NUPR1 inhibitor ZZW-115 induces ferroptosis in a mitochondria-dependent manner.
NUPR1 inhibitor ZZW-115 induces ferroptosis in a mitochondria-dependent manner.
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DOI：
10.1038/s41420-021-00662-2
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发表时间：
2021-10-01
影响因子：
7
通讯作者：
Iovanna J
中科院分区：
文献类型：
--
作者：
Huang C;Santofimia-Castaño P;Liu X;Xia Y;Peng L;Gotorbe C;Neira JL;Tang D;Pouyssegur J;Iovanna J
铁凋亡是一种铁依赖性细胞死亡，其特征是过氧化氢磷脂的积累。在这里，我们报告说，NUPR 1抑制剂ZZW-115诱导ROS积累，然后是铁蛋白细胞死亡，这可以通过铁蛋白抑制素-1（Fer-1）和ROS清除剂来预防。通过抑制胰腺导管腺癌（PDAC）和肝细胞癌（HCC）衍生细胞中的抗氧化因子，可以提高促铁活性。此外，ZZW-115处理增加了这些细胞中过氧化氢脂质的积累。我们还发现，ZZW-115处理后，GSH和GPX依赖性抗氧化系统中的关键酶的活性丧失和强烈的失调。这些结果已经在用ZZW-115治疗期间在裸鼠中用PDAC-和HCC-衍生的细胞诱导的异种移植物中得到验证。更重要的是，我们证明了ZZW-115诱导的线粒体形态学变化，与铁凋亡过程，以及线粒体网络解体和强大的线粒体代谢功能障碍，这是由Fer-1和N-乙酰半胱氨酸（NAC）拯救。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。TFAM的强制表达能够挽救由ZZW-115或NUPR 1的遗传抑制诱导的形态和功能线粒体改变、ROS产生和细胞死亡。总之，这些结果表明，NUPR 1抑制剂ZZW-115介导的线粒体细胞死亡完全被Fer-1拯救，但也通过TFAM互补。因此，TFAM可被认为是铁凋亡细胞死亡的拮抗剂。
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.
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影响因子：
64.5
作者：
Dixon SJ;Lemberg KM;Lamprecht MR;Skouta R;Zaitsev EM;Gleason CE;Patel DN;Bauer AJ;Cantley AM;Yang WS;Morrison B 3rd;Stockwell BR
通讯作者：
Stockwell BR
影响因子：
9
作者：
通讯作者：
--
影响因子：
21.3
作者：
Friedmann Angeli JP;Schneider M;Proneth B;Tyurina YY;Tyurin VA;Hammond VJ;Herbach N;Aichler M;Walch A;Eggenhofer E;Basavarajappa D;Rådmark O;Kobayashi S;Seibt T;Beck H;Neff F;Esposito I;Wanke R;Förster H;Yefremova O;Heinrichmeyer M;Bornkamm GW;Geissler EK;Thomas SB;Stockwell BR;O'Donnell VB;Kagan VE;Schick JA;Conrad M
通讯作者：
Conrad M
影响因子：
64.8
作者：
Mao C;Liu X;Zhang Y;Lei G;Yan Y;Lee H;Koppula P;Wu S;Zhuang L;Fang B;Poyurovsky MV;Olszewski K;Gan B
通讯作者：
Gan B
影响因子：
15.9
作者：
Hamidi, Tewfik;Alguel, Hana;Iovanna, Juan Lucio
通讯作者：
Iovanna, Juan Lucio