<br>冬凌草甲素通过调节氧化应激信号通路JNK/Nrf2/HO-1促进RSL3诱导的乳腺癌细胞铁死亡,European Journal of Pharmacology

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冬凌草甲素通过调节氧化应激信号通路JNK/Nrf2/HO-1促进RSL3诱导的乳腺癌细胞铁死亡
European Journal of Pharmacology ( IF 4.2 ) Pub Date : 2024-04-27 , DOI: 10.1016/j.ejphar.2024.176620
Shiying Ye ₁ , Xiangyan Hu ₁ , Shaowei Sun ₂ , Bo Su ₂ , Jiye Cai ₃ , Jinhuan Jiang ₂

Affiliation

乳腺癌作为全球女性最常见的恶性肿瘤，发病率和死亡率逐年上升，极大威胁女性健康。铁死亡是一种铁和脂质活性氧（ROS）依赖性过程，是一种不同于细胞凋亡的新型细胞死亡形式，与乳腺癌的进展密切相关。诱导肿瘤细胞发生铁死亡可有效阻断其恶性进展。冬凌草甲素 (ORI) 是从中草药中提取的主要活性成分，已被证明可引起谷胱甘肽耗竭，并直接抑制谷胱甘肽过氧化物酶 4 诱导的铁死亡引起的细胞死亡，但其在乳腺癌中的作用机制尚未充分阐明。因此，我们进一步研究ORI是否可以通过调节氧化应激通路JNK/Nrf2/HO-1来促进RSL3诱导的乳腺癌细胞铁死亡。在我们的研究中，我们通过MTT测定评估了RSL3和ORI处理的细胞存活率，并发现RSL3和ORI的共同处理抑制了细胞增殖，如克隆测定所证明的。为了研究 ORI 促进 RSL3 诱导的乳腺癌细胞铁死亡的能力，我们测量了 ROS、丙二醛、谷胱甘肽、超氧化物歧化酶和 Fe 含量的水平。 ORI与RSL3共处理诱导的脂质过氧化、ROS和线粒体膜电位水平被ferrostatin-1逆转，进一步证实RSL3和ORI诱导的细胞死亡是铁死亡而不是其他程序性细胞死亡模式。此外，蛋白质印迹和靶标激活剂验证表明，RSL3 和 ORI 联合治疗可调节 JNK/Nrf2/HO-1 轴。我们的结果表明，ORI 可以增强 RSL3 对乳腺癌细胞活力和铁死亡诱导的抑制作用。从机制上讲，它通过激活 JNK/Nrf2/HO-1 轴来增强 RSL3 诱导的乳腺癌细胞铁死亡。该研究为基于铁死亡机制的ORI应用提供了理论依据，并为癌症的预防和治疗提供了潜在的天然候选药物。

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Oridonin promotes RSL3-induced ferroptosis in breast cancer cells by regulating the oxidative stress signaling pathway JNK/Nrf2/HO-1

The incidence and mortality of breast cancer, the most common malignant tumor among women in the world, are increasing year by year, which greatly threatens women's health. Ferroptosis is an iron and lipid reactive oxygen species (ROS)-dependent process, a novel form of cell death that is distinct from apoptosis and is closely related to the progression of breast cancer. Inducing the occurrence of ferroptosis in tumor cells can effectively block its malignant progress . Oridonin (ORI), the primary active ingredient extracted from the Chinese herbal medicine , has been shown to cause glutathione depletion and directly inhibit glutathione peroxidase 4 induced cell death by ferroptosis, but its mechanism of action in breast cancer remains inadequately elucidated. Therefore, we further investigated whether ORI could promote RSL3-induced ferroptosis in breast cancer cells by regulating the oxidative stress pathway JNK/Nrf2/HO-1. In our study, we assessed cell survival of RSL3 and ORI treatment by MTT assay, and found that co-treatment with RSL3 and ORI inhibited cell proliferation, as evidenced by the cloning assay. To investigate the ability of ORI to promote RSL3-induced ferroptosis in breast cancer cells, we measured levels of ROS, malondialdehyde, glutathione, superoxide dismutase, and Fe content. Lipid peroxidation, ROS, and mitochondrial membrane potential levels induced by co-treatment of ORI with RSL3 were reversed by ferrostatin-1, further confirming that the cell death induced by RSL3 and ORI was ferroptosis rather than other programmed cell death modes. Moreover, RSL3 and ORI co-treatment regulated the JNK/Nrf2/HO-1 axis, as demonstrated by western blotting and target activator validation. Our results showed that ORI could enhance the inhibitory effect of RSL3 on breast cancer cells viability the induction of ferroptosis. Mechanistically, it potentiated RSL3-induced ferroptosis in breast cancer cells by activating the JNK/Nrf2/HO-1 axis. This study provides a theoretical basis for the application of ORI based on the mechanism of ferroptosis, and provides potential natural drug candidates for cancer prevention and treatment.

更新日期：2024-04-27

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