CWP232228 targets liver cancer stem cells through Wnt/β‑catenin signaling: a novel therapeutic approach for liver cancer treatment
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Ji-Young Kim1,2,*, Hwa-Yong Lee3,*, Kwan-Kyu Park4, Yang-Kyu Choi2, Jeong-Seok Nam5, In-Sun Hong6,7
1Center of Animal Care and Use, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Republic of Korea
2Department of Laboratory Animal Medicine, College of Veterinary Medicine, Konkuk University, Seoul, Korea
3The Faculty of Liberal Arts, Jungwon University, Chungbuk, Republic of Korea
4Department of Pathology, College of Medicine, Catholic University of Daegu, Daegu, South Korea
5School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, Republic of Korea
6Laboratory of Stem Cell Research, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, South Korea
7Department of Molecular Medicine, School of Medicine, Gachon University, Incheon, Republic of Korea
*These authors have contributed equally to this work
Jeong-Seok Nam, e-mail: [email protected]
In-Sun Hong, e-mail: [email protected]
Keywords: CWP232228, cancer stem cells, Wnt/β-catenin signaling, CD133, ALDH
Received: September 11, 2015 Accepted: January 16, 2016 Published: March 07, 2016
Liver cancer stem cells (CSCs) are resistant to conventional chemotherapy and radiation, which may destroy tumor masses, but not all liver CSCs contribute to tumor initiation, metastasis, and relapse. In the present study, we showed that liver CSCs with elevated Wnt/β-catenin signaling possess much greater self-renewal and clonogenic potential. We further documented that the increased clonogenic potential of liver CSCs is highly associated with changes in Wnt/β-catenin signaling and that Wnt/β-catenin signaling activity is positively correlated with CD133 expression and aldehyde dehydrogenase (ALDH) enzymatic activity. Notably, the small molecule inhibitor CWP232228, which antagonizes the binding of β-catenin to TCF in the nucleus, inhibits Wnt/β-catenin signaling and depletes CD133+/ALDH+ liver CSCs, thus ultimately diminishing the self-renewal capacity of CSCs and decreasing tumorigenicity in vitro and in vivo. Taken together, our findings suggest that CWP232228 acts as a candidate therapeutic agent for liver cancer by preferentially targeting liver CSCs.
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