Phenazine derivatives attenuate the stemness of breast cancer cells through triggering ferroptosis
Phenazine derivatives attenuate the stemness of breast cancer cells through triggering ferroptosis
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吩嗪衍生物通过引发铁死亡来减弱乳腺癌细胞的干性
DOI：
10.1007/s00018-022-04384-1
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发表时间：
2022-06
影响因子：
8
通讯作者：
Lufeng Zheng
中科院分区：
文献类型：
--
作者：
Yue Yang;Yuanyuan Lu;Chunhua Zhang;Qianqian Guo;Wenzhou Zhang;Ting Wang;Zhuolu Xia;Jing Liu;Xiangyu Cheng;Tao Xi;Feng Jiang;Lufeng Zheng
乳腺癌干细胞（BCSCs）与乳腺癌的转移、化疗耐药和复发呈正相关。然而，目前临床上还没有针对BCSCs的药物用于乳腺癌的治疗。在此，我们尝试从之前建立的非那嗪文库中筛选出靶向BCSCs的小分子化合物。我们专注于不影响细胞活力的化合物，并筛选出三种可能的化合物（CPUL119, CPUL129, CPUL149），它们可以显著减弱乳腺癌细胞的干性，这可以通过降低干性标志物表达，CD44+/CD24 -亚群，乳腺球体形成能力和肿瘤启动能力来证明。此外，这些化合物在体外和体内抑制乳腺癌细胞的转移能力。结合转录组测序分析，分别在CPUL119、CPUL129和CPUL149上调最多的通路顶部显示铁下垂。在机制上，我们发现这三种化合物可以通过与铁相互作用在溶酶体中积累和隔离铁，并通过调节参与铁运输和储存的蛋白质（IRP2, TfR1，铁蛋白）的表达来触发铁凋亡。此外，抑制铁下垂恢复了这三种化合物对乳腺癌细胞干细胞的抑制。本研究提示CPUL119、CPUL129和CPUL149可以通过触发铁下垂特异性抑制乳腺癌细胞的干性，可能是治疗乳腺癌的潜在化合物。
Breast cancer stem cells (BCSCs) are positively correlated with the metastasis, chemoresistance, and recurrence of breast cancer. However, there are still no drugs targeting BCSCs in clinical using for breast cancer treatment. Here, we tried to screen out small-molecule compounds targeting BCSCs from the phenazine library established by us before. We focused on the compounds without affecting cell viability and screened out three potential compounds (CPUL119, CPUL129, CPUL149) that can significantly attenuate the stemness of breast cancer cells, as evident by the decrease of stemness marker expression, CD44+/CD24– subpopulation, mammary spheroid-formation ability, and tumor-initiating capacity. Additionally, these compounds suppressed the metastatic ability of breast cancer cells in vitro and in vivo. Combined with the transcriptome sequencing analysis, ferroptosis was shown on the top of the most upregulated pathways by CPUL119, CPUL129, and CPUL149, respectively. Mechanistically, we found that these three compounds could trigger ferroptosis by accumulating and sequestering iron in lysosomes through interacting with iron, and by regulating the expression of proteins (IRP2, TfR1, ferritin) engaged in iron transport and storage. Furthermore, inhibition of ferroptosis rescued the suppression of these three compounds on breast cancer cell stemness. This study suggests that CPUL119, CPUL129, and CPUL149 can specifically inhibit the stemness of breast cancer cells through triggering ferroptosis and may be the potential compounds for breast cancer treatment.
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影响因子：
21.8
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
通讯作者：
Rodriguez R
影响因子：
7.3
作者：
Yang H;Kundra S;Chojnacki M;Liu K;Fuse MA;Abouelhassan Y;Kallifidas D;Zhang P;Huang G;Jin S;Ding Y;Luesch H;Rohde KH;Dunman PM;Lemos JA;Huigens RW 3rd
通讯作者：
Huigens RW 3rd
影响因子：
4.5
作者：
Jie Sun;Xiuqin Cheng;S. Pan;Liangjing Wang;Wenhuan Dou;Jie-Teng Liu;Xiaohua Shi
通讯作者：
Jie Sun;Xiuqin Cheng;S. Pan;Liangjing Wang;Wenhuan Dou;Jie-Teng Liu;Xiaohua Shi
影响因子：
3.3
作者：
Bajbouj, Khuloud;Shafarin, Jasmin;Hamad, Mawieh
通讯作者：
Hamad, Mawieh
影响因子：
3.1
作者：
BONKOVSKY, HL
通讯作者：
BONKOVSKY, HL