Dichloroacetate attenuates the stemness of colorectal cancer cells via trigerring ferroptosis through sequestering iron in lysosomes
Dichloroacetate attenuates the stemness of colorectal cancer cells via trigerring ferroptosis through sequestering iron in lysosomes
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DOI：
10.1002/tox.23057
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发表时间：
2020-11
影响因子：
4.5
通讯作者：
Jie Sun;Xiuqin Cheng;S. Pan;Liangjing Wang;Wenhuan Dou;Jie-Teng Liu;Xiaohua Shi
中科院分区：
文献类型：
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作者：
Jie Sun;Xiuqin Cheng;S. Pan;Liangjing Wang;Wenhuan Dou;Jie-Teng Liu;Xiaohua Shi
结直肠癌干细胞（CSC）被认为是结直肠癌进展的根源。然而，临床上尚无针对结直肠CSC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 可以以剂量依赖的方式降低结直肠癌细胞干性，这通过干性标记物表达、肿瘤细胞球形成和细胞迁移能力的降低来证明。此外，还发现DCA引发结直肠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上调，并降低细胞活力。机制研究表明，DCA 可以螯合溶酶体中的铁，从而引发铁死亡，这对于 DCA 介导的结直肠癌细胞干性减弱是必要的。综上所述，这项工作表明 DCA 可能是结直肠 CSC 杀手。
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.