NFE2L2 and SLC25A39 drive cuproptosis resistance through GSH metabolism.

Autor: Liu J; DAMP Laboratory, The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, 510150, Guangdong, China. 2018683073@gzhmu.edu.cn., Tang H; DAMP Laboratory, The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, 510150, Guangdong, China., Chen F; DAMP Laboratory, The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, 510150, Guangdong, China., Li C; Department of Endoscopy Center, China-Japan Union Hospital of Jilin University, Changchun, 130033, Jilin, China., Xie Y; Department of Oncology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China., Kang R; Department of Surgery, UT Southwestern Medical Center, Dallas, TX, 75390, USA., Tang D; Department of Surgery, UT Southwestern Medical Center, Dallas, TX, 75390, USA. daolin.tang@utsouthwestern.edu.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2024 Nov 28; Vol. 14 (1), pp. 29579. Date of Electronic Publication: 2024 Nov 28.
DOI: 10.1038/s41598-024-81317-x
Abstrakt: Cuproptosis is a recently discovered form of regulated cell death triggered by mitochondrial copper accumulation and proteotoxic stress. Here, we provide the first evidence that glutathione (GSH), a major non-protein thiol in cells, acts as a cuproptosis inhibitor in pancreatic ductal adenocarcinoma (PDAC) cells. Mechanistically, GSH inhibits cuproptosis by chelating copper, contrasting its role in blocking ferroptosis by inhibiting lipid peroxidation. The classical cuproptosis inducer, ES-Cu (elesclomol plus copper), increases the protein stability of the transcription factor NFE2L2 (also known as NRF2), leading to the upregulation of gene expression of glutamate-cysteine ligase modifier subunit (GCLM) and glutamate-cysteine ligase catalytic subunit (GCLC). GCLM and GCLC are rate-limiting enzymes in GSH synthesis, and increased GSH is transported into mitochondria via the solute carrier family 25 member 39 (SLC25A39) transporter. Consequently, genetic inhibition of the NFE2L2-GSH-SLC25A39 pathway enhances cuproptosis-mediated tumor suppression in cell culture and in mouse tumor models. These findings not only reveal distinct mechanisms of GSH in inhibiting cuproptosis and ferroptosis, but also suggest a potential combination strategy to suppress PDAC tumor growth.
Competing Interests: Declarations. Competing interests: The authors declare no competing interests.
(© 2024. The Author(s).)
Databáze: MEDLINE
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