Combinatorial TGF-beta attenuation with paclitaxel inhibits the epithelial-to-mesenchymal transition and breast cancer stem-like cells
- Authors
- Park, So-Yeon; Kim, Min-Jin; Park, Sang-A; Kim, Jung-Shin; Min, Kyung-Nan; Kim, Dae-Kee; Lim, Woosung; Nam, Jeong-Seok; Sheen, Yhun Yhong
- Issue Date
- 10-Nov-2015
- Publisher
- IMPACT JOURNALS LLC
- Keywords
- paclitaxel; metastasis; Snail; epithelial-to-mesenchymal transition (EMT); transforming growth factor-beta (TGF-beta)
- Citation
- ONCOTARGET, v.6, no.35, pp.37535 - 37552
- Journal Title
- ONCOTARGET
- Volume
- 6
- Number
- 35
- Start Page
- 37535
- End Page
- 37552
- URI
- https://scholarworks.bwise.kr/gachon/handle/2020.sw.gachon/9944
- ISSN
- 1949-2553
- 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-beta signaling with the TGF-beta 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.
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