铁是几乎所有生物系统中必不可少的金属。然而,细胞内的铁含量需要严格调节,因为过量的铁会随着ROS的产生而产生破坏性影响,铁死亡是一种新型的由铁依赖性脂质过氧化作用引起的氧化调节细胞死亡。铁死亡涉及遗传、代谢和蛋白质的调节、...铁是几乎所有生物系统中必不可少的金属。然而,细胞内的铁含量需要严格调节,因为过量的铁会随着ROS的产生而产生破坏性影响,铁死亡是一种新型的由铁依赖性脂质过氧化作用引起的氧化调节细胞死亡。铁死亡涉及遗传、代谢和蛋白质的调节、触发和执行机制,在很大程度上与其他形式的受调节细胞死亡不重叠。脂质代谢对于肿瘤的增殖以及侵袭、转染都具有很重要的作用,例如细胞膜层面的高水平膜脂质与肿瘤细胞抵御活性氧(ROS)的损伤密切相关,由于高饱和度的膜脂对于氧化反应的刺激不敏感这为肿瘤细胞无形中提供了保护作用。目前主流的肿瘤化疗采用诱导凋亡的方式杀死或抑制肿瘤细胞。然而,越来越明显地是,肿瘤细胞可能对这些依赖凋亡的抗肿瘤方式表现出内在或获得性抵抗,从而大大增加了治疗失败和治疗后复发的风险。对于肿瘤而言,越来越多研究表明,在肿瘤组织中,铁死亡被显著抑制,导致了肿瘤不受控制地转移以及侵袭,这也为调节靶向肿瘤细胞的死亡对于肿瘤的免疫治疗提供了一种新的治疗方式以及为其他以异常细胞增生的疾病提供新的治疗思路。有趣的是,治疗耐药的癌细胞,特别是那些间充质状态和易于转移的癌细胞,非常容易发生铁死亡。目前许多研究证实:铁死亡与肿瘤存在密切的联系,并且涉及一系列机制,并且铁死亡还可以根除一些凋亡不敏感的肿瘤细胞,激活铁死亡途径可能是克服传统癌症治疗耐药机制的潜在策略。故此铁死亡的相关研究进展对于肿瘤的治疗而言具有重要的意义。Iron is an essential metal in almost all biological systems. However, the intracellular iron content needs to be strictly regulated because excessive iron can have destructive effects along with the generation of reactive oxygen species (ROS). Ferroptosis is a novel type of oxidative regulated cell death caused by iron-dependent lipid peroxidation. Ferroptosis involves the regulatory, triggering and execution mechanisms of genetics, metabolism and proteins, and largely does not overlap with other forms of regulated cell death. Lipid metabolism plays a very important role in the proliferation. High levels of membrane lipids at the cellular membrane level are highly correlated with the ability of tumor cells to avoid damage from reactive oxygen species (ROS). Because membrane lipids with high saturation are insensitive to the stimuli of oxidation reactions, they provide an invisible protective effect for tumor cells. Currently, the mainstream tumor chemotherapy uses the method of inducing apoptosis to kill or inhibit tumor cells. However, it is becoming increasingly evident that tumor cells may exhibit intrinsic or acquired resistance to these apoptosis-dependent anti-tumor approaches, which greatly increases the risk of treatment failure and recurrence after treatment. For tumors, more and more studies have shown that in tumor tissues, ferroptosis is significantly inhibited, leading to uncontrolled metastasis and invasion of tumors. This also provides a new treatment approach for tumor immunotherapy by regulating the death of targeted tumor cells, and offers new treatment ideas for other diseases characterized by abnormal cell proliferation. Interestingly, cancer cells resistant to treatment, especially those in a mesenchymal state and prone to metastasis, are highly susceptible to ferroptosis. Currently, many studies have confirmed that there is a close relationship between ferroptosis and tumors, involving a series of mechanisms. Moreover, ferroptosis can also eradicate some tumor cells that are insensitive to apoptosis. Activating the ferroptosis pathway may be a potential strategy to overcome the resistance mechanisms of traditional cancer treatments. Therefore, the relevant research progress of ferroptosis is of great significance for the treatment of tumors.展开更多
Disruption of mitochondrial reactive oxygen species （mitoROS） plays a major role in cancer cell apoptosis. Here, we designed a core/shell-structured mitochondriatargeting upconversion-based nano-photosensitizer （TP...Disruption of mitochondrial reactive oxygen species （mitoROS） plays a major role in cancer cell apoptosis. Here, we designed a core/shell-structured mitochondriatargeting upconversion-based nano-photosensitizer （TPP-UC（PS）） with a lanthanidedoped upconversion nanoparticle （UCNP） core coated by a photosensitizer （PS）-incorporated dense silica shell. Following irradiation with external nearinfrared laser （NIR）, TPP-UC（PS） in mitochondria caused serious mitochondrial matrix swelling for the activated upconversion-based photodynamic therapy （UC-PDT）, and the mobilization of cytochrome c （cyt c） was amplified in response to the increased mitoROS. Specifically, this heme-containing cyt c could be monitored by varying TPP-UC（PS）＇s upconversion luminescence signal （UCL）, which may facilitate the in situ detection of cyt c for apoptosis research. As a proof of concept, our designed TPP-UC（PS） may provide significant opportunities for controlling cancer cell apoptosis under NIR stimulation and for studying apoptosis using the dynamic UCL, which is influenced by local cyt c.展开更多
文摘铁是几乎所有生物系统中必不可少的金属。然而,细胞内的铁含量需要严格调节,因为过量的铁会随着ROS的产生而产生破坏性影响,铁死亡是一种新型的由铁依赖性脂质过氧化作用引起的氧化调节细胞死亡。铁死亡涉及遗传、代谢和蛋白质的调节、触发和执行机制,在很大程度上与其他形式的受调节细胞死亡不重叠。脂质代谢对于肿瘤的增殖以及侵袭、转染都具有很重要的作用,例如细胞膜层面的高水平膜脂质与肿瘤细胞抵御活性氧(ROS)的损伤密切相关,由于高饱和度的膜脂对于氧化反应的刺激不敏感这为肿瘤细胞无形中提供了保护作用。目前主流的肿瘤化疗采用诱导凋亡的方式杀死或抑制肿瘤细胞。然而,越来越明显地是,肿瘤细胞可能对这些依赖凋亡的抗肿瘤方式表现出内在或获得性抵抗,从而大大增加了治疗失败和治疗后复发的风险。对于肿瘤而言,越来越多研究表明,在肿瘤组织中,铁死亡被显著抑制,导致了肿瘤不受控制地转移以及侵袭,这也为调节靶向肿瘤细胞的死亡对于肿瘤的免疫治疗提供了一种新的治疗方式以及为其他以异常细胞增生的疾病提供新的治疗思路。有趣的是,治疗耐药的癌细胞,特别是那些间充质状态和易于转移的癌细胞,非常容易发生铁死亡。目前许多研究证实:铁死亡与肿瘤存在密切的联系,并且涉及一系列机制,并且铁死亡还可以根除一些凋亡不敏感的肿瘤细胞,激活铁死亡途径可能是克服传统癌症治疗耐药机制的潜在策略。故此铁死亡的相关研究进展对于肿瘤的治疗而言具有重要的意义。Iron is an essential metal in almost all biological systems. However, the intracellular iron content needs to be strictly regulated because excessive iron can have destructive effects along with the generation of reactive oxygen species (ROS). Ferroptosis is a novel type of oxidative regulated cell death caused by iron-dependent lipid peroxidation. Ferroptosis involves the regulatory, triggering and execution mechanisms of genetics, metabolism and proteins, and largely does not overlap with other forms of regulated cell death. Lipid metabolism plays a very important role in the proliferation. High levels of membrane lipids at the cellular membrane level are highly correlated with the ability of tumor cells to avoid damage from reactive oxygen species (ROS). Because membrane lipids with high saturation are insensitive to the stimuli of oxidation reactions, they provide an invisible protective effect for tumor cells. Currently, the mainstream tumor chemotherapy uses the method of inducing apoptosis to kill or inhibit tumor cells. However, it is becoming increasingly evident that tumor cells may exhibit intrinsic or acquired resistance to these apoptosis-dependent anti-tumor approaches, which greatly increases the risk of treatment failure and recurrence after treatment. For tumors, more and more studies have shown that in tumor tissues, ferroptosis is significantly inhibited, leading to uncontrolled metastasis and invasion of tumors. This also provides a new treatment approach for tumor immunotherapy by regulating the death of targeted tumor cells, and offers new treatment ideas for other diseases characterized by abnormal cell proliferation. Interestingly, cancer cells resistant to treatment, especially those in a mesenchymal state and prone to metastasis, are highly susceptible to ferroptosis. Currently, many studies have confirmed that there is a close relationship between ferroptosis and tumors, involving a series of mechanisms. Moreover, ferroptosis can also eradicate some tumor cells that are insensitive to apoptosis. Activating the ferroptosis pathway may be a potential strategy to overcome the resistance mechanisms of traditional cancer treatments. Therefore, the relevant research progress of ferroptosis is of great significance for the treatment of tumors.
基金This work has been financially supported by the National Natural Science Foundation of China （Nos. 51372260, 51132009, and 81471714）, and the Shanghai Excellent Academic Leaders Program （No. 16XD1404000）. Thanks to Linlin Zhang, Heliang Yao, Qingfeng Xiao,Huaiyong Xing, Wenpei Fan, Zhaowen Cui, Li Jiang, and Jianan Liu from Shanghai Institute of Ceramics, Chinese Academy of Sciences for useful discussions.
文摘Disruption of mitochondrial reactive oxygen species （mitoROS） plays a major role in cancer cell apoptosis. Here, we designed a core/shell-structured mitochondriatargeting upconversion-based nano-photosensitizer （TPP-UC（PS）） with a lanthanidedoped upconversion nanoparticle （UCNP） core coated by a photosensitizer （PS）-incorporated dense silica shell. Following irradiation with external nearinfrared laser （NIR）, TPP-UC（PS） in mitochondria caused serious mitochondrial matrix swelling for the activated upconversion-based photodynamic therapy （UC-PDT）, and the mobilization of cytochrome c （cyt c） was amplified in response to the increased mitoROS. Specifically, this heme-containing cyt c could be monitored by varying TPP-UC（PS）＇s upconversion luminescence signal （UCL）, which may facilitate the in situ detection of cyt c for apoptosis research. As a proof of concept, our designed TPP-UC（PS） may provide significant opportunities for controlling cancer cell apoptosis under NIR stimulation and for studying apoptosis using the dynamic UCL, which is influenced by local cyt c.
