Tryptophan Metabolism Acts as a New Anti-Ferroptotic Pathway to Mediate Tumor Growth.
Tryptophan Metabolism Acts as a New Anti-Ferroptotic Pathway to Mediate Tumor Growth.
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DOI：
10.1002/advs.202204006
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发表时间：
2023-03
期刊：
影响因子：
15.1
通讯作者：
Chu, Bo
中科院分区：
文献类型：
--
作者：
Liu, Dong;Liang, Chun-hui;Huang, Bin;Zhuang, Xiao;Cui, Weiwei;Yang, Li;Yang, Yinghong;Zhang, Yudan;Fu, Xiaolong;Zhang, Xiaoju;Du, Lutao;Gu, Wei;Wang, Xiangdong;Yin, Chengqian;Chai, Renjie;Chu, Bo
关键词：
新的证据表明，氨基酸代谢在铁链细胞死亡中起着重要作用。众所周知，蛋氨酸转化为半胱氨酸可以通过转氨基作用保护肿瘤细胞免受半胱氨酸饥饿引起的铁下垂的侵袭。然而，氨基酸产生的代谢物是否独立于半胱氨酸途径参与铁下垂尚不清楚。在这里，作者表明，色氨酸代谢产物5-羟色胺(5-HT)和3-羟基邻氨基苯甲酸(3-HA)显著促进肿瘤细胞逃避铁下垂，与半胱氨酸介导的铁下垂抑制不同。从机制上讲，5-羟色胺和3-HA都是有效的自由基捕获抗氧化剂(RTA)，可以消除脂质过氧化，从而抑制铁链细胞的死亡。单胺氧化酶A(MAOA)通过降解5-羟色胺而显著消除5-羟色胺的保护作用。MAOA的缺失使癌细胞在5-羟色胺治疗时对铁下垂产生抵抗。犬尿氨酸酶(KYNU)是3-HA产生所必需的，它使细胞抵抗铁性细胞死亡，而3-羟基邻氨基苯甲酸双加氧酶(HAAO)通过消耗3-HA显著阻断3-HA介导的铁下垂抑制。此外，HAAO的表达水平与脂质过氧化及临床转归呈正相关。综上所述，这些发现表明色氨酸代谢作为一种新的抗铁上链途径来促进肿瘤的生长，而靶向这一途径将是一种有前景的癌症治疗方法。色氨酸代谢产物5-羟色胺和3-羟基磷灰石在体外和体内都是有效的自由基捕捉抗氧化剂，可以抑制铁下垂。色氨酸代谢产物介导的铁下垂抑制是一种新的抗铁下垂途径，有别于半胱氨酸介导的铁下垂抑制或任何其他促进肿瘤发展的经典抗铁下垂途径。因此，靶向这一通路将是一种很有前途的癌症治疗方法。
Emerging evidence reveals that amino acid metabolism plays an important role in ferroptotic cell death. The conversion of methionine to cysteine is well known to protect tumour cells from ferroptosis upon cysteine starvation through transamination. However, whether amino acids‐produced metabolites participate in ferroptosis independent of the cysteine pathway is largely unknown. Here, the authors show that the tryptophan metabolites serotonin (5‐HT) and 3‐hydroxyanthranilic acid (3‐HA) remarkably facilitate tumour cells to escape from ferroptosis distinct from cysteine‐mediated ferroptosis inhibition. Mechanistically, both 5‐HT and 3‐HA act as potent radical trapping antioxidants (RTA) to eliminate lipid peroxidation, thereby inhibiting ferroptotic cell death. Monoamine oxidase A (MAOA) markedly abrogates the protective effect of 5‐HT via degrading 5‐HT. Deficiency of MAOA renders cancer cells resistant to ferroptosis upon 5‐HT treatment. Kynureninase (KYNU), which is essential for 3‐HA production, confers cells resistant to ferroptotic cell death, whereas 3‐hydroxyanthranilate 3,4‐dioxygenase (HAAO) significantly blocks 3‐HA mediated ferroptosis inhibition by consuming 3‐HA. In addition, the expression level of HAAO is positively correlated with lipid peroxidation and clinical outcome. Together, the findings demonstrate that tryptophan metabolism works as a new anti‐ferroptotic pathway to promote tumour growth, and targeting this pathway will be a promising therapeutic approach for cancer treatment. Tryptophan metabolites 5‐HT and 3‐HA act as potent radical trapping antioxidants to inhibit ferroptosis both in vitro and in vivo. Tryptophan metabolites‐mediated ferroptosis suppression is a new anti‐ferroptosis pathway distinct from cysteine‐mediated ferroptosis inhibition or any other classical anti‐ferroptotic pathways to facilitate tumor development. Therefore, targeting this pathway will be a promising therapeutic approach for 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：
14.8
作者：
Kagan VE;Mao G;Qu F;Angeli JP;Doll S;Croix CS;Dar HH;Liu B;Tyurin VA;Ritov VB;Kapralov AA;Amoscato AA;Jiang J;Anthonymuthu T;Mohammadyani D;Yang Q;Proneth B;Klein-Seetharaman J;Watkins S;Bahar I;Greenberger J;Mallampalli RK;Stockwell BR;Tyurina YY;Conrad M;Bayır H
通讯作者：
Bayır H
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：
20.8
作者：
Murphy, Michael P.;Bayir, Hulya;Belousov, Vsevolod;Chang, Christopher J.;Davies, Kelvin J. A.;Davies, Michael J.;Dick, Tobias P.;Finkel, Toren;Forman, Henry J.;Janssen-Heininger, Yvonne;Gems, David;Kagan, Valerian E.;Kalyanaraman, Balaraman;Larsson, Nils-Goran;Milne, Ginger L.;Nystrom, Thomas;Poulsen, Henrik E.;Radi, Rafael;Van Remmen, Holly;Schumacker, Paul T.;Thornalley, Paul J.;Toyokuni, Shinya;Winterbourn, Christine C.;Yin, Huiyong;Halliwell, Barry
通讯作者：
Halliwell, Barry
影响因子：
--
作者：
Ma H;Wang X;Zhang W;Li H;Zhao W;Sun J;Yang M
通讯作者：
Yang M