Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan 750004, China.
Department of Clinical Pathology, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan 750004, China.
J Zhejiang Univ Sci B. 2022 Apr 15;23(4):286-299. doi: 10.1631/jzus.B2100748.
Breast cancer is one of the most malignant tumors and is associated with high mortality rates among women. polysaccharide (LBP) is an extract from the fruits of the traditional Chinese herb, . LBP is a promising anticancer drug, due to its high activity and low toxicity. Although it has anticancer properties, its mechanisms of action have not been fully established. Ferroptosis, which is a novel anticancer strategy, is a cell death mechanism that relies on iron-dependent lipid reactive oxygen species (ROS) accumulation. In this study, human breast cancer cells (Michigan Cancer Foundation-7 (MCF-7) and MD Anderson-Metastatic Breast-231 (MDA-MB-231)) were treated with LBP. LBP inhibited their viability and proliferation in association with high levels of ferroptosis. Therefore, we aimed to ascertain whether LBP reduced cell viability through ferroptosis. We found that the structure and function of mitochondria, lipid peroxidation, and expression of solute carrier family 7 member 11 (SLC7A11, also known as xCT, the light-chain subunit of cystine/glutamate antiporter system X) and glutathione peroxidase 4 (GPX4) were altered by LBP. Moreover, the ferroptosis inhibitor, Ferrostatin-1 (Fer-1), rescued LBP-induced ferroptosis-associated events including reduced cell viability and glutathione (GSH) production, accumulation of intracellular free divalent iron ions and malondialdehyde (MDA), and down-regulation of the expression of xCT and GPX4. Erastin (xCT inhibitor) and RSL3 (GPX4 inhibitor) inhibited the expression of xCT and GPX4, respectively, which was lower after the co-treatment of LBP with Erastin and RSL3. These results suggest that LBP effectively prevents breast cancer cell proliferation and promotes ferroptosis via the xCT/GPX4 pathway. Therefore, LBP exhibits novel anticancer properties by triggering ferroptosis, and may be a potential therapeutic option for breast cancer.
乳腺癌是最恶性的肿瘤之一，与女性死亡率高有关。多糖（LBP）是一种从传统中药果实中提取的物质。LBP 是一种有前途的抗癌药物，因为它具有高活性和低毒性。虽然它具有抗癌特性，但作用机制尚未完全确定。铁死亡是一种新的抗癌策略，是一种依赖铁的脂质活性氧（ROS）积累的细胞死亡机制。在这项研究中，用人乳腺癌细胞（密歇根癌症基金会-7（MCF-7）和 MD 安德森转移性乳腺-231（MDA-MB-231））用 LBP 处理。LBP 抑制其活力和增殖与高水平的铁死亡有关。因此，我们旨在确定 LBP 是否通过铁死亡降低细胞活力。我们发现 LBP 改变了线粒体的结构和功能、脂质过氧化以及溶质载体家族 7 成员 11（SLC7A11，也称为 xCT，胱氨酸/谷氨酸反向转运蛋白系统 X 的轻链亚基）和谷胱甘肽过氧化物酶 4（GPX4）的表达。此外，铁死亡抑制剂 Ferrostatin-1（Fer-1）挽救了 LBP 诱导的铁死亡相关事件，包括降低细胞活力和谷胱甘肽（GSH）产生、细胞内游离二价铁离子和丙二醛（MDA）积累以及 xCT 和 GPX4 的表达下调。Erastin（xCT 抑制剂）和 RSL3（GPX4 抑制剂）分别抑制 xCT 和 GPX4 的表达，在用 Erastin 和 RSL3 共同处理后表达水平更低。这些结果表明，LBP 通过 xCT/GPX4 途径有效预防乳腺癌细胞增殖并促进铁死亡。因此，LBP 通过触发铁死亡表现出新型抗癌特性，可能是治疗乳腺癌的潜在选择。
