DHODH-mediated ferroptosis defence is a targetable vulnerability in cancer.
DHODH-mediated ferroptosis defence is a targetable vulnerability in cancer.
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DOI：
10.1038/s41586-021-03539-7
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发表时间：
2021-05
期刊：
影响因子：
64.8
通讯作者：
Gan B
中科院分区：
文献类型：
--
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
铁下垂是一种由过度的脂质过氧化引起的调节性细胞死亡，近年来已成为一种关键的肿瘤抑制机制。谷胱甘肽过氧化物酶4(Gpx4)和铁下垂抑制蛋白1(FSP1)构成了两个主要的铁下垂防御系统。在这里，我们显示，在癌细胞中使用Gpx4抑制剂治疗会导致嘧啶生物合成中间体N-氨基甲酰-L-天冬氨酸(C-Asp)的急性耗竭，并伴随尿苷的积累。补充DHO脱氢酶(DHODH)的底物和产物二氢罗酸盐(DHO)或甲酸(OA)分别减轻或加强由Gpx4抑制引起的铁下垂，这些效应在Gpx4(GPX4low)低表达的癌细胞中尤为明显。DHODH失活诱导GPX4低癌细胞线粒体脂质过氧化和铁下垂，而DHODH失活与铁下垂诱导剂协同作用诱导GPX4高癌细胞线粒体脂质过氧化和铁下垂。机制上，DHODH与线粒体Gpx4(但不依赖细胞质Gpx4或FSP1)平行作用，通过将泛醌(CoQ)还原为具有抗铁下垂活性的自由基捕获抗氧化剂泛喹(CoQH2)来抑制线粒体内膜的铁下垂。我们进一步表明，脱氢表雄酮脱氢酶抑制剂brequina通过诱导铁下垂选择性地抑制GPX4低肿瘤生长，而与FDA批准的具有铁性下垂诱导活性的药物柳氮磺胺吡啶联合治疗，协同诱导铁下垂并抑制GPX4高肿瘤生长。我们的结果确定了DHODH介导的线粒体铁下垂防御机制，并提出了一种针对癌症治疗中铁下垂的治疗策略。
Ferroptosis, a form of regulated cell death induced by excessive lipid peroxidation, has recently emerged as a key tumor suppression mechanism. Glutathione peroxidase 4 (GPX4) and ferroptosis suppressor protein 1 (FSP1) constitute two major ferroptosis defense systems. Here we show that treatment with GPX4 inhibitors in cancer cells results in an acute depletion of N-carbamoyl-L-aspartate (C-Asp), a pyrimidine biosynthesis intermediate, with a concomitant accumulation of uridine. Supplementation of dihydroorotate (DHO) or orotate (OA), the substrate and product of DHO dehydrogenase (DHODH), attenuates or potentiates ferroptosis induced by GPX4 inhibition, respectively, and these effects are particularly pronounced in cancer cells with low expression of GPX4 (GPX4low). DHODH inactivation induces extensive mitochondrial lipid peroxidation and ferroptosis in GPX4low cancer cells, whereas DHODH inactivation synergizes with ferroptosis inducers to induce mitochondrial lipid peroxidation and ferroptosis in GPX4high cancer cells. Mechanistically, DHODH operates in parallel to mitochondrial GPX4 (but independent of cytosolic GPX4 or FSP1) to inhibit ferroptosis in the mitochondrial inner membrane, through reducing ubiquinone (CoQ) to ubiquinol (CoQH2), a radical-trapping antioxidant with anti-ferroptosis activity. We further show that the DHODH inhibitor brequinar selectively suppresses GPX4low tumor growth through inducing ferroptosis, whereas combined treatment with brequinar and sulfasalazine, an FDA-approved drug with ferroptosis inducing activity, synergistically induces ferroptosis and suppresses GPX4high tumor growth. Our results identify a DHODH-mediated ferroptosis defense mechanism in mitochondria and suggest a therapeutic strategy to target ferroptosis in cancer treatment.
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ACSL4 通过塑造细胞脂质成分来决定铁死亡敏感性。
影响因子：
14.8
作者：
Doll S;Proneth B;Tyurina YY;Panzilius E;Kobayashi S;Ingold I;Irmler M;Beckers J;Aichler M;Walch A;Prokisch H;Trümbach D;Mao G;Qu F;Bayir H;Füllekrug J;Scheel CH;Wurst W;Schick JA;Kagan VE;Angeli JP;Conrad M
通讯作者：
Conrad M
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：
64.5
作者：
Basu A;Bodycombe NE;Cheah JH;Price EV;Liu K;Schaefer GI;Ebright RY;Stewart ML;Ito D;Wang S;Bracha AL;Liefeld T;Wawer M;Gilbert JC;Wilson AJ;Stransky N;Kryukov GV;Dancik V;Barretina J;Garraway LA;Hon CS;Munoz B;Bittker JA;Stockwell BR;Khabele D;Stern AM;Clemons PA;Shamji AF;Schreiber SL
通讯作者：
Schreiber SL
影响因子：
8
作者：
通讯作者：
--
影响因子：
4.6
作者：
Heinrich, Paul;Kohler, Christian;Dettmer, Katja
通讯作者：
Dettmer, Katja