Salt-Inducible Kinase 2 Couples Ovarian Cancer Cell Metabolism with Survival at the Adipocyte-Rich Metastatic Niche
Salt-Inducible Kinase 2 Couples Ovarian Cancer Cell Metabolism with Survival at the Adipocyte-Rich Metastatic Niche
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DOI：
10.1016/j.ccell.2016.06.020
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发表时间：
2016-08-08
期刊：
影响因子：
50.3
通讯作者：
Ahmed, Ahmed Ashour
中科院分区：
文献类型：
--
作者：
Miranda, Fabrizio;Mannion, David;Ahmed, Ahmed Ashour
富含脂肪细胞的微环境形成了卵巢癌转移的利基环境，但推动这一过程的机制尚不完全清楚。在这里，我们显示盐诱导蛋白2(SIK2)在富含脂肪细胞的转移性沉积中与卵巢原发灶相比过度表达。SIK2在卵巢癌细胞中过表达促进腹壁转移，而SIK2缺失则抑制体内转移。重要的是，脂肪细胞诱导SIK2的钙依赖激活和自磷酸化。激活的SIK2在增强AMPK诱导的乙酰辅酶A羧化酶的磷酸化和通过P85α-S154磷酸化激活PI3K/AKT通路方面具有双重作用。这些发现确定了SIK2位于脂肪细胞诱导的癌细胞信号级联反应的顶端，并为将SIK2靶向治疗卵巢癌提供了一个令人信服的理由。
The adipocyte-rich microenvironment forms a niche for ovarian cancer metastasis, but the mechanisms driving this process are incompletely understood. Here we show that salt-inducible kinase 2 (SIK2) is over-expressed in adipocyte-rich metastatic deposits compared with ovarian primary lesions. Overexpression of SIK2 in ovarian cancer cells promotes abdominal metastasis while SIK2 depletion prevents metastasis in vivo. Importantly, adipocytes induce calcium-dependent activation and autophosphorylation of SIK2. Activated SIK2 plays a dual role in augmenting AMPK-induced phosphorylation of acetyl-CoA carboxylase and in activating the PI3K/AKT pathway through p85 alpha-S154 phosphorylation. These findings identify SIK2 at the apex of the adipocyte-induced signaling cascades in cancer cells and make a compelling case for targeting SIK2 for therapy in ovarian cancer.