TY - JOUR
T1 - Artemisinin compounds sensitize cancer cells to ferroptosis by regulating iron homeostasis
AU - Chen, Guo Qing
AU - Benthani, Fahad A.
AU - Wu, Jiao
AU - Liang, Deguang
AU - Bian, Zhaoxiang
AU - Jiang, Xuejun
PY - 2020/1/1
Y1 - 2020/1/1
N2 - The antimalarial drug artemisinin and its derivatives have been explored as potential anticancer agents, but their underlying mechanisms are controversial. In this study, we found that artemisinin compounds can sensitize cancer cells to ferroptosis, a new form of programmed cell death driven by iron-dependent lipid peroxidation. Mechanistically, dihydroartemisinin (DAT) can induce lysosomal degradation of ferritin in an autophagy-independent manner, increasing the cellular free iron level and causing cells to become more sensitive to ferroptosis. Further, by associating with cellular free iron and thus stimulating the binding of iron-regulatory proteins (IRPs) with mRNA molecules containing iron-responsive element (IRE) sequences, DAT impinges on IRP/IRE-controlled iron homeostasis to further increase cellular free iron. Importantly, in both in vitro and a mouse xenograft model in which ferroptosis was triggered in cancer cells by the inducible knockout of GPX4, we found that DAT can augment GPX4 inhibition-induced ferroptosis in a cohort of cancer cells that are otherwise highly resistant to ferroptosis. Collectively, artemisinin compounds can sensitize cells to ferroptosis by regulating cellular iron homeostasis. Our findings can be exploited clinically to enhance the effect of future ferroptosis-inducing cancer therapies.
AB - The antimalarial drug artemisinin and its derivatives have been explored as potential anticancer agents, but their underlying mechanisms are controversial. In this study, we found that artemisinin compounds can sensitize cancer cells to ferroptosis, a new form of programmed cell death driven by iron-dependent lipid peroxidation. Mechanistically, dihydroartemisinin (DAT) can induce lysosomal degradation of ferritin in an autophagy-independent manner, increasing the cellular free iron level and causing cells to become more sensitive to ferroptosis. Further, by associating with cellular free iron and thus stimulating the binding of iron-regulatory proteins (IRPs) with mRNA molecules containing iron-responsive element (IRE) sequences, DAT impinges on IRP/IRE-controlled iron homeostasis to further increase cellular free iron. Importantly, in both in vitro and a mouse xenograft model in which ferroptosis was triggered in cancer cells by the inducible knockout of GPX4, we found that DAT can augment GPX4 inhibition-induced ferroptosis in a cohort of cancer cells that are otherwise highly resistant to ferroptosis. Collectively, artemisinin compounds can sensitize cells to ferroptosis by regulating cellular iron homeostasis. Our findings can be exploited clinically to enhance the effect of future ferroptosis-inducing cancer therapies.
UR - http://www.scopus.com/inward/record.url?scp=85066888302&partnerID=8YFLogxK
U2 - 10.1038/s41418-019-0352-3
DO - 10.1038/s41418-019-0352-3
M3 - Journal article
C2 - 31114026
AN - SCOPUS:85066888302
SN - 1350-9047
VL - 27
SP - 242
EP - 254
JO - Cell Death and Differentiation
JF - Cell Death and Differentiation
IS - 1
ER -