SIK2 是一种中心体激酶，对于有丝分裂纺锤体的形成具有双极作用，为卵巢癌的治疗提供了一个潜在的靶点。
SIK2 is a centrosome kinase required for bipolar mitotic spindle formation that provides a potential target for therapy in ovarian cancer.
机构信息
Department of Experimental Therapeutics, M.D. Anderson Cancer Center, University of Texas, Houston, 77030, USA.
出版信息
Cancer Cell. 2010 Aug 9;18(2):109-21. doi: 10.1016/j.ccr.2010.06.018.
Abstract
Regulators of mitosis have been successfully targeted to enhance response to taxane chemotherapy. Here, we show that the salt inducible kinase 2 (SIK2) localizes at the centrosome, plays a key role in the initiation of mitosis, and regulates the localization of the centrosome linker protein, C-Nap1, through S2392 phosphorylation. Interference with the known SIK2 inhibitor PKA induced SIK2-dependent centrosome splitting in interphase while SIK2 depletion blocked centrosome separation in mitosis, sensitizing ovarian cancers to paclitaxel in culture and in xenografts. Depletion of SIK2 also delayed G1/S transition and reduced AKT phosphorylation. Higher expression of SIK2 significantly correlated with poor survival in patients with high-grade serous ovarian cancers. We believe these data identify SIK2 as a plausible target for therapy in ovarian cancers.
摘要
有丝分裂调控因子已被成功靶向以增强对紫杉烷化疗的反应。在这里，我们表明盐诱导激酶 2（SIK2）定位于中心体，在有丝分裂的起始中发挥关键作用，并通过 S2392 磷酸化调节中心体连接蛋白 C-Nap1 的定位。干扰已知的 SIK2 抑制剂 PKA 会诱导有丝分裂间期的 SIK2 依赖性中心体分裂，而 SIK2 耗竭则阻止有丝分裂中的中心体分离，使卵巢癌细胞对紫杉醇在培养物和异种移植物中敏感。SIK2 的耗竭也会延迟 G1/S 期过渡并减少 AKT 磷酸化。在高级别浆液性卵巢癌患者中，SIK2 的高表达与较差的生存显著相关。我们相信这些数据将 SIK2 确定为卵巢癌治疗的合理靶点。
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