NUPR1 inhibitor ZZW-115 induces ferroptosis in a mitochondria-dependent manner - Archive ouverte HAL Access content directly
Journal Articles Cell Death Discovery Year : 2021

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

Can Huang
Patricia Santofimia-Castaño
Xi Liu
  • Function : Author
Yi Xia
Célia Gotorbe
  • Function : Author
Jose Luis Neira
  • Function : Author
Daolin Tang
Jacques Pouyssegur
  • Function : Author
Juan Iovanna

Abstract

Abstract 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.

Dates and versions

hal-03536613 , version 1 (20-01-2022)

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Cite

Can Huang, Patricia Santofimia-Castaño, Xi Liu, Yi Xia, Ling Peng, et al.. NUPR1 inhibitor ZZW-115 induces ferroptosis in a mitochondria-dependent manner. Cell Death Discovery, 2021, 7 (1), pp.269. ⟨10.1038/s41420-021-00662-2⟩. ⟨hal-03536613⟩
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