Upregulated WDR26 serves as a scaffold to coordinate PI3K/ AKT pathway-driven breast cancer cell growth, migration, and invasion.
Upregulated WDR26 serves as a scaffold to coordinate PI3K/ AKT pathway-driven breast cancer cell growth, migration, and invasion.
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DOI：
10.18632/oncotarget.7439
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发表时间：
2016-04-05
期刊：
影响因子：
--
通讯作者：
Chen S
中科院分区：
文献类型：
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作者：
Ye Y;Tang X;Sun Z;Chen S
磷脂酰肌醇3-激酶(PI3K)/AKT信号通路在受体酪氨酸激酶和G蛋白偶联受体(GPCRs)下游传递信号，是乳腺癌中调控最严重的信号通路之一。PI3Ks和AKts由多种异构体组成，在乳腺癌细胞的生长和转移中发挥着截然不同的甚至相反的作用。然而，目前尚不清楚各种PI3K和AKT亚型的活性在乳腺癌进展过程中是如何协调的。以前，我们已经证明WDR26是一种新的WD40蛋白，它与Gβγ结合并促进Gβγ信号转导。在这里，我们证明了WDR26在高度恶性的乳腺肿瘤细胞系和人类乳腺癌样本中过表达，并且WDR26过表达与乳腺癌患者的生存期缩短有关。在高度恶性的细胞系(MDA-MB231、DU4475和BT549)中，WDR26表达的下调选择性地减轻了GPCR-而不是EGF受体刺激的PI3K/AKT信号转导和肿瘤细胞的生长、迁移和侵袭。相反，在恶性程度较低的细胞系(MCF7)中，WDR26的过度表达具有相反的效果。更多的研究表明，在gpr刺激的下游，WDR26作为一个支架，促进由Gβγ、PI3Kβ和AKT2组成的特定信号复合体的组装。在乳腺癌原位移植小鼠模型中，通过在MDA-MB231细胞中过表达WDR26突变体，扰乱了这种复合体的形成，取消了PI3K/AKT的激活，并抑制了肿瘤细胞的生长和转移。总之，我们的结果确定了一种新的机制，调控乳腺肿瘤细胞中依赖于GPCR的PI3K/AKT信号轴的激活，并准确地指出WDR26是乳腺癌的潜在治疗靶点。
The phosphatidylinositol 3-kinase (PI3K)/AKT pathway transmits signals downstream of receptor tyrosine kinases and G protein-coupled receptors (GPCRs), and is one of the most dysregulated pathways in breast cancer. PI3Ks and AKTs consist of multiple isoforms that play distinct and even opposite roles in breast cancer cell growth and metastasis. However, it remains unknown how the activities of various PI3K and AKT isoforms are coordinated during breast cancer progression. Previously, we showed WDR26 is a novel WD40 protein that binds Gβγ and promotes Gβγ signaling. Here, we demonstrate that WDR26 is overexpressed in highly malignant breast tumor cell lines and human breast cancer samples, and that WDR26 overexpression correlates with shortened survival of breast cancer patients. In highly malignant cell lines (MDA-MB231, DU4475 and BT549), downregulation of WDR26 expression selectively alleviated GPCR- but not EGF receptor-stimulated PI3K/AKT signaling and tumor cell growth, migration and invasion. In contrast, in a less malignant cell line (MCF7), WDR26 overexpression had the opposite effect. Additional studies indicate that downstream of GPCR stimulation, WDR26 serves as a scaffold that fosters assembly of a specific signaling complex consisting of Gβγ, PI3Kβ and AKT2. In an orthotopic xenograft mouse model of breast cancer, disrupting formation of this complex, by overexpressing WDR26 mutants in MDA-MB231 cells, abrogated PI3K/AKT activation and tumor cell growth and metastasis. Together, our results identify a novel mechanism regulating GPCR-dependent activation of the PI3K/AKT signaling axis in breast tumor cells, and pinpoint WDR26 as a potential therapeutic target for breast cancer.