Direct inhibition of ACTN4 by ellagic acid limits breast cancer metastasis via regulation of β-catenin stabilization in cancer stem cells.
Direct inhibition of ACTN4 by ellagic acid limits breast cancer metastasis via regulation of β-catenin stabilization in cancer stem cells.
复制标题
鞣花酸直接抑制 ACTN4 通过调节癌症干细胞中 β-连环蛋白的稳定性来限制乳腺癌转移
DOI：
10.1186/s13046-017-0635-9
复制
发表时间：
2017-12-02
期刊：
影响因子：
--
通讯作者：
Xie X
中科院分区：
文献类型：
--
作者：
Wang N;Wang Q;Tang H;Zhang F;Zheng Y;Wang S;Zhang J;Wang Z;Xie X
研究背景基于药理学的靶点识别已成为发现新的病理生物标志物的新策略。鞣花酸（EA），一种膳食多酚化合物，具有强大的抗癌活性，然而，其潜在的机制仍不清楚。本研究旨在确定ACTN 4表达在人乳腺癌转移和EA为基础的therapeutic. MethodsEA的抗转移能力的作用和调节进行了验证MMTV-PyMT小鼠和体外细胞模型。利用药物亲和力响应靶点稳定性（DARTS）来鉴定作为EA的直接靶点的ACTN 4。通过癌症干细胞（CSC）相关试验评估了ACTN 4的转移调节功能，包括乳腺球形成、致瘤能力、再附着分化和信号通路分析。通过免疫印迹、免疫共沉淀和泛素化分析研究了ACTN 4对β-catenin稳定化的作用机制。ACTN 4的临床意义是基于人类组织芯片（TMA）分析和癌症基因组图谱（TCGA）数据库exploration.ResultsEA抑制乳腺癌的生长和转移，通过直接靶向ACTN 4在体外和体内，并伴随着有限的CSC人口。ACTN 4基因敲低可阻断恶性肿瘤细胞增殖、集落形成，并改善转移潜能。ACTN 4阳性CSC表现出更高的ESA+比例，增加的乳腺球形成能力，并增强体内成瘤能力。其机制探讨表明，阻断ACTN 4/β-catenin相互作用可激活β-catenin蛋白酶体降解。ACTN 4表达增加与晚期癌症阶段，转移的发生率增加，和总生存期差。ConclusionsTaken在一起，我们的研究结果表明，ACTN 4起着重要的作用，在乳腺癌相关的转移，是一个新的治疗目标EA治疗。
BackgroundPharmacology-based target identification has become a novel strategy leading to the discovery of novel pathological biomarkers. Ellagic acid (EA), a dietary polyphenol compound, exhibits potent anticancer activities; however, the underlying mechanisms remain unclear. The current study sought to determine the role and regulation of ACTN4 expression in human breast cancer metastasis and EA-based therapy.MethodsThe anti-metastasis ability of EA was validated by MMTV-PyMT mice and in vitro cell models. Drug affinity responsive target stability (DARTS) was utilized to identify ACTN4 as the direct target of EA. The metastatic regulated function of ACTN4 were assessed by cancer stem cells (CSCs)-related assays, including mammosphere formation, tumorigenic ability, reattachment differentiation, and signaling pathway analysis. The mechanisms of ACTN4 on β-catenin stabilization were investigated by western blotting, co-immunoprecipitation and ubiquitination assays. The clinical significance of ACTN4 was based on human tissue microarray (TMA) analysis and The Cancer Genome Atlas (TCGA) database exploration.ResultsEA inhibited breast cancer growth and metastasis via directly targeting ACTN4 in vitro and in vivo, and was accompanied by a limited CSC population. ACTN4 knockdown resulted in the blockage of malignant cell proliferation, colony formation, and ameliorated metastasis potency. ACTN4-positive CSCs exhibited a higher ESA+proportion, increased mammosphere-formation ability, and enhanced in vivo tumorigenesis ability. Mechanism exploration revealed that interruption of ACTN4/β-catenin interaction will result in the activation of β-catenin proteasome degradation. Increased ACTN4 expression was directly associated with the advanced cancer stage, an increased incidence of metastasis, and poor overall survival period.ConclusionsTaken together, our results suggest that ACTN4 plays an important role in breast CSCs-related metastasis and is a novel therapeutic target of EA treatment.
登录
查看更多内容
影响因子：
7.4
作者：
Fillmore, Christine M.;Kuperwasser, Charlotte
通讯作者：
Kuperwasser, Charlotte
通过植物化学物质靶向癌症干细胞和信号通路：乳腺癌治疗的新方法。
影响因子：
14.5
作者：
Dandawate PR;Subramaniam D;Jensen RA;Anant S
通讯作者：
Anant S
影响因子：
46.9
作者：
通讯作者：
--
影响因子：
78.5
作者：
Klein, Christoph A.
通讯作者：
Klein, Christoph A.
DOI：
10.1186/bcr2106
发表时间：
2008
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Grimshaw MJ;Cooper L;Papazisis K;Coleman JA;Bohnenkamp HR;Chiapero-Stanke L;Taylor-Papadimitriou J;Burchell JM
通讯作者：
Burchell JM