Disulfiram inhibits TGF-β-induced epithelial-mesenchymal transition and stem-like features in breast cancer via ERK/NF-κB/Snail pathway

Abstract

Disulfiram (DSF), an anti-alcoholism drug, has been reported as an inhibitor of NF-κB. NF-κB is involved in epithelial-mesenchymal transition (EMT) and self-renewal of breast cancer stem cells (CSCs). In this study, we treated MCF-7 and MDA-MB-231 breast cancer cells with TGF-β to induce EMT and cancer stem-like features and studied whether DSF can reverse this process. We found that DSF inhibited TGF-β induced EMT in breast cancer cells in a dose-dependent manner. Also, DSF inhibited EMT-associated stem-like features, migration and invasion of tumor cells as well as tumor growth in xenograft model. The activation of NF-κB was linked with EMT and stem-like cells. We conclude that DSF can suppress NF-κB activity and downregulate ERK/NF-κB/Snail pathway, leading to reverse EMT and stem-like features. Our data suggest that DSF inhibits EMT and stem-like properties in breast cancer cells associated with inhibition of the ERK/NF-κB/Snail pathway.

Epithelial‐mesenchymal transition inducer Snail1 and invasive potential of intraductal breast cancer

“…Most recent studies suggest that Snail1 suppression can reduce invasive propensity of breast cancer cells . Moreover, some drugs and anti‐tumor agents have been reported to inhibit EMT by down‐regulation of Snail1 signaling pathway, which results in anti‐metastatic effect . Those findings and our results support the idea that Snail1 and upstream regulators of its expression and activity could be the logical therapeutic targets for suppressing the development of invasive breast cancer …”

Anti-hepatocellular carcinoma properties of the anti-alcoholism drug disulfiram discovered to enzymatically inhibit the AMPK-related kinase SNARK in vitro

“…Intriguingly, a recent study reported that DSF inhibited TGF-β-induced epithelial-mesenchymal transition in breast cancer cells [11] in conformity with the downregulation of TGF-β signaling by DSF in zebra fish cells [25]. Furthermore, fibrosis-attenuating properties of DSF were observed in a mouse model of non-alcoholic steatohepatitis [26].…”

Gab2 Ablation Reverses the Stemness of HER2-Overexpressing Breast Cancer Cells

“…HER2-overexpressing BCSCs are causally associated with an aggressive phenotype and radiotherapy resistance [19]. HER2 regulates BCSCs through several signaling pathways, such as the PI3K/AKT, Wnt [21, 53], and MAPK/ERK pathways [54, 55]. In HER2-positive breast cancers, HER2 interacts with CXCR1, which is selectively expressed in BCSCs [56].…”