TXNRD1: A Key Regulator Involved in the Ferroptosis of CML Cells Induced by Cysteine Depletion In Vitro.
TXNRD1: A Key Regulator Involved in the Ferroptosis of CML Cells Induced by Cysteine Depletion In Vitro.
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DOI：
10.1155/2021/7674565
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发表时间：
2021
影响因子：
--
通讯作者：
Lin D
中科院分区：
文献类型：
--
作者：
Liu S;Wu W;Chen Q;Zheng Z;Jiang X;Xue Y;Lin D
半胱氨酸代谢对癌细胞的存活起着至关重要的作用。半胱氨酸耗竭被报道抑制肿瘤生长和诱导胰腺癌细胞铁下垂。然而，半胱氨酸耗竭在慢性粒细胞白血病(CML)中的作用仍有待探讨。在这项工作中，我们发现半胱氨酸耗竭可以诱导K562/G01细胞死亡，但不能以铁下垂的形式诱导K562细胞死亡。然而，半胱氨酸耗竭后，两株CML细胞的谷胱甘肽/谷胱甘肽过氧化物酶4途径均被阻断。这一意想不到的结果引导我们进行RNA-Seq来筛选影响CML细胞对半胱氨酸耗竭敏感性的关键基因。令人兴奋的是，半胱氨酸耗竭后，与细胞氧化还原代谢有关的硫氧还蛋白还原酶1(TXNRD1)在K562/G01细胞中显著上调。我们进一步推测，TXNRD1的酶活性降低是上调的负反馈。然后，我们应用TXNRD1shRNA和TXNRD1抑制剂Auranofin在半胱氨酸耗竭后的K562细胞中触发铁下垂。综上所述，我们有理由相信TXNRD1是参与体外半胱氨酸耗竭诱导的CML细胞铁性下垂的关键调节因子。这些发现突出了半胱氨酸耗竭作为克服化疗耐药慢性粒细胞白血病的潜在治疗策略。
Cysteine metabolism plays a critical role in cancer cell survival. Cysteine depletion was reported to inhibit tumor growth and induce pancreatic cancer cell ferroptosis. Nevertheless, the effect of cysteine depletion in chronic myeloid leukemia (CML) remains to be explored. In this work, we showed that cysteine depletion can induce K562/G01 but not K562 cell death in the form of ferroptosis. However, the glutathione (GSH)/glutathione peroxidase 4 (GPX4) pathways of the two CML cell lines were both blocked after cysteine depletion. This unexpected outcome guided us to perform RNA-Seq to screen the key genes that affect the sensitivity of CML cells to cysteine depletion. Excitingly, thioredoxin reductase 1 (TXNRD1), which related to cell redox metabolism, was significantly upregulated in K562/G01 cells after cysteine depletion. We further inferred that the upregulation is negatively feedback by the enzyme activity decrease of TXNRD1. Then, we triggered the ferroptosis by applying TXNRD1 shRNA and TXNRD1 inhibitor auranofin in K562 cells after cysteine depletion. In summary, we have reason to believe that TXNRD1 is a key regulator involved in the ferroptosis of CML cells induced by cysteine depletion in vitro. These findings highlight that cysteine depletion serves as a potential therapeutic strategy for overcoming chemotherapy resistance CML.
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DOI：
10.1126/science.aaw9872
发表时间：
2020-04-03
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Badgley MA;Kremer DM;Maurer HC;DelGiorno KE;Lee HJ;Purohit V;Sagalovskiy IR;Ma A;Kapilian J;Firl CEM;Decker AR;Sastra SA;Palermo CF;Andrade LR;Sajjakulnukit P;Zhang L;Tolstyka ZP;Hirschhorn T;Lamb C;Liu T;Gu W;Seeley ES;Stone E;Georgiou G;Manor U;Iuga A;Wahl GM;Stockwell BR;Lyssiotis CA;Olive KP
通讯作者：
Olive KP
影响因子：
--
作者：
Gao J;Zhang Z;Liu Y;Zhang Z;Wang M;Gong A;Xia L;Liao X;Wang D;Zhu H
通讯作者：
Zhu H
影响因子：
2.9
作者：
Ste Marie EJ;Wehrle RJ;Haupt DJ;Wood NB;van der Vliet A;Previs MJ;Masterson DS;Hondal RJ
通讯作者：
Hondal RJ
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：
82.9
作者：
通讯作者：
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