Feedback Activation of SGK3 and AKT Contributes to Rapamycin Resistance by Reactivating mTORC1/4EBP1 Axis via TSC2 in Breast Cancer
Feedback Activation of SGK3 and AKT Contributes to Rapamycin Resistance by Reactivating mTORC1/4EBP1 Axis via TSC2 in Breast Cancer
复制标题
SGK3 和 AKT 的反馈激活通过 TSC2 重新激活乳腺癌中的 mTORC1/4EBP1 轴，从而导致雷帕霉素耐药
DOI：
10.7150/ijbs.32489
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发表时间：
2019-01-01
影响因子：
9.2
通讯作者：
Li, Shanhu
中科院分区：
文献类型：
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作者：
Wang, Hongtao;Huang, Fang;Li, Shanhu
mTORC 1抑制剂如雷帕霉素及其类似物在临床上显示有限的抗肿瘤活性，其原因尚未明确阐明。在这里，我们致力于揭示雷帕霉素有限疗效的潜在机制，并发现4 EBP 1磷酸化的转运抑制导致乳腺癌细胞中帽依赖性翻译和细胞增殖。AKT仅部分促进4 EBP 1的再磷酸化。通过利用基于质谱的磷酸化蛋白质组学分析，我们鉴定了SGK 3作为参与4 EBP 1再磷酸化的有效激酶。SGK 3缺失抑制4 EBP 1磷酸化和帽依赖性翻译。重要的是，在67例临床乳腺癌标本中，4 EBP 1磷酸化与SGK 3活性呈正相关。此外，SGK 3缺失结合AKT抑制几乎阻断了雷帕霉素诱导的4 EBP 1再磷酸化，并在体外和体内MCF 7乳腺癌小鼠异种移植模型中显著增强了雷帕霉素诱导的生长抑制。从机制上讲，雷帕霉素对SGK 3的反馈激活依赖于hVps 34和mTORC 2，并通过磷酸化TSC 2重新激活mTORC 1/4 EBP 1轴。总的来说，我们的研究揭示了SGK 3在介导雷帕霉素耐药性中的关键作用，并为靶向SGK 3以改善mTOR靶向治疗提供了理论基础。
The mTORC1 inhibitors, such as rapamycin and its analogs, show limited antitumor activity in clinic, reasons for which have not been clearly elucidated. Here, we undertook an effort to uncover the mechanisms underlying the limited efficacy of rapamycin, and found that the transit suppression of 4EBP1 phosphorylation led to cap-dependent translation and cell proliferation in breast cancer cells. AKT only partially contributed to 4EBP1 re-phosphorylation. By taking advantage of mass spectrometry-based phosphoproteomic analysis, we identified SGK3 as a potent kinase involved in 4EBP1 re-phosphorylation. SGK3 deletion inhibited 4EBP1 phosphorylation and cap-dependent translation. Importantly, 4EBP1 phosphorylation was positively correlated with SGK3 activity in 67 clinical breast cancer specimens. Moreover, SGK3 deletion in combination with AKT inhibition almost blocked the 4EBP1 re-phosphorylation that was induced by rapamycin and profoundly enhanced rapamycin-induced growth inhibition in vitro and in an MCF7 breast cancer mouse xenograft model in vivo. Mechanistically, the feedback activation of SGK3 by rapamycin was dependent on hVps34 and mTORC2, and reactivated mTORC1/4EBP1 axis by phosphorylating TSC2. Collectively, our study reveals a critical role of SGK3 in mediating rapamycin resistance, and provides a rationale for targeting SGK3 to improve mTOR-targeted therapies.