Dihydroartemisinin exerts its anticancer activity through depleting cellular iron via transferrin receptor-1.
Dihydroartemisinin exerts its anticancer activity through depleting cellular iron via transferrin receptor-1.
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双氢青蒿素通过转铁蛋白受体 1 消耗细胞铁来发挥抗癌活性
DOI：
10.1371/journal.pone.0042703
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Wang H
中科院分区：
文献类型：
--
作者：
Ba Q;Zhou N;Duan J;Chen T;Hao M;Yang X;Li J;Yin J;Chu R;Wang H
青蒿素及其主要活性代谢物双氢青蒿素是临床上使用的具有低宿主毒性的抗疟药，最近在各种人类癌症模型中显示出有效的抗癌活性。虽然涉及铁介导的氧化损伤，但这些活动的机制仍不清楚。在目前的研究中，我们发现双氢青蒿素以时间和浓度依赖性方式引起细胞铁耗竭。它降低了癌细胞的铁摄取，扰乱了铁的稳态，这是独立的氧化损伤。此外，双氢青蒿素降低与细胞膜相关的转铁蛋白受体-1的水平。双氢青蒿素对转铁蛋白受体-1的调节作用可被制霉菌素逆转，制霉菌素是一种胆固醇螯合剂，但不是网格蛋白依赖性内吞作用的抑制剂。双氢青蒿素还诱导转铁蛋白受体-1棕榈酰化和与小窝蛋白-1的共定位，这表明脂质筏介导的内化途径参与了该过程。制霉菌素逆转了双氢青蒿素对细胞周期和凋亡相关基因的影响，siRNA下调转铁蛋白受体1的表达，有效降低了细胞对双氢青蒿素的敏感性。这些结果表明，双氢青蒿素可以通过调节细胞表面转铁蛋白受体1的非经典内吞途径抗肿瘤，这可能是DHA独立于氧化损伤的新的作用机制。
Artemisinin and its main active metabolite dihydroartemisinin, clinically used antimalarial agents with low host toxicity, have recently shown potent anticancer activities in a variety of human cancer models. Although iron mediated oxidative damage is involved, the mechanisms underlying these activities remain unclear. In the current study, we found that dihydroartemisinin caused cellular iron depletion in time- and concentration-dependent manners. It decreased iron uptake and disturbed iron homeostasis in cancer cells, which were independent of oxidative damage. Moreover, dihydroartemisinin reduced the level of transferrin receptor-1 associated with cell membrane. The regulation of dihydroartemisinin to transferrin receptor-1 could be reversed by nystatin, a cholesterol-sequestering agent but not the inhibitor of clathrin-dependent endocytosis. Dihydroartemisinin also induced transferrin receptor-1 palmitoylation and colocalization with caveolin-1, suggesting a lipid rafts mediated internalization pathway was involved in the process. Also, nystatin reversed the influences of dihydroartemisinin on cell cycle and apoptosis related genes and the siRNA induced downregulation of transferrin receptor-1 decreased the sensitivity to dihydroartemisinin efficiently in the cells. These results indicate that dihydroartemisinin can counteract cancer through regulating cell-surface transferrin receptor-1 in a non-classical endocytic pathway, which may be a new action mechanism of DHA independently of oxidative damage.
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影响因子：
5.3
作者：
Chen T;Li M;Zhang R;Wang H
通讯作者：
Wang H
影响因子：
64.5
作者：
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作者：
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通讯作者：
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作者：
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作者：
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