Huang Can, Santofimia-Castaño Patricia, Liu Xi, Xia Yi, Peng Ling, Gotorbe Célia, Neira Jose Luis, Tang Daolin, Pouyssegur Jacques, Iovanna Juan
Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes; Parc Scientifique et Technologique de Luminy, 163 Avenue de Luminy, 13288, Marseille, France.
Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School of Pharmaceutical Sciences, Chongqing University, No.55 Daxuecheng South Road, 401331, Chongqing, P. R. China.
Cell Death Discov. 2021 Oct 1;7(1):269. doi: 10.1038/s41420-021-00662-2.
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.
铁死亡是一种铁依赖性细胞死亡，其特征是氢过氧化物磷脂的积累。在此，我们报告NUPR1抑制剂ZZW-115诱导活性氧（ROS）积累，随后导致铁死亡性细胞死亡，而铁抑素-1（Fer-1）和ROS清除剂可预防这种情况。通过抑制胰腺导管腺癌（PDAC）和肝细胞癌（HCC）来源细胞中的抗氧化因子，可提高铁死亡活性。此外，ZZW-115处理会增加这些细胞中氢过氧化脂质的积累。我们还发现，ZZW-115处理后，参与谷胱甘肽（GSH）和谷胱甘肽过氧化物酶（GPX）依赖性抗氧化系统的关键酶活性丧失且受到强烈失调。这些结果在用ZZW-115处理的裸鼠中由PDAC和HCC来源细胞诱导的异种移植中得到了验证。更重要的是，我们证明ZZW-115诱导的线粒体形态变化与铁死亡过程一致，以及线粒体网络紊乱和强烈的线粒体代谢功能障碍，而Fer-1和N-乙酰半胱氨酸（NAC）均可挽救这些情况。值得注意的是，线粒体生物发生的关键调节因子TFAM的表达被ZZW-115下调。强制表达TFAM能够挽救由ZZW-115或NUPR1基因抑制诱导的线粒体形态和功能改变、ROS产生及细胞死亡。总之，这些结果表明，NUPR1抑制剂ZZW-115介导的线粒体细胞死亡可被Fer-1完全挽救，也可通过TFAM互补来挽救。总之，TFAM可被视为铁死亡性细胞死亡的拮抗剂。
