期刊
MOLECULAR CANCER THERAPEUTICS
卷 19, 期 3, 页码 765-776出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1535-7163.MCT-19-0668
关键词
-
类别
资金
- Ministry of Education, Culture, Sports, Science and Technology, Japan [KAKENHI 16H06276]
- Japan Society for the Promotion of Science [16H04716, 18K07337]
- Project for Cancer Research and Therapeutic Evolution, Japan Agency for Medical Research and Development [18cm0106102h0003]
- Nippon Foundation
- Princess Takamatsu Cancer Research Fund
- Grants-in-Aid for Scientific Research [16H04716, 18K07337] Funding Source: KAKEN
Cancer stem cells (CSC) constitute heterogeneous cell subpopulations of a tumor. Although targeting CSCs is important for cancer eradication, no clinically approved drugs that target CSCs have been established. Tankyrase poly(ADP-ribosyl)ates and destabilizes AXIN, a negative regulator of beta-catenin, and promotes beta-catenin signaling. Here, we report that tankyrase inhibitors downregulate c-KIT tyrosine kinase and inhibit the growth of CD44-positive colorectal CSCs. c-KIT expression in CD44-positive subpopulations of cobrectal cancer COLO-320DM cells is associated with their tumor-initiating potential in vivo. Tankyrase inhibitors downregulate c-KIT expression in established cell lines, such as COLO-320DM and DLD-1, and colorectal cancer patient-derived cells. These effects of tankyrase inhibitors are caused by reducing the recruitment of SP1 transcription factor to the c-KIT gene promoter and depend on AXIN2 stabilization but not beta-catenin downregulation. Whereas c-KIT knockdown inhibits the growth of CD44-positive COLO-320DM cells, c-KIT overexpression in DLD-1 cells confers resistance to tankyrase inhibitors. Combination of a low-dose tankyrase inhibitor and irinotecan significantly inhibited the growth of COLO-320DM tumors in a mouse xenograft model. These observations suggest that tankyrase inhibitors target c-KIT-positive colorectal CSCs and provide a novel therapeutic strategy for cancer.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据