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

Abstract

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.Electronic supplementary materialThe online version of this article (10.1186/s13046-017-0635-9) contains supplementary material, which is available to authorized users.

CTCF‐induced upregulation of HOXA11‐AS facilitates cell proliferation and migration by targeting miR‐518b/ACTN4 axis in prostate cancer

“…For example, ACTN4 promotes the proliferation of melanoma through regulating the stability of RIPK1 28 . ACTN4 inhibition suppresses cell proliferation and metastasis in breast cancer 29 . The current study proved that ACTN4 was highly expressed in PCa tissues and cells.…”

“…28 ACTN4 inhibition suppresses cell proliferation and metastasis in breast cancer. 29 The current study proved that ACTN4 was highly expressed in PCa tissues and cells. And HOXA11-AS could upregulate ACTN4 expression by competitively binding with miR-518b in PCa.…”

Elevated TRIP13 drives the AKT/mTOR pathway to induce the progression of hepatocellular carcinoma via interacting with ACTN4

“…ACTN4, known as an actinin-binding protein, is important for the regulation of cytoskeletal integrity and cell movement. Previous studies showed that it has a critical role in the pathogenesis of cancer due to its ability to promote cancer cell invasion and metastasis, as well as signaling pathways regulation [13,[24][25][26]. An et al indicated that ACTN4 induces EMT through the AKT signaling pathway in cervical cancer [12].…”

Ellagic Acid Inhibits Extracellular Acidity-Induced Invasiveness and Expression of COX1, COX2, Snail, Twist 1, and c-myc in Gastric Carcinoma Cells

“…We investigated whether ellagic acid can be a useful agent for metastatic alteration of gastric cancer cells caused by the acidosis. Ellagitanins and their derivatives from black raspberry or pomegranate have shown inhibitory effects on several types of malignancies, including breast, ovarian, and prostate cancer, in studies in vivo and in vitro [16,[21][22][23]. The majority of previous studies have focused on the cytotoxic and cytostatic activity of ellagic acid in various types of cancers.…”