【作者】 周波；

【导师】 吴乔；

【作者基本信息】 厦门大学 ， 细胞生物学， 2020， 博士

【摘要】 ROS与肿瘤发展和肿瘤细胞死亡密切相关。ROS可以作为信号分子或者通过诱发基因组不稳定和DNA突变促进肿瘤的发生发展,加速肿瘤细胞的增殖、侵袭、存活和转移。但是,过量的ROS增强细胞氧化应激,导致蛋白质、脂质或者DNA损伤,引起肿瘤细胞程序性坏死或者凋亡。因此,通过化疗药物提高肿瘤细胞中的ROS水平已应用于临床肿瘤治疗。铁在多种细胞死亡,如铁死亡、细胞凋亡以及细胞程序性坏死等过程中发挥重要的调控作用。铁可以通过提高细胞内的活性氧(ROS)引起氧化压力。然而,铁激活的ROS与细胞焦亡的相关性目前并没有报道。本文研究发现,铁激活的ROS可以通过Tom20-caspase-GSDME信号通路诱导黑色素瘤细胞焦亡。在黑色素瘤细胞中,铁激活的ROS诱导线粒体外膜蛋白Tom20发生累积,敲低Tom20能够显著地阻断CCCP/铁诱导的细胞焦亡。进一步的机制研究表明,Tom20能够感知铁激活的ROS信号,导致线粒体发生聚集。聚集的线粒体进一步促进细胞色素C释放到胞浆,进而激活Caspase-9/3,活化的Caspase-3剪切并激活GSDME,最终诱导细胞焦亡。因此,在铁诱导的黑色素瘤细胞焦亡过程中ROS是一个诱因,Tom20负责ROS信号的感知及传递,GSDME是细胞焦亡的执行者。本文研究阐明了通过铁诱导细胞焦亡的新通路。黑色瘤细胞高表达GSDME有利于焦亡的诱导。因此,铁诱导的细胞焦亡可能为治疗黑色素瘤提供一个新策略,也为靶向GSDME药物研发黑色素的治疗提供新的研究方向。更多还原

【Abstract】 Reactive oxygen species(ROS)have been reported to be associated with cancer development and cancer cell death.ROS promote tumor development by acting as signaling molecules or inducing genomic instability and DNA mutations that accelerate cancer cell proliferation,invasion,survival and metastasis.In contrast,excessive levels of ROS enhance cellular oxidative stress,which causes damage to proteins,lipids or DNA,leading to necroptotic or apoptotic cell death.Therefore,boosting ROS in cancer cells by chemotherapeutic drugs has been applied in clinical cancer therapy.Iron has been shown to participate in different modes of cell death,such as ferroptosis,apoptosis and necroptosis.Iron can trigger oxidative stress by elevating ROS.However,whether iron-elevated ROS is also linked to pyroptosis has not been reported.Here,we demonstrate that iron-activated ROS induces pyroptosis via a Tom20caspase-GSDME pathway.In melanoma cells,CCCP/iron elevated ROS signaling,and caused accumulation of mitochondrial outer membrane protein Tom20.Knockdown of Tom20 abolished pyroptosis induced by CCCP/iron.Futhermore,Tom20-sensed CCCP/iron-elevated ROS signaling led to mitochondrial aggregation.Aggregated mitochondria facilitated cytochrome c release to the cytosol to further activate caspase9/3,eventually triggered pyroptosis by inducing GSDME cleavage.Therefore,in this process ROS acts as a causative factor,Tom20 senses ROS signaling and GSDME functions as executor for iron-driven pyroptosis of melanoma cells.In sum,the current study demonstrates that iron can induce a novel pathway of cell death through pyroptosis,especially for melanoma cells that express high GSDME level,which suggests that higher GSDME expression may serve as an Achilles’ heel for melanoma.We thus not only implicate a novel iron-based intervention strategy for melanoma therapy,but also point out future research direction for drug development targeting GSDME and melanoma treatment.更多还原