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// So-Yeon Park 1 , Min-Jin Kim 1 , Sang-A Park 1 , Jung-Shin Kim 1 , Kyung-Nan Min 2 , Dae-Kee Kim 1 , Woosung Lim 3 , Jeong-Seok Nam 4,5 and Yhun Yhong Sheen 1 1 College of Pharmacy, Ewha Womans University, Seoul, South Korea 2 Pharmaceutical Examination Division, Korean Intellectual Property Office, Daejeon, South Korea 3 Department of Surgery, School of Medicine, Ewha Womans University, Mokdong Hospital, Seoul, South Korea 4 Laboratory of Tumor Suppressor, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, South Korea 5 Department of Molecular Medicine, School of Medicine, Gachon University, Incheon, South Korea Correspondence to: Yhun Yhong Sheen, email: // Jeong-Seok Nam, email: // Keywords : paclitaxel, metastasis, Snail, epithelial-to-mesenchymal transition (EMT), transforming growth factor-β (TGF-β) Received : July 31, 2015 Accepted : September 24, 2015 Published : October 09, 2015 Abstract Distant relapse after chemotherapy is an important clinical issue for treating breast cancer patients and results from the development of cancer stem-like cells (CSCs) during chemotherapy. Here we report that blocking epithelial-to-mesenchymal transition (EMT) suppresses paclitaxel-induced CSCs properties by using a MDA-MB-231-xenografted mice model ( in vivo ), and breast cancer cell lines ( in vitro ). Paclitaxel, one of the cytotoxic taxane-drugs such as docetaxel, increases mesenchymal markers (Vimentin and Fibronectin) and decreases an epithelial marker (Zo-1). Blocking TGF-β signaling with the TGF-β type I receptor kinase (ALK5) inhibitor, EW-7197, suppresses paclitaxel-induced EMT and CSC properties such as mammosphere-forming efficiency (MSFE), aldehyde dehydrogenase (ALDH) activity, CD44 + /CD24 - ratio, and pluripotency regulators (Oct4, Nanog, Klf4, Myc, and Sox2). The combinatorial treatment of EW-7197 improves the therapeutic effect of paclitaxel by decreasing the lung metastasis and increasing the survival time in vivo . We confirmed that Snail is increased by paclitaxel-induced intracellular reactive oxygen species (ROS) and EW-7197 suppresses the paclitaxel-induced Snail and EMT by attenuating paclitaxel-induced intracellular ROS. Knock-down of SNAI1 suppresses paclitaxel-induced EMT and CSC properties. These data together suggest that blocking the Snail-induced EMT with the ALK5 inhibitor attenuates metastasis after paclitaxel-therapy and that this combinatorial approach could prove useful in treating breast cancer. |
