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 β-catenin, and promotes β-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 colorectal 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 β-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.

中文翻译：

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端锚聚合酶抑制剂通过 AXIN 依赖性 c-KIT 酪氨酸激酶下调靶向结直肠癌干细胞

癌症干细胞 (CSC) 构成肿瘤的异质细胞亚群。尽管靶向 CSCs 对于根除癌症很重要，但尚未建立针对 CSCs 的临床批准药物。端锚聚合酶聚（ADP-核糖基）使 AXIN（β-连环蛋白的负调节因子）不稳定并使其不稳定，并促进 β-连环蛋白信号传导。在这里，我们报告了端锚聚合酶抑制剂下调 c-KIT 酪氨酸激酶并抑制 CD44 阳性结直肠 CSC 的生长。c-KIT 在结直肠癌 COLO-320DM 细胞的 CD44 阳性亚群中的表达与其体内肿​​瘤起始潜力有关。端锚聚合酶抑制剂可下调已建立的细胞系（如 COLO-320DM 和 DLD-1）以及源自结肠直肠癌患者的细胞中的 c-KIT 表达。端锚聚合酶抑制剂的这些作用是由减少 SP1 转录因子向 c-KIT 基因启动子的募集引起的，并且取决于 AXIN2 的稳定性，而不是 β-连环蛋白的下调。虽然 c-KIT 敲低会抑制 CD44 阳性 COLO-320DM 细胞的生长，但 DLD-1 细胞中的 c-KIT 过表达赋予对端锚聚合酶抑制剂的抗性。低剂量端锚聚合酶抑制剂和伊立替康的组合显着抑制了小鼠异种移植模型中 COLO-320DM 肿瘤的生长。这些观察结果表明，端锚聚合酶抑制剂靶向 c-KIT 阳性结直肠 CSCs，并为癌症提供了一种新的治疗策略。DLD-1 细胞中的 c-KIT 过表达赋予对端锚聚合酶抑制剂的抗性。低剂量端锚聚合酶抑制剂和伊立替康的组合显着抑制了小鼠异种移植模型中 COLO-320DM 肿瘤的生长。这些观察结果表明，端锚聚合酶抑制剂靶向 c-KIT 阳性结直肠 CSCs，并为癌症提供了一种新的治疗策略。DLD-1 细胞中的 c-KIT 过表达赋予对端锚聚合酶抑制剂的抗性。低剂量端锚聚合酶抑制剂和伊立替康的组合显着抑制了小鼠异种移植模型中 COLO-320DM 肿瘤的生长。这些观察结果表明，端锚聚合酶抑制剂靶向 c-KIT 阳性结直肠 CSCs，并为癌症提供了一种新的治疗策略。