Longdaysin inhibits Wnt/beta-catenin signaling and exhibits antitumor activity against breast cancer
Longdaysin inhibits Wnt/beta-catenin signaling and exhibits antitumor activity against breast cancer
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Longdaysin 抑制 Wnt/β-catenin 信号传导并表现出抗乳腺癌活性
DOI：
10.2147/ott.s193024
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发表时间：
2019
影响因子：
4
通讯作者：
Lu Desheng
中科院分区：
文献类型：
--
作者：
Xiong Yanpeng;Zhou Liang;Su Zijie;Song Jiaxing;Sun Qi;Liu Shan-Shan;Xia Yuqing;Wang Zhongyuan;Lu Desheng
背景：CK 1参与调节Wnt/β-caten信号通路，是乳腺癌治疗的一个有前景的靶点。嘌呤衍生物longdaysin最近被鉴定为通过靶向蛋白激酶CK 1 δ、CK 1 α和ERK 2的细胞昼夜节律的新型调节剂。然而，龙胆草素的抗肿瘤活性及其机制尚不清楚。方法：采用SuperTOPFlash报告系统，研究长日照素对Wnt/beta-catenin信号通路的抑制作用。通过蛋白质印迹检测磷酸化LRP 6、总LRP 6、DVL 2、活性β-连环蛋白和总β-连环蛋白的水平。使用实时PCR测定Wnt靶基因的表达。通过集落形成实验检测乳腺癌细胞的集落形成能力。用transwell实验评估了长戴素对癌细胞迁移和侵袭的影响。通过成球实验检测龙达素对肿瘤干细胞的影响。使用MDA-MB-231乳腺癌异种移植物评价了长日霉素的体内抗肿瘤作用。结果：Longdaysin通过抑制HEK 293 T细胞CK 1 δ和CKI β，抑制Wnt/beta-catenin信号通路。在乳腺癌Hs 578 T和MDA-MB-231细胞中，微摩尔浓度的longdaysin减弱了LRP 6和DVL 2的磷酸化，降低了活性β-连环蛋白和总β-连环蛋白的表达，导致Wnt靶基因Axin 2、DKK 1、LEF 1和Survivin的下调。此外，longdaysin抑制乳腺癌细胞的殖民地形成、迁移、侵袭和球体形成。在MDA-MB-231乳腺癌异种移植物中，用longdaysin治疗抑制了与Wnt/β-连环蛋白信号传导抑制相关的肿瘤生长。结论：Longdaysin是一种新型Wnt/beta-catenin信号通路抑制剂。它通过阻断CK 1 δ/ε依赖性Wnt信号传导发挥抗肿瘤作用。
Background: CK1 is involved in regulating Wnt/beta-caten in signaling and represents a promising target for the treatment of breast cancer. A purine derivative longdaysin has recently been identified as a novel modulator of cellular circadian rhythms through targeting the protein kinases CK1 delta, CK1 alpha, and ERK2. However, the antitumor activity of longdaysin and its underlying mechanisms remain unclear. Methods: The inhibitory effect of longdaysin on Wnt/beta-catenin signaling was investigated using the SuperTOPFlash reporter system. The levels of phosphorylated LRP6, total LRP6, DVL2, active beta-catenin, and total beta-catenin were examined by Western blot. The expression of Wnt target genes was determined using real-time PCR. The ability of colony formation of breast cancer cells was measured by colony formation assay. The effects of longdaysin on cancer cell migration and invasion were assessed using transwell assays. The effect of longdaysin on cancer stem cells was tested by sphere formation assay. The in vivo antitumor effect of longdaysin was evaluated using M DA-MB-231 breast cancer xenografts. Results: Longdaysin suppressed Wnt/beta-catenin signaling through inhibition of CK1 delta and CKI epsilon in HEK293T cells. In breast cancer Hs578T and MDA-MB-231 cells, micromolar concentrations of longdaysin attenuated the phosphorylation of LRP6 and DVL2 and reduced the expression of active beta-catenin and total beta-catenin, leading to the downregulation of Wnt target genes Axin2, DKK1, LEF1, and Survivin. Furthermore, longdaysin inhibited the colony formation, migration, invasion, and sphere formation of breast cancer cells. In MDA-MB-231 breast cancer xenografts, treatment with longdaysin suppressed tumor growth in association with inhibition of Wnt/beta-catenin signaling. Conclusion: Longdaysin is a novel inhibitor of the Wnt/beta-catenin signaling pathway. It exerts antitumor effect through blocking CK1 delta/epsilon-dependent Wnt signaling.