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Merck

Nedd4 ubiquitylates VDAC2/3 to suppress erastin-induced ferroptosis in melanoma.

Nature communications (2020-01-25)
Yongfei Yang, Meiying Luo, Kexin Zhang, Jun Zhang, Tongtong Gao, Douglas O' Connell, Fengping Yao, Changwen Mu, Bingyu Cai, Yuxue Shang, Wei Chen
์ดˆ๋ก

Ferroptosis is a newly defined form of regulated cell death characterized by the iron-dependent accumulation of lipid hydroperoxides. Erastin, the ferroptosis activator, binds to voltage-dependent anion channels VDAC2 and VDCA3, but treatment with erastin can result in the degradation of the channels. Here, the authors show that Nedd4 is induced following erastin treatment, which leads to the ubiquitination and subsequent degradation of the channels. Depletion of Nedd4 limits the protein degradation of VDAC2/3, which increases the sensitivity of cancer cells to erastin. By understanding the molecular mechanism of erastin-induced cellular resistance, we can discover how cells adapt to new molecules to maintain homeostasis. Furthermore, erastin-induced resistance mediated by FOXM1-Nedd4-VDAC2/3 negative feedback loop provides an initial framework for creating avenues to overcome the drug resistance of ferroptosis activators.

MATERIALS
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L-Glutathione reduced, โ‰ฅ98.0%
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Anti-HAโˆ’Peroxidase antibody, Mouse monoclonal, clone HA-7, purified from hybridoma cell culture
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Corn oil, delivery vehicle for fat-soluble compounds
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2-Vinylpyridine, 97%
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Glutathione Assay Kit, sufficient for 700 assays
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Deferoxamine mesylate salt, ≥92.5% (TLC), powder
Millipore
Glutathioneโˆ’Agarose, lyophilized powder
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Monoclonal ANTI-FLAGยฎ M2 antibody produced in mouse, clone M2, purified immunoglobulin (Purified IgG1 subclass), buffered aqueous solution (10 mM sodium phosphate, 150 mM NaCl, pH 7.4, containing 0.02% sodium azide)
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(Tyr[SO3H]27)Cholecystokinin fragment 26-33 Amide, โ‰ฅ97% (HPLC), powder
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Cell Counting Kit - 8, for quantitation of viable cell number in proliferation and cytotoxicity assays
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Anti-VDAC1 Antibody, clone N152B/23, clone N152B/23, from mouse
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Ciclopirox, ≥98% (HPLC)