Bufalin通过调节2,4-二烯酰基-COA还原酶（Depd1）-Slc7a11轴来诱导铁铁蛋白
Bufalin induces ferroptosis by modulating the 2,4-dienoyl-CoA reductase (DECR1)-SLC7A11 axis in breast cancer
影响因子:8.30000
分区:医学1区 Top / 药物化学1区 全科医学与补充医学1区 药学1区 植物科学1区
发表日期:2024 Dec
作者:
Shiqi Wu, Xuemin Wu, Qin Wang, Zhigang Chen, Li Li, Hongdan Chen, Hongyi Qi
摘要
乳腺癌（BC）是全球与癌症相关死亡率的主要原因。 2,4-二烯酰基-COA还原酶（Dept1）是β-氧化的辅助成分，因其在增强脂质过氧化和诱导前列腺癌中促脂毒中的作用而被认可。但是，它参与乳腺癌仍然没有探索。我们的研究表明，乳腺癌组织中降低1的表达显着升高，这与恶性特征的增加相关。重要的是，减少1的过表达显着增强了MDA-MB-231细胞中的增殖和迁移能力。通过全面的高含量筛选方法，我们确定了Bufalin及其衍生物是降低1表达的有效抑制剂。值得注意的是，Bufalin在分子对接研究过程中表现出最高的结合能，并发现通过自噬和泛素化促进降解1的降解。此外，Bufalin通过调节丙二醛（MDA），甘油三酸酯（TG），反应性氧（ROS）和Fe2+的水平，诱导MDA-MB-231细胞的螺旋病，同时下调了激素敏感性脂肪酶（HSL），fper蛋白蛋白1（FPN）1（FPN）的表达（FPN）1（FPN）。 （SLC7A11）和谷胱甘肽过氧化物酶4（GPX4）。这些效果通过减少1过表达来抵消。体内实验表明，Bufalin抑制了肿瘤的生长，同时降低了HSL，FPN，SLC7A11和GPX4的表达水平，同时4-羟基烯烯（4-HNE）的水平升高。至关重要的是，Bufalin在体内诱导的铁凋亡作用也通过降低1过表达逆转。随后，我们发现SLC7A11与降低1相互作用，SLC7A11的抑制导致降低1的表达水平降低，而MDA和Fe2+的积累，这些效应也会因降低1的过表达而逆转。总体而言，我们的发现表明，针对DESW1的靶向治疗与进一步抑制其涉及SLC7A11/GPX4的下游途径的进一步抑制可能是治疗乳腺癌的有希望的策略。
Abstract
Breast cancer (BC) is a leading cause of cancer-related mortality worldwide. 2,4-dienoyl-CoA reductase (DECR1), an auxiliary component of beta-oxidation, has been recognized for its role in enhancing lipid peroxidation and inducing ferroptosis in prostate cancer. However, its involvement in breast cancer remains largely unexplored. Our study revealed a notably elevated expression of DECR1 in breast cancer tissues, which correlated with increased malignant characteristics. Importantly, the overexpression of DECR1 significantly enhanced proliferation and migration capabilities in MDA-MB-231 cells. Through a comprehensive high-content screening approach, we identified bufalin and its derivative as potent inhibitors of DECR1 expression. Notably, bufalin demonstrated the highest binding energy during molecular docking studies and was found to promote the degradation of DECR1 via autophagy and ubiquitination. Furthermore, bufalin induced ferroptosis in MDA-MB-231 cells by modulating levels of malondialdehyde (MDA), triglycerides (TG), reactive oxygen species (ROS) and Fe2+ while downregulating the expression of hormone-sensitive lipase (HSL), ferritin heavy chain protein 1 (FPN), solute carrier family 7 member 11 (SLC7A11), and glutathione peroxidase 4 (GPX4). These effects were counteracted by DECR1 overexpression. In vivo experiments demonstrated that bufalin inhibited the tumor growth, while decreasing the expression levels of HSL, FPN, SLC7A11, and GPX4, alongside increasing levels of 4-hydroxynonenal (4-HNE). Crucially, the ferroptosis effects induced by bufalin in vivo were also reversed by DECR1 overexpression. Subsequently, we discovered that SLC7A11 interacts with DECR1, inhibition of SLC7A11 led to decreased expression levels of DECR1 along with an accumulation of MDA and Fe2+, effects that were similarly reversed by DECR1 overexpression. Collectively, our findings suggest that targeted therapy against DECR1 combined with further inhibition of its downstream pathway involving SLC7A11/GPX4 may represent a promising strategy for treating breast cancer.