Bufalin通过调节2,4-二烯酰辅酶A还原酶（DECR1）-SLC7A11轴诱导铁死亡在乳腺癌中的作用

Bufalin induces ferroptosis by modulating the 2,4-dienoyl-CoA reductase (DECR1)-SLC7A11 axis in breast cancer

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PHYTOMEDICINE

影响因子:8.3

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

DOI: 10.1016/j.phymed.2024.156130

摘要

乳腺癌（BC）是全球癌症相关死亡的主要原因之一。作为β-氧化的辅助组分，2,4-二烯酰辅酶A还原酶（DECR1）已被证实在增强脂质过氧化和诱导前列腺癌中的铁死亡方面发挥作用，但其在乳腺癌中的研究尚不充分。本研究发现乳腺癌组织中DECR1表达明显升高，并与恶性程度增加相关。DECR1的过表达显著增强了MDA-MB-231细胞的增殖和迁移能力。通过高通量筛选，我们鉴定出Bufalin及其衍生物为DECR1的强效抑制剂。分子对接显示Bufalin具有最高的结合能，且能通过自噬和泛素化促进DECR1的降解。Bufalin还通过调节MDA、甘油三酯（TG）、活性氧（ROS）和Fe2+的水平，诱导MDA-谷胱甘肽过氧化酶4（GPX4）表达下降，激发铁死亡，同时抑制激素敏感脂肪酶（HSL）、铁蛋白重链蛋白（FPN）、SLC7A11和GPX4的表达。DECR1过表达可逆转这些作用。体内实验显示，Bufalin抑制肿瘤生长的同时，降低HSL、FPN、SLC7A11和GPX4的表达，增加4-羟基壬烯醛（4-HNE）水平。DECR1过表达亦能逆转Bufalin引起的铁死亡效应。进一步发现，SLC7A11与DECR1相互作用，抑制SLC7A11导致DECR1表达下降及MDA和Fe2+的积累，且此效应同样被DECR1过表达所逆转。综上所述，靶向DECR1联合抑制其下游的SLC7A11/GPX4通路，可能为乳腺癌的有效治疗策略提供新思路。

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.