Direct inhibition of ACTN4 by ellagic acid limits breast cancer metastasis via regulation of β-catenin stabilization in cancer stem cells

• Published in: Journal of experimental & clinical cancer research Vol. 36; no. 1; p. 172
• Main Authors: Wang, Neng, Wang, Qi, Tang, Hailin, Zhang, Fengxue, Zheng, Yifeng, Wang, Shengqi, Zhang, Jin, Wang, Zhiyu, Xie, Xiaoming
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 02.12.2017; BioMed Central; BMC
• Subjects: Actinin - antagonists & inhibitors; Actinin - biosynthesis; Actinin - genetics; ACTN4; Animals; beta Catenin - metabolism; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cancer stem cells; Cancer therapies; Cell cycle; Cell Line, Tumor; Cell Proliferation - drug effects; Development and progression; Dietary supplements; Ellagic acid; Ellagic Acid - pharmacology; Female; Gene amplification; Gene expression; Genetic aspects; Humans; Identification; Laboratory animals; Lung Neoplasms - drug therapy; Lung Neoplasms - secondary; MCF-7 Cells; Medical prognosis; Metastasis; Mice; Mice, Transgenic; Neoplasm Metastasis; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Penicillin; Random Allocation; Stem cells; Studies; Transfection; Tumors; Xenograft Model Antitumor Assays; β-catenin; China; United States > US; β-catenin; ACTN4; Metastasis; Cancer stem cells; Ellagic acid
• ISSN: 1756-9966; 0392-9078; 1756-9966
• DOI: 10.1186/s13046-017-0635-9

Pharmacology-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. The 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. EA 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. Taken together, our results suggest that ACTN4 plays an important role in breast CSCs-related metastasis and is a novel therapeutic target of EA treatment.