盐诱导激酶 2 将卵巢癌细胞代谢与富含脂肪的转移灶中的存活联系起来。
Salt-Inducible Kinase 2 Couples Ovarian Cancer Cell Metabolism with Survival at the Adipocyte-Rich Metastatic Niche.
机构信息
Ovarian Cancer Cell Laboratory, Weatherall Institute of Molecular Medicine, University of Oxford, Headington, Oxford OX3 9DS, UK; Nuffield Department of Obstetrics and Gynaecology, University of Oxford, Women's Centre, John Radcliffe Hospital, Oxford OX3 9DU, UK.
Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA; Center for RNAi and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
出版信息
Cancer Cell. 2016 Aug 8;30(2):273-289. doi: 10.1016/j.ccell.2016.06.020. Epub 2016 Jul 28.
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 overexpressed 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 p85α-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.
富含脂肪细胞的微环境为卵巢癌转移形成了一个龛位，但驱动这一过程的机制尚不完全清楚。在这里，我们发现盐诱导激酶 2（SIK2）在富含脂肪细胞的转移性沉积物中的表达高于卵巢原发性病变。在卵巢癌细胞中过表达 SIK2 可促进腹部转移，而 SIK2 耗竭可防止体内转移。重要的是，脂肪细胞诱导 SIK2 的钙依赖性激活和自身磷酸化。激活的 SIK2 在增强 AMPK 诱导的乙酰辅酶 A 羧化酶磷酸化和通过 p85α-S154 磷酸化激活 PI3K/AKT 途径方面发挥双重作用。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，并为针对卵巢癌的 SIK2 治疗提供了强有力的依据。
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