Mitochondrial Breast Cancer Resistant Protein Sustains the Proliferation and Survival of Drug-Resistant Breast Cancer Cells by Regulating Intracellular Reactive Oxygen Species.
Mitochondrial Breast Cancer Resistant Protein Sustains the Proliferation and Survival of Drug-Resistant Breast Cancer Cells by Regulating Intracellular Reactive Oxygen Species.
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线粒体乳腺癌抗性蛋白通过调节细胞内活性氧维持耐药乳腺癌细胞的增殖和存活
DOI：
10.3389/fcell.2021.719209
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发表时间：
2021
影响因子：
5.5
通讯作者：
Zhang F
中科院分区：
文献类型：
--
作者：
Zhang H;Han X;Wang Z;Wang Z;Cui Y;Tian R;Zhu Y;Han B;Liu H;Zuo X;Ren S;Tian J;Niu R;Zhang F
atp结合盒（ABC）转运蛋白家族是乳腺癌细胞耐药建立的主要贡献者。乳腺癌耐药蛋白（Breast cancer resistant protein， BCRP）是ABC转运蛋白之一，长期以来被认为是治疗药物抗浓度梯度外排的泵。然而，最近的研究表明，BCRP的生物学功能并不局限于其药物泵活性。本研究旨在探讨BCRP在耐药乳腺癌细胞增殖和存活中的作用。我们发现BCRP不是表达多种ABC转运蛋白的耐药细胞外排表阿霉素的主要药物泵。在体外和体内实验中，沉默BCRP可显著抑制耐药细胞的增殖，诱导耐药细胞凋亡。rna测序和高通量蛋白质组学表明BCRP是氧化磷酸化（OXPHOS）的抑制因子。进一步研究表明，BCRP定位于耐药细胞的线粒体中。下调BCRP可提高细胞内活性氧水平，最终促进细胞凋亡。本研究表明，BCRP在耐药乳腺癌细胞中发挥重要的促癌功能，而不依赖于其众所周知的药物外排活性，这为理解ABC转运体在耐药细胞中的复杂功能作用提供了新的思路。
ATP-binding cassette (ABC) transporter family are major contributors to the drug resistance establishment of breast cancer cells. Breast cancer resistant protein (BCRP), one of the ABC transporters, has long been recognized as a pump that effluxes the therapeutic drugs against the concentration gradient. However, recent studies suggest that the biological function of BCRP is not limited in its drug pump activity. Herein, the role of BCRP in the proliferation and survival of drug-resistant breast cancer cells was investigated. We found that BCRP is not the major drug pump to efflux epirubicin in the resistant cells that express multiple ABC transporters. Silencing of BCRP significantly impairs cell proliferation and induces apoptosis of the resistant cells in vitro and in vivo. RNA-sequencing and high-throughput proteomics suggest that BCRP is an inhibitory factor of oxidative phosphorylation (OXPHOS). Further research suggests that BCRP is localized in the mitochondria of the resistant cells. Knockdown of BCRP elevated the intracellular reactive oxygen species level and eventually promotes the cell to undergo apoptosis. This study demonstrated that BCRP exerts important onco-promoting functions in the drug-resistant breast cancer cells independent of its well-recognized drug efflux activity, which shed new light on understanding the complex functional role of ABC transporters in drug-resistant cells.
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影响因子：
9.3
作者：
Okon IS;Zou MH
通讯作者：
Zou MH
DOI：
10.1186/s13046-015-0275-x
发表时间：
2015-12-30
期刊：
Journal of experimental & clinical cancer research : CR
影响因子：
--
作者：
Westover D;Li F
通讯作者：
Li F
影响因子：
64.5
作者：
Vyas S;Zaganjor E;Haigis MC
通讯作者：
Haigis MC
影响因子：
5.7
作者：
Singh A;Wu H;Zhang P;Happel C;Ma J;Biswal S
通讯作者：
Biswal S
影响因子：
2.1
作者：
Hlavac, Viktor;Brynychova, Veronika;Soucek, Pavel
通讯作者：
Soucek, Pavel