Cystine and Methionine Deficiency Promotes Ferroptosis by Inducing B-Cell Translocation Gene 1
| Autor: | Il-Je Cho, Doyeon Kim, Eun-Ok Kim, Kyung-Hwan Jegal, Jae-Kwang Kim, Sang-Mi Park, Rongjie Zhao, Sung-Hwan Ki, Sang-Chan Kim, Sae-Kwang Ku |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: | |
| Zdroj: | Antioxidants, Vol 10, Iss 10, p 1543 (2021) |
| Druh dokumentu: | article |
| ISSN: | 10101543 2076-3921 |
| DOI: | 10.3390/antiox10101543 |
| Popis: | Ferroptosis is a type of programmed necrosis triggered by iron-dependent lipid peroxidation. We investigated the role of B-cell translocation gene 1 (BTG1) in cystine and methionine deficiency (CST/Met (−))-mediated cell death. CST/Met (−) depleted reduced and oxidized glutathione in hepatocyte-derived cells, increased prostaglandin-endoperoxide synthase 2 expression, and promoted reactive oxygen species accumulation and lipid peroxidation, as well as necrotic cell death. CST/Met (−)-mediated cell death and lipid peroxidation was specifically inhibited by pretreatment with ferroptosis inhibitors. In parallel with cell death, CST/Met (−) blocked global protein translation and increased the expression of genes associated with the integrated stress response. Moreover, CST/Met (−) significantly induced BTG1 expression. Using a BTG1 promoter-harboring reporter gene and siRNA, activating transcription factor 4 (ATF4) was identified as an essential transcription factor for CST/Met (−)-mediated BTG1 induction. Although knockout of BTG1 in human HAP1 cells did not affect the accumulation of reactive oxygen species induced by CST/Met (−), BTG1 knockout significantly decreased the induction of genes associated with the integrated stress response, and reduced lipid peroxidation and cell death in response to CST/Met (−). The results demonstrate that CST/Met (−) induces ferroptosis by activating ATF4-dependent BTG1 induction. |
| Databáze: | Directory of Open Access Journals |
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