SphK1 inhibitor SKI II inhibits the proliferation of human hepatoma HepG2 cells via the Wnt5A/β-catenin signaling pathway
SphK1 inhibitor SKI II inhibits the proliferation of human hepatoma HepG2 cells via the Wnt5A/β-catenin signaling pathway
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SphK1抑制剂SKI II通过Wnt5A/β-catenin信号通路抑制人肝癌HepG2细胞增殖
DOI：
10.1016/j.lfs.2016.02.098
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发表时间：
2016-04-15
期刊：
影响因子：
6.1
通讯作者：
Shao, Rong-Guang
中科院分区：
文献类型：
--
作者：
Liu, Hong;Zhang, Cai-Xia;Shao, Rong-Guang
目的：1-磷酸鞘氨醇（S1 P）促进细胞生长、增殖和存活。鞘氨醇激酶1（SphK 1）将鞘氨醇转化为S1 P，是癌症的关键启动子。我们先前发现SphK 1抑制剂II（SKI II）抑制人肝癌HepG 2细胞的生长并诱导细胞凋亡。但SKI II抑制肿瘤生长的确切调控机制和信号通路尚不清楚。主要方法：采用Western blot方法检测HepG 2细胞中β-catenin及Wnt/β-catenin信号相关分子的表达。RT-PCR检测β-catenin mRNA的表达。Wnt 5A基因被siRNA沉默。通过用结晶紫染色来确定殖民地形成。结果：SKI Ⅱ能降低β-catenin及其下游信号通路分子的表达，促进β-catenin的降解。此外，SKI II诱导Wnt 5A的表达，然后触发β-连环蛋白降解。结论：SKI Ⅱ抑制HepG 2细胞增殖与Wnt信号通路有关，Wnt 5A基因沉默可通过抑制β-catenin及其下游分子的表达而降低SKI Ⅱ的抗肿瘤作用。我们的研究揭示了一种新的信号通路参与SKI II抑制人肝癌细胞的细胞增殖。(C)2016 Elsevier Inc. All rights reserved.
Aim: Sphingosine 1-phosphate (S1P) promotes cell growth, proliferation and survival. Sphingosine kinase 1 (SphK1), which converts sphingosine to S1P, is a key promoter in cancer. We previously found that the SphK1 inhibitor II (SKI II), suppresses the cell growth and induces apoptosis in human hepatoma HepG2 cells. However, the precise regulatory mechanism and signaling pathway on SKI II inhibiting tumor growth remains unknown.Main methods: The expressions of beta-catenin and related molecules of Wnt/beta-catenin signal were detected by western blot in HepG2 cells. And the mRNA expression of beta-catenin was detected by RT-PCR. The Wnt5A gene was silenced by siRNA. The colony formation was determined by staining with crystal violet. And the cell growth was examined by SRB assay and BrdU assay.Key findings: We found that SKI II decreased the expression of beta-catenin and the downstream molecules of beta-catenin signal pathway and promotes the beta-catenin degradation. In addition, SKI II induced the expression of Wnt5A, and then triggered beta-catenin degradation. Furthermore, silencing Wnt5A decreased the anti-tumor effects of SKI II through recovering the expressions of beta-catenin and downstream molecules of beta-catenin signal pathway.Significance: SKI II-induced downregulation of HepG2 cell proliferation was associated with Wnt signaling pathway through Wnt5A-mediated beta-catenin degradation. Our study revealed that a novel signal pathway was involved in SKI II-inhibited cell proliferation in human hepatoma cells. (C) 2016 Elsevier Inc. All rights reserved.