dihydroartemisinin exerts its anticancer activity through depleting cellular iron via transferrin receptor-1通过消耗dihydroartemisinin发挥其抗癌活性细胞通过转铁蛋白铁receptor-1.pdfVIP

Dihydroartemisinin Exerts Its Anticancer Activity through Depleting Cellular Iron via Transferrin Receptor-1 1 2 1 1 1 1 1 1 Qian Ba , Naiyuan Zhou , Juan Duan , Tao Chen , Miao Hao , Xinying Yang , Junyang Li , Jun Yin , 1 1 Ruiai Chu , Hui Wang * 1 Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Graduate School of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China, 2 China National Center for Biotechnology Development, Beijing, China Abstract 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