Salinomycin kills cancer stem cells by sequestering iron in lysosomes.
Salinomycin kills cancer stem cells by sequestering iron in lysosomes.
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DOI：
10.1038/nchem.2778
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发表时间：
2017-10
期刊：
影响因子：
21.8
通讯作者：
Rodriguez R
中科院分区：
文献类型：
--
作者：
Mai TT;Hamaï A;Hienzsch A;Cañeque T;Müller S;Wicinski J;Cabaud O;Leroy C;David A;Acevedo V;Ryo A;Ginestier C;Birnbaum D;Charafe-Jauffret E;Codogno P;Mehrpour M;Rodriguez R
肿瘤干细胞(CSCs)代表肿瘤内具有自我更新和肿瘤播种能力的细胞亚群。CSCs通常对传统治疗方法无效，并与转移和复发有关。盐霉素通过一种仍然难以捉摸的机制作为一种选择性药物来对抗CSCs。在这里，我们提供的证据表明，盐霉素的合成衍生物，我们命名为伊诺霉素(AM5)，在体外和体内对乳腺CSCs显示出更强的选择性活性，在溶酶体中积累和隔离铁。作为对随后细胞质中铁的耗尽的反应，细胞触发了溶酶体中铁蛋白的降解，导致该细胞器中进一步的铁负荷。铁介导的活性氧物种的产生促进了溶酶体膜的通透性，激活了与铁下垂一致的细胞死亡途径。这些发现揭示了铁在乳腺CSCs中的普遍存在，表明铁和铁介导的过程是针对这些细胞的潜在靶点。
Cancer stem cells (CSCs) represent a subset of cells within tumours that exhibit self-renewal and tumour seeding capacity. CSCs are typically refractory to conventional treatments and have been associated to metastasis and relapse. Salinomycin operates as a selective agent against CSCs through mechanisms that remain elusive. Here, we provide evidence that a synthetic derivative of salinomycin, which we named ironomycin (AM5), exhibits a more potent and selective activity against breast CSCs in vitro and in vivo, accumulates and sequesters iron in lysosomes. In response to the ensuing cytoplasmic depletion of iron, cells triggered the degradation of ferritin in lysosomes, leading to further iron loading in this organelle. Iron-mediated production of reactive oxygen species promoted lysosomal membrane permeabilization, activating a cell death pathway consistent with ferroptosis. These findings reveal the prevalence of iron homeostasis in breast CSCs, pointing towards iron and iron-mediated processes as potential targets against these cells.
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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：
--
作者：
Naujokat C;Steinhart R
通讯作者：
Steinhart R
影响因子：
4
作者：
Huang, Xiaoli;Borgstrom, Bjorn;Strand, Daniel
通讯作者：
Strand, Daniel
DOI：
10.1073/pnas.1110431108
发表时间：
2011-08-09
影响因子：
11.1
作者：
Lu, Desheng;Choi, Michael Y.;Carson, Dennis A.
通讯作者：
Carson, Dennis A.
影响因子：
8.4
作者：
Hirayama, Tasuku;Okuda, Kensuke;Nagasawa, Hideko
通讯作者：
Nagasawa, Hideko