DHA inhibits proliferation and induces ferroptosis of leukemia cells through autophagy dependent degradation of ferritin
DHA inhibits proliferation and induces ferroptosis of leukemia cells through autophagy dependent degradation of ferritin
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DOI：
10.1016/j.freeradbiomed.2018.12.011
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发表时间：
2019-02-01
影响因子：
7.4
通讯作者：
Tong, Xiangmin
中科院分区：
文献类型：
--
作者：
Du, Jing;Wang, Tongtong;Tong, Xiangmin
二氢烷蛋白（DHA）已被证明能够抑制癌症的生长，而在很大程度上仍然难以捉摸，DHA的基本分子机制诱导了急性骨髓性白血病（AML）细胞死亡。在本研究中，我们检查了DHA对AML细胞增殖和繁殖的影响，并阐明了潜在的分子机制。我们发现DHA在G0/G1期间强烈抑制AML细胞系的生存能力和阻止细胞周期。进一步的研究发现，DHA有效诱导了AML细胞的铁胞菌病，该血液依赖性依赖性，并伴有线粒体功能障碍。从机械上讲，DHA通过调节AMPK/MTOR/P70S6K信号通路的活性来诱导自噬，从而加速了铁蛋白的降解，增加了不稳定的铁池，促进了细胞ROS的积累，并最终导致了铁毒细胞死亡。超过ISCU的表达（铁硫簇组装酶，一种线粒体蛋白）通过调节铁代谢，挽救线粒体功能并提高GSH水平，从而显着减弱DHA诱导的DHA诱导的血液吞噬作用。同时，FTH重构的AML细胞还表现出降低的脂质过氧化物含量，并恢复了DHA诱导的铁铁作用。总而言之，这些结果提供了有关DHA诱导的铁毒性详细机制的实验证据，并表明DHA可能代表了优先靶向AML细胞的有希望的治疗剂。
Dihydroartemisinin (DHA) has been shown to be capable of inhibiting cancer growth, whereas it remains largely elusive that the underlying molecular mechanism of DHA induced acute myeloid leukemia (AML) cell death. In the present study, we examined the effects of DHA on the proliferation and ferroptosis of AML cells as well as to elucidate the underlying molecular mechanisms. We found that DHA strongly inhibited the viability of AML cell lines and arrest cell cycle at G0/G1 phase. Further studies found that DHA effectively induced AML cells ferroptosis, which was iron-dependent and accompanied by mitochondrial dysfunction. Mechanistically, DHA induced autophagy by regulating the activity of AMPK/mTOR/p70S6k signaling pathway, which accelerated the degradation of ferritin, increased the labile iron pool, promoted the accumulation of cellular ROS and eventually led to ferroptotic cell death. Over expression of ISCU (Iron-sulfur cluster assembly enzyme, a mitochondrial protein) significantly attenuated DHA induced ferroptosis by regulating iron metabolism, rescuing the mitochondrial function and increasing the level of GSH. Meanwhile, FTH reconstituted AML cells also exhibited the reduced lipid peroxides content and restored the DHA-induced ferroptosis. In summary, these results provide experimental evidences on the detailed mechanism of DHA-induced ferroptosis and reveal that DHA might represent a promising therapeutic agent to preferentially target AML cells.