SIK2 enhances synthesis of fatty acid and cholesterol in ovarian cancer cells and tumor growth through PI3K/Akt signaling pathway
SIK2 enhances synthesis of fatty acid and cholesterol in ovarian cancer cells and tumor growth through PI3K/Akt signaling pathway
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SIK2通过PI3K/Akt信号通路增强卵巢癌细胞脂肪酸和胆固醇的合成以及肿瘤生长
DOI：
10.1038/s41419-019-2221-x
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发表时间：
2020-01-13
影响因子：
9
通讯作者：
Liu, Shujuan
中科院分区：
文献类型：
--
作者：
Zhao, Jing;Zhang, Xiaohong;Liu, Shujuan
盐诱导激酶2（SIK 2）已被确定为包括细胞代谢在内的多种生物过程的调节剂。最近的一项研究报道，SIK 2是脂肪细胞诱导的卵巢癌（OC）生存所必需的，通过促进脂肪酸氧化。然而，SIK 2是否也在OC细胞中的脂质合成中起作用仍然是难以捉摸的。在这里，我们发现SIK 2显著促进OC细胞中的脂质合成。一方面，SIK 2通过上调固醇调节元件结合蛋白1c（SREBP 1c）的表达，从而上调主要脂肪生成酶FASN的转录，增强脂肪酸合成。另一方面，SIK 2通过上调固醇调节元件结合蛋白2（SREBP 2）的表达从而上调主要胆固醇合成酶HMGCR的转录来促进胆固醇合成。PI 3 K/Akt信号通路参与了OC细胞SREBP 1c和SREBP 2的上调。此外，体外和体内试验表明，SIK 2调节的脂肪酸和胆固醇合成在OC细胞的生长中发挥着关键作用。我们的研究结果表明，SIK 2是OC细胞中脂质合成的关键调节因子，从而促进OC生长，这为该分子用作治疗这种恶性肿瘤的治疗靶点提供了强有力的证据。
Salt-inducible kinase 2 (SIK2) has been established as a regulator of diverse biological processes including cell metabolism. A recent study has reported that SIK2 is required for adipocyte-induced ovarian cancer (OC) survival through facilitating fatty acid oxidation. However, whether SIK2 also plays a role in the lipid synthesis in OC cells remains elusive. Here, we showed that SIK2 significantly promoted the lipid synthesis in OC cells. On the one hand, SIK2 enhanced fatty acid synthesis through upregulating the expression of sterol regulatory element binding protein 1c (SREBP1c) and thus the transcription of major lipogenic enzyme FASN. On the other hand, SIK2 promoted cholesterol synthesis through upregulating the expression of sterol regulatory element binding protein 2 (SREBP2) and thus the transcription of major cholesterol synthesis enzymes HMGCR. Moreover, PI3K/Akt signaling pathway was found to be involved in the upregulation of SREBP1c and SREBP2 in OC cells. Moreover, in vitro and in vivo assays indicated that the SIK2-regulated fatty acid and cholesterol synthesis played a critical role in the growth of OC cells. Our findings demonstrate that SIK2 is a critical regulator of lipid synthesis in OC cells and thus promotes OC growth, which provides a strong line of evidence for this molecule to be used as a therapeutic target in the treatment of this malignancy.