitor OSU03012 induced mitochondrial-dependent apoptosis of medulloblastoma cells and enhanced the cytotoxic effects of chemotherapeutic drugs in a synergistic or additive manner. In vivo, OSU03012 inhibited the growth of established medulloblastoma xenograft tumors in a dose-dependent manner and augmented the antitumor effects of mammalian target of rapamycin inhibitor CCI-779. These findings demonstrate the importance of cross-talk between the PI3K/Akt and beta-catenin pathways in medulloblastoma and rationalize the PI3K/Akt signaling pathway as a therapeutic target in treatment of this disease. Cancer Res; 70(1); 266-76. (C) 2010 AACR.