2-Methoxyestradiol Suppresses Stemness and Epithelial-Mesenchymal Transition in Drug-Resistant Esophageal Squamous Cell Carcinoma by Targeting the Snail Signaling Pathway in Cancer Stem Cells.

Cancer stem cells (CSCs) and epithelial-mesenchymal transition (EMT) are critical contributors to tumor drug resistance, which represents a major obstacle to successful cancer therapy. 2-Methoxyestradiol (2ME2) is an endogenous metabolite of 17β-estradiol, and accumulating evidence has demonstrated that 2ME2 suppresses stemness and EMT in multiple cancer types. However, whether 2ME2 overcomes drug resistance remains unclear. In this study, 2ME2 was found to inhibit cell viability and increases susceptibility to paclitaxel in drug-resistant esophageal cancer cells. Besides, 2ME2 suppress CSC-like traits and cell migration. Mechanically, 2ME2 inhibited the activation of the TGFβ1/Smad signaling pathway, reduced Snail protein levels by promoting its degradation in paclitaxel-resistant esophageal squamous cell carcinoma cells. Importantly, Snail is at least partially involved in the inhibitory effect of 2ME2 on cell migration in drug-resistant cancer cells. Collectively, our results reveal that 2ME2 effectively attenuates CSC stemness and inhibits EMT to overcome paclitaxel resistance in esophageal cancer. Accordingly, further development of more potent 2ME2 analogs and optimized delivery systems in future preclinical studies is warranted, which may provide therapy strategy for resistant ESCC treatment.Clinical Trial Registration: Not applicable.