Colorectal cancer stem cell (CSC) has been regarded to be the root of colorectal cancer progression. However, there is still no effective therapeutic method targeting colorectal CSC in clinical application. Here, we investigated the effects of dichloroacetate (DCA) on colorectal cancer cell stemness. We showed that DCA could reduce colorectal cancer cell stemness in a dose-dependent manner, which is evident by the decreased expression of stemness markers, tumor cell sphere-formation and cell migration ability. In addition, it was found that DCA trigerred the ferroptosis of colorectal CSC, which is characterized as the upregulation of iron concentration, lipid peroxides, and glutathione level, and decreased cell viability. Mechanistic studies demonstrated that DCA could sequester iron in lysosome and thus trigger ferroptosis, which is necessary for DCA-mediated attenuation on colorectal cancer cell stemness. Taken together, this work suggests that DCA might be a colorectal CSC-killer.

中文翻译：

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二氯乙酸盐通过在溶酶体中螯合铁，引发铁死亡，从而减弱结直肠癌细胞的干性

结直肠癌干细胞（CSC）被认为是结直肠癌进展的根源。然而，临床上还没有针对结直肠癌干细胞的有效治疗方法。在这里，我们研究了二氯乙酸 (DCA) 对结直肠癌细胞干性的影响。我们发现 DCA 可以以剂量依赖性方式降低结直肠癌细胞的干细胞，这通过干细胞标志物的表达降低、肿瘤细胞球形成和细胞迁移能力的降低来证明。此外，发现DCA引发了结直肠CSC的铁死亡，其特征是铁浓度、脂质过氧化物和谷胱甘肽水平的上调，以及细胞活力的降低。机理研究表明，DCA 可以在溶酶体中螯合铁，从而引发铁死亡，这对于 DCA 介导的结直肠癌细胞干细胞衰减是必需的。总之，这项工作表明 DCA 可能是结直肠 CSC 的杀手。