Patients with triple negative breast cancer (TNBC) lack the estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2; thus, conventional hormone and targeted therapies have minimal effect on them. Therefore, clinical treatment of TNBC is still based on chemotherapy and supplemented by other methods. Doxorubicin (DOX), a common drug used in TNBC chemotherapy, has high affinity for cardiolipin, and the nematosomes are rich in cardiolipin; therefore, DOX has high mitochondria-targeting ability. DOX accumulates and plunders the electrons of nicotinamide adenine dinucleotide phosphate (NADPH) and cytochrome C in mitochondria to produce semiquinone DOX. Under the action of oxygen molecules, semiquinone DOX is reduced to DOX and reactive oxygen species (ROS) are generated. The accumulation of ROS can cause mitochondrial dysfunction and lead to mitochondrial dependent apoptosis. Bioinformatic analysis of samples from TNBC patients revealed that peroxiredoxin 1 (PRDX1) was highly expressed in TNBC tissues, and the poor prognosis of patients with high PRDX1 expression was considerably increased. Previous studies determined that DOX can upregulate the expression of the PRDX1 protein in the human TNBC cell line (MDA-MB-231). Thus, we speculate that PRDX1 plays an important role in the process of DOX-induced TNBC cell apoptosis. In this study, we aimed to explore the role of PRDX1 in the process of DOX-induced TNBC cell apoptosis. We found that PRDX1 deletion increased the sensitivity of MDA-MB-231 cells to DOX, which was mainly due to mitochondrial oxidative stress caused by intracellular ROS accumulation, leading to mitochondria-dependent apoptosis. Deletion of PRDX1 promotes the PI3K/Akt signaling pathway to mediate the expression of GSK3β. Gsk3β is an upstream signal of mitochondria-dependent apoptosis, and is also an important target of ROS. PRDX1 participates in adriamycin-induced apoptosis of TNBC cells by regulating the expression level of GSK3β. Our findings present new insights to treat breast cancer and TNBC, outlines the clinical use of DOX, and provides a basic theory to develop PRDX1 gene function.

中文翻译：

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过氧还蛋白 1 (PRDX1) 对阿霉素诱导的三阴性乳腺癌细胞凋亡的调节作用

三阴性乳腺癌（TNBC）患者缺乏雌激素受体、孕激素受体和人表皮生长因子受体2；因此，传统的激素和靶向治疗对他们的影响很小。因此，TNBC的临床治疗仍以化疗为主，其他方法为辅。多柔比星（DOX）是三阴乳腺癌化疗中常用的药物，对心磷脂具有高亲和力，线虫体内富含心磷脂；因此，DOX 具有较高的线粒体靶向能力。DOX 在线粒体中积累和掠夺烟酰胺腺嘌呤二核苷酸磷酸 (NADPH) 和细胞色素 C 的电子，从而产生半醌 DOX。在氧分子的作用下，半醌 DOX 被还原为 DOX 并产生活性氧（ROS）。ROS的积累可导致线粒体功能障碍并导致线粒体依赖性细胞凋亡。对 TNBC 患者样本的生物信息学分析显示，过氧化还原蛋白 1 (PRDX1) 在 TNBC 组织中高表达，PRDX1 高表达患者的不良预后显着增加。先前的研究确定 DOX 可以上调人 TNBC 细胞系 (MDA-MB-231) 中 PRDX1 蛋白的表达。因此，我们推测 PRDX1 在 DOX 诱导的 TNBC 细胞凋亡过程中起重要作用。本研究旨在探讨 PRDX1 在 DOX 诱导的 TNBC 细胞凋亡过程中的作用。我们发现 PRDX1 缺失增加了 MDA-MB-231 细胞对 DOX 的敏感性，这主要是由于细胞内 ROS 积累引起的线粒体氧化应激，导致线粒体依赖性细胞凋亡。PRDX1的缺失促进PI3K/Akt信号通路介导GSK3β的表达。Gsk3β是线粒体依赖性细胞凋亡的上游信号，也是ROS的重要靶点。PRDX1 通过调节 GSK3β 的表达水平参与阿霉素诱导的 TNBC 细胞凋亡。我们的研究结果为治疗乳腺癌和 TNBC 提供了新的见解，概述了 DOX 的临床应用，并为开发 PRDX1 基因功能提供了基本理论。