NUPR1 inhibitor ZZW-115 induces ferroptosis in a mitochondria-dependent manner

Ferroptosis is an iron-dependent cell death characterized by the accumulation of hydroperoxided phospholipids. Here, we report that the NUPR1 inhibitor ZZW-115 induces ROS accumulation followed by a ferroptotic cell death, which could be prevented by ferrostatin-1 (Fer-1) and ROS-scavenging agents....

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Published in:Cell death discovery 2021-10, Vol.7 (1), p.269-269, Article 269
Main Authors: Huang, Can, Santofimia-Castaño, Patricia, Liu, Xi, Xia, Yi, Peng, Ling, Gotorbe, Célia, Neira, Jose Luis, Tang, Daolin, Pouyssegur, Jacques, Iovanna, Juan
Format: Article
Language:English
Subjects:
631/67/1504/1713
692/699/67/2327
Acetylcysteine
Adenocarcinoma
Antioxidants
Apoptosis
Biochemistry
Biomedical and Life Sciences
Cell Biology
Cell Cycle Analysis
Cell death
Complementation
Ferroptosis
Hepatocellular carcinoma
Life Sciences
Lipids
Mitochondria
Morphology
Pancreas
Phospholipids
Stem Cells
Xenografts
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Summary:Ferroptosis is an iron-dependent cell death characterized by the accumulation of hydroperoxided phospholipids. Here, we report that the NUPR1 inhibitor ZZW-115 induces ROS accumulation followed by a ferroptotic cell death, which could be prevented by ferrostatin-1 (Fer-1) and ROS-scavenging agents. The ferroptotic activity can be improved by inhibiting antioxidant factors in pancreatic ductal adenocarcinoma (PDAC)- and hepatocellular carcinoma (HCC)-derived cells. In addition, ZZW-115-treatment increases the accumulation of hydroperoxided lipids in these cells. We also found that a loss of activity and strong deregulation of key enzymes involved in the GSH- and GPX-dependent antioxidant systems upon ZZW-115 treatment. These results have been validated in xenografts induced with PDAC- and HCC-derived cells in nude mice during the treatment with ZZW-115. More importantly, we demonstrate that ZZW-115-induced mitochondrial morphological changes, compatible with the ferroptotic process, as well as mitochondrial network disorganization and strong mitochondrial metabolic dysfunction, which are rescued by both Fer-1 and N-acetylcysteine (NAC). Of note, the expression of TFAM, a key regulator of mitochondrial biogenesis, is downregulated by ZZW-115. Forced expression of TFAM is able to rescue morphological and functional mitochondrial alterations, ROS production, and cell death induced by ZZW-115 or genetic inhibition of NUPR1. Altogether, these results demonstrate that the mitochondrial cell death mediated by NUPR1 inhibitor ZZW-115 is fully rescued by Fer-1 but also via TFAM complementation. In conclusion, TFAM could be considered as an antagonist of the ferroptotic cell death.
ISSN:2058-7716
2058-7716
DOI:10.1038/s41420-021-00662-2