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.
Highlights
The concept of ferroptosis, an iron-dependent mode of cell death, characterized by the accumulation of lipid reactive oxygen species (ROS) was first proposed in 2012 [1]
This gene was found to be strongly related to ferroptosis by using an expression cloning or metabolic method developed to identify regulators that complement the loss of glutathione peroxidase 4 (GPX4) [8, 9]
We studied the mRNA levels by qRT-PCR analysis of nation with the collapse of the antioxidant defense system, GPX4 and key genes involved in ferroptosis, such as ferroptosis suppressor protein 1 (FSP1), which leading to combined cell death via apoptosis and ferroptosis. confers protection against ferroptosis elicited by GPX4 deletion
Summary
The concept of ferroptosis, an iron-dependent mode of cell death, characterized by the accumulation of lipid reactive oxygen species (ROS) was first proposed in 2012 [1]. Other laboratories have cell death, we performed experiments combining ZZW-115 with shown that genetic inactivation of NUPR1 stops the growth of several unrelated antioxidants agents and measured their survival Leads to an increased susceptibility to ROS accumulation, oxidative Treatments of cancer cells with siRNA directed against NUPR1 or stress, and ferroptosis [10].
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