Oncotarget

Research Papers:

Combinatorial TGF-β attenuation with paclitaxel inhibits the epithelial-to-mesenchymal transition and breast cancer stem-like cells

So-Yeon Park, Min-Jin Kim, Sang-A Park, Jung-Shin Kim, Kyung-Nan Min, Dae-Kee Kim, Woosung Lim, Jeong-Seok Nam and Yhun Yhong Sheen _

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Oncotarget. 2015; 6:37526-37543. https://doi.org/10.18632/oncotarget.6063

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Abstract

So-Yeon Park1, Min-Jin Kim1, Sang-A Park1, Jung-Shin Kim1, Kyung-Nan Min2, Dae-Kee Kim1, Woosung Lim3, Jeong-Seok Nam4,5 and Yhun Yhong Sheen1

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.


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