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Research Achievement of Beijing Institute of Technology is Published Online on Nature Communications

release date :2020-04-08 03:47:00  |   [ close window ]ViewCount:

  Beijing Institute of Technology, April 8th, 2020: Cell death is of vital importance in different aspects of mammalian development, homeostasis and disease. Different forms of programmed cell death, such as apoptosis, cell necrosis, and autophagic cell death, have unique regulatory mechanisms. Ferroptosis is a new form of programmed cell death that has only been discovered in recent years. It is significantly different from other types of programmed cell death at the morphological, biochemical, and genetic levels. It has been proven that cellular ferroptosis is closely related to diseases such as renal failure, cardiovascular disease, neurodegenerative diseases, viral immunity, tumors, and diabetes, etc. However, at present, due to the insufficient scientific understanding of ferroptosis, especially the functional mechanism and molecular mechanism of the ferroptosis process in various diseases still need to be analyzed.

  Recently, the research team of Yang Yongfei from the School of Life Sciences of Beijing Institute of Technology and the research team of Chen Wei from the Academy of Military Medical Sciences published a research article titled Nedd4 ubiquitylates VDAC2/3 to suppress erastin-induced ferroptosis in melanoma in Nature Communications. The study revealed the molecular mechanism by which ubiquitinated ligase Nedd4 reduces the sensitivity of melanoma cells to the small molecule inducer elastin of ferroptosis by specifically recognizing and degrading mitochondrial channel protein VDAC2/3.

       Erastin is the first discovered small-molecule activator of ferroptosis which shows significant lethality in tumor cells carrying mutations in oncogenes HRAS, KRAS, and BRAF. Erastin can inhibit the glutamate/cystine reverse transporter systemXc- (xCT) on the cell membrane, reduce the intracellular cysteine content, leading to reduced GSH synthesis and lipid ROS aggregation, thereby inducing ferroptosis. The voltage-dependent anion channel (VDAC) regulating the entry and exit of large amounts of ions and metabolites between the cytoplasm and mitochondria is located on the outer mitochondrial membrane, thereby regulating various cellular processes, such as apoptosis, metabolism, and ion homeostasis, thus affecting many diseases. Erastin can not only induce ferroptosis of tumor cells, but also enhance the effects of chemotherapy, targeted therapy and immunotherapy of certain tumor cells. However, after 10 hours of erastin therapy, the expression level of VDAC2/3 in tumor cells decreased, and the sensitivity of tumor cells to erastin was reduced.

  The study found that erastin downregulates the expression of Nedd4 by activating the ROS-responsive transcription factor FOXM1 to activate neuronal precursor cell expression and development. Nedd4 is an important member of the E3 ligase family of the HECT domain of eukaryotes and remains conservative during evolution. Nedd4 binds to the PPxY sequence of VDAC2/3 through its WW domain and promotes the degradation of VDAC2/3, thereby reducing the sensitivity of cancer cells to erastin. In order to reduce the degradation of VDAC2/3 protein, by inhibiting the expression of Nedd4 and FOXM1, the sensitivity of cancer cells to elastin can be increased. This study illustrates a negative feedback loop based on FOXM1-Nedd4-VDAC2/3, revealing how tumor cells adapt to new small molecule drugs and maintain the molecular mechanism of intracellular homeostasis. It also indicates a new way to treat cancer with Nedd4 as a target therapy and cell ferroptosis.

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About the author:
       Luo Meiying, a 2017 doctoral student at the School of Life Sciences, Beijing Institute of Technology, has published 5 articles in SCI journals such as Nature Communications, Cell Death Differ, and Cell Signal, including 3 articles by the first author.
Zhang Kexin, a 2017 successive master-doctor program student at the School of Life Sciences, Beijing Institute of Technology, has published 5 articles in SCI journals such as Nature Communications, Cell Death Differ, and Cell Signal.

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