CWP232228 targets liver cancer stem cells through Wnt/β-catenin signaling: a novel therapeutic approach for liver cancer treatment.
CWP232228 targets liver cancer stem cells through Wnt/β-catenin signaling: a novel therapeutic approach for liver cancer treatment.
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DOI：
10.18632/oncotarget.7954
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发表时间：
2016-04-12
期刊：
影响因子：
--
通讯作者：
Hong IS
中科院分区：
文献类型：
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作者：
Kim JY;Lee HY;Park KK;Choi YK;Nam JS;Hong IS
肝癌干细胞 (CSC) 对传统化疗和放疗具有抵抗力，这可能会破坏肿瘤块，但并非所有肝脏 CSC 都会导致肿瘤发生、转移和复发。在本研究中，我们发现 Wnt/β-catenin 信号传导升高的肝脏 CSC 具有更大的自我更新和克隆形成潜力。我们进一步证明，肝脏 CSC 的克隆形成潜力增加与 Wnt/β-catenin 信号传导的变化高度相关，并且 Wnt/β-catenin 信号传导活性与 CD133 表达和乙醛脱氢酶 (ALDH) 酶活性呈正相关。值得注意的是，小分子抑制剂CWP232228可以拮抗β-连环蛋白与细胞核中TCF的结合，抑制Wnt/β-连环蛋白信号传导并消耗CD133+/ALDH+肝脏CSC，从而最终削弱CSC的自我更新能力，降低体外和体内的致瘤性。综上所述，我们的研究结果表明，CWP232228 通过优先靶向肝脏 CSC 作为肝癌的候选治疗剂。
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.