Tom20 senses iron-activated ROS signaling to promote melanoma cell pyroptosis.
Tom20 senses iron-activated ROS signaling to promote melanoma cell pyroptosis.
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Tom20 感知铁激活的 ROS 信号，促进黑色素瘤细胞焦亡。
DOI：
10.1038/s41422-018-0090-y
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发表时间：
2018-12
期刊：
影响因子：
44.1
通讯作者：
Wu Q
中科院分区：
文献类型：
--
作者：
Zhou B;Zhang JY;Liu XS;Chen HZ;Ai YL;Cheng K;Sun RY;Zhou D;Han J;Wu Q
铁已被证明通过升高活性氧（ROS）触发氧化应激，并参与不同的细胞死亡模式，如铁凋亡、凋亡和坏死性凋亡。然而，铁升高的ROS是否也与焦亡有关尚未报道。在这里，我们证明了铁激活的ROS可以通过Tom 20-caspase-GSDME途径诱导细胞凋亡。在黑色素瘤细胞中，铁增强了CCCP启动的ROS信号传导，导致线粒体外膜蛋白Tom 20的氧化和寡聚化。Bax被氧化的Tom 20募集到线粒体中，这促进细胞色素c释放到胞质溶胶中以激活半胱天冬酶-3，最终通过诱导GSDME切割触发焦亡性死亡。因此，ROS作为一个致病因子和Tom 20传感ROS信号的铁驱动的黑色素瘤细胞的pyropottic死亡。由于铁激活ROS的GSDME依赖性细胞凋亡诱导和黑色素瘤细胞特异性表达高水平的GSDME，铁可能是一个潜在的候选人黑色素瘤治疗。基于上述铁的功能机制，我们进一步证明，在缺铁患者中使用的剂量的铁补充足以最大化临床ROS诱导药物的抗肿瘤作用，以通过GSDME依赖性焦亡抑制异种移植肿瘤生长和黑色素瘤细胞的转移。而且临床药物与铁剂联合治疗对小鼠正常组织器官无明显毒副作用。这项研究不仅确定了铁作为一种敏化剂放大ROS信号，以驱动pyroptosis，但也涉及一种新的铁为基础的黑色素瘤治疗的干预策略。
Iron has been shown to trigger oxidative stress by elevating reactive oxygen species (ROS) and to participate in different modes of cell death, such as ferroptosis, apoptosis and necroptosis. However, whether iron-elevated ROS is also linked to pyroptosis has not been reported. Here, we demonstrate that iron-activated ROS can induce pyroptosis via a Tom20-Bax-caspase-GSDME pathway. In melanoma cells, iron enhanced ROS signaling initiated by CCCP, causing the oxidation and oligomerization of the mitochondrial outer membrane protein Tom20. Bax is recruited to mitochondria by oxidized Tom20, which facilitates cytochrome c release to cytosol to activate caspase-3, eventually triggering pyroptotic death by inducing GSDME cleavage. Therefore, ROS acts as a causative factor and Tom20 senses ROS signaling for iron-driven pyroptotic death of melanoma cells. Since iron activates ROS for GSDME-dependent pyroptosis induction and melanoma cells specifically express a high level of GSDME, iron may be a potential candidate for melanoma therapy. Based on the functional mechanism of iron shown above, we further demonstrate that iron supplementation at a dosage used in iron-deficient patients is sufficient to maximize the anti-tumor effect of clinical ROS-inducing drugs to inhibit xenograft tumor growth and metastasis of melanoma cells through GSDME-dependent pyroptosis. Moreover, no obvious side effects are observed in the normal tissues and organs of mice during the combined treatment of clinical drugs and iron. This study not only identifies iron as a sensitizer amplifying ROS signaling to drive pyroptosis, but also implicates a novel iron-based intervention strategy for melanoma therapy.
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