Tom20 senses iron-activated ROS signaling to promote melanoma cell pyroptosis

Autor: Kang Cheng, Dawang Zhou, Yuan-li Ai, Hang-zi Chen, Ru-yue Sun, Jiahuai Han, Jia-yuan Zhang, Bo Zhou, Xian-shuo Liu, Qiao Wu
Rok vydání: 2018
Předmět:
0301 basic medicine
Carbonyl Cyanide m-Chlorophenyl Hydrazone
Programmed cell death
Iron
Necroptosis
Cell
Mice
Nude
Antineoplastic Agents
Receptors
Cell Surface
Mitochondrion
Biology
medicine.disease_cause
Article
03 medical and health sciences
Cell Line
Tumor
Antineoplastic Combined Chemotherapy Protocols
Mitochondrial Precursor Protein Import Complex Proteins
Pyroptosis
medicine
Animals
Humans
Melanoma
Molecular Biology
bcl-2-Associated X Protein
Mice
Inbred BALB C
Caspase 3
Cytochromes c
Membrane Transport Proteins
Cell Biology
Xenograft Model Antitumor Assays
Mitochondria
Cell biology
HEK293 Cells
030104 developmental biology
medicine.anatomical_structure
Receptors
Estrogen
Apoptosis
Mitochondrial Membranes
Signal transduction
Reactive Oxygen Species
Oxidative stress
Signal Transduction
Zdroj: Cell Research
ISSN: 1748-7838
1001-0602
Popis: 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.
Databáze: OpenAIRE
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