Wnt信号通路
结直肠癌
体内
医学
传统医学
信号转导
癌症
癌症研究
药理学
化学
生物
内科学
生物化学
遗传学
作者
Lingmei Kong,Tao Feng,Yuanyuan Wang,Xing-Yao Li,Zhen-Nan Ye,Tao An,Qing Chen,Xiao‐Dong Luo,Yan Li
出处
期刊:Oncotarget
[Impact Journals, LLC]
日期:2016-02-04
卷期号:7 (9): 10203-10214
被引量:17
标识
DOI:10.18632/oncotarget.7190
摘要
Wnt signaling pathway is aberrantly activated in a variety of cancers, especially in colorectal cancer and small molecule antagonists of Wnt/β-catenin signaling are attractive candidates for developing effective therapeutics. In the present study, we identified Bisleuconothine A, a bisindole alkaloid with an eburnane-aspidosperma type skeleton, as a novel and selective Wnt signaling inhibitor by using a cell-based luciferase assay system. Our study found that Bisleuconothine A down-regulated the endogenous Wnt target gene expression through promoting phosphorylation of β-catenin and the subsequent inhibition of its nuclear translocation in HCT116 and SW480 colorectal cancer cells. In vitro, Bisleuconothine A inhibited cell proliferation through induction of apoptosis by increasing the cleavage of caspases in HCT116 and SW480 colorectal cancer cells. Moreover, in vivo, Bisleuconothine A dramatically suppressed tumor growth in HCT116 Xenograft. And further analysis showed that Bisleuconothine A suppressed the Wnt target gene expression in HCT116 Xenograft, which was associated with up-regulation of β-catenin phosphorylation and subsequent Wnt signaling inhibition. Taken together, our study indicated that bisindole alkaloids could be included as a new chemotype of small-molecule Wnt signaling inhibitors, and have great potential to be further developed for anti-tumor agents.
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