Targeting hypoxia-induced CBS expression inhibits breast cancer stem cells through the induction of ferroptosis.
Targeting hypoxia-induced CBS expression inhibits breast cancer stem cells through the induction of ferroptosis.
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DOI：
10.1016/j.gendis.2023.02.034
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发表时间：
2023-11
期刊：
影响因子：
6.8
通讯作者：
Lu, Haiquan
中科院分区：
文献类型：
--
作者：
Wei, Guangyao;Liu, Jia;Lan, Jie;Ji, Guangyu;Xia, Huize;Zhao, Zhiqun;Yu, Zhaoxue;Sun, Rong;Zhang, Chuanzhao;Lu, Haiquan
三阴性乳腺癌(TNBC)具有侵袭性和缺乏靶向治疗的特点，预后较差。1最近有报道称，TNBC对铁性下垂敏感，这是一种铁依赖的程序性细胞死亡，使其成为治疗TNBC的潜在靶点。2乳腺癌干细胞(BCSCs)是一小部分癌细胞，具有无限的增殖潜能和致癌特性，在肿瘤耐药中发挥重要作用。3BCSC对铁下垂诱导剂的反应存在争议，目前尚不清楚。肿瘤内缺氧(缺氧)是乳腺癌的常见特征，并通过依赖于缺氧诱导因子(HIF)的多条途径促进BCSC的维持和规范，HIF是O2稳态的主要调节因子。4我们首先研究了缺氧对TNBC细胞株MDA-MB-231、SUM159和Hs578T铁下垂的影响，分别用半胱氨酸转运蛋白XCT抑制剂erastin(ERA)或柳氮磺胺吡啶(SSA)在20%或1%氧气浓度下处理细胞48小时。这两种药物在20%氧气浓度下都能使三种TNBC细胞铁下垂的细胞存活率降低50%，但在1%氧气条件下不能诱导细胞铁下垂(图1A；图1)。S1a、B)。Erastin治疗增加了脂质过氧化，这是铁性下垂的一个标志，在20%的氧气下，但不是1%的氧气下(图1A)。敲除HIF-1α，而不是HIF-2α，使肿瘤细胞系对XCT抑制剂诱导的铁下垂和Erastin诱导的脂质过氧化重新敏感(图1B；图1)。S1C)，表明缺氧以HIF-1依赖的方式介导TNBC的铁下垂抵抗。
Triple-negative breast cancer (TNBC) has a poor prognosis because of its aggressive characteristics and lack of targeted therapies. 1 Recently, it has been reported that TNBC is sensitive to ferroptosis, an iron-dependent type of programmed cell death, making it a potential target for the treatment of TNBC. 2 Breast cancer stem cells (BCSCs), a small population of cancer cells that possess the infinite proliferative potential and tumor-initiating properties, play important roles in drug resistance. 3 The responses of BCSCs to ferroptosis-inducing agents are controversial and remain elusive.Intratumoral hypoxia (lack of oxygen) is a common feature of breast cancer and promotes BCSC maintenance and specification via multiple pathways dependent on hypoxia-inducible factors (HIFs), which are the master regulators of O 2 homeostasis. 4 We first investigated the effect of hypoxia on ferroptosis by treating TNBC cell lines MDA-MB-231, SUM159, and Hs578T with cystine transporter xCT inhibitor erastin (Era) or sulfasalazine (SSA) under 20% or 1% of oxygen concentration for 48 h. Both agents reduced cell viability by> 50% through ferroptosis in all three TNBC cell lines under 20% of oxygen but failed to induce ferroptosis under 1% of oxygen (Fig. 1 A; Fig. S1A, B). Erastin treatment increased lipid peroxidation, a hallmark of ferroptosis, 5 under 20% but not 1% of oxygen (Fig. 1 A). Knockdown of HIF-1α, but not HIF-2α, re-sensitized TNBC cell lines to xCT inhibitor-induced ferroptosis, and erastin-induced lipid peroxidation (Fig. 1 B; Fig. S1C), under 1% of oxygen, indicating that hypoxia mediates ferroptosis resistance in a HIF-1-dependent manner in TNBC.
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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
DOI：
10.1146/annurev-cancerbio-030518-055844
发表时间：
2019-01-01
期刊：
ANNUAL REVIEW OF CANCER BIOLOGY, VOL 3
影响因子：
--
作者：
Dixon, Scott J.;Stockwell, Brent R.
通讯作者：
Stockwell, Brent R.
影响因子：
5.6
作者：
Zheng Q;Zhang M;Zhou F;Zhang L;Meng X
通讯作者：
Meng X
DOI：
10.1016/j.bbamcr.2015.05.036
发表时间：
2016-03
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
Semenza GL
通讯作者：
Semenza GL