Deregulated Gab2 phosphorylation mediates aberrant AKT and STAT3 signaling upon PIK3R1 loss in ovarian cancer
Deregulated Gab2 phosphorylation mediates aberrant AKT and STAT3 signaling upon PIK3R1 loss in ovarian cancer
复制标题
卵巢癌中 PIK3R1 缺失后 Gab2 磷酸化失调介导异常 AKT 和 STAT3 信号转导
DOI：
10.1038/s41467-019-08574-7
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发表时间：
2019-02-12
影响因子：
16.6
通讯作者：
Cheung, Lydia W. T.
中科院分区：
文献类型：
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作者：
Li, Xinran;Mak, Victor C. Y.;Cheung, Lydia W. T.
在所有癌症类型中，PIK 3R 1（p85 α）的拷贝数丢失最常见于卵巢癌。在这里，我们报告卵巢癌细胞表现出一系列的致瘤表型后敲除PIK 3R 1。PIK 3R 1缺失通过诱导对接蛋白Gab 2磷酸化的变化激活AKT和p110非依赖性JAK 2/STAT 3信号传导，从而分别解除对AKT的负抑制和促进JAK 2/STAT 3信号体的组装。导致AKT活化的其他机制包括p110 α激酶活性增强和PTEN水平降低。PIK 3R 1缺失使卵巢癌细胞容易受到AKT或JAK 2/STAT 3抑制的影响。与单药治疗相比，AKT和STAT 3抑制剂的组合显著增加了抗肿瘤作用。总之，我们的研究结果为基于机制的治疗方法提供了理论基础，该方法靶向PIK 3R 1缺失的肿瘤。
Copy number loss of PIK3R1 (p85 alpha) most commonly occurs in ovarian cancer among all cancer types. Here we report that ovarian cancer cells manifest a spectrum of tumorigenic phenotypes upon knockdown of PIK3R1. PIK3R1 loss activates AKT and p110-independent JAK2/STAT3 signaling through inducing changes in the phosphorylation of the docking protein Gab2, thereby relieving the negative inhibition on AKT and promoting the assembly of JAK2/STAT3 signalosome, respectively. Additional mechanisms leading to AKT activation include enhanced p110 alpha kinase activity and a decrease in PTEN level. PIK3R1 loss renders ovarian cancer cells vulnerable to inhibition of AKT or JAK2/STAT3. The combination of AKT and STAT3 inhibitors significantly increases the anti-tumor effect compared to single-agent treatments. Together, our findings provide a rationale for mechanism-based therapeutic approach that targets tumors with loss of PIK3R1.