Rationale: Colorectal cancer (CRC) is a common malignant tumor of the digestive system. However, the efficacy of surgery and chemotherapy is limited. Ferroptosis is an iron- and reactive oxygen species (ROS)-dependent form of regulated cell death (RCD) and plays a vital role in tumor suppression. Ferroptosis inducing agents have been studied extensively as a novel promising way to fight against therapy resistant cancers. The aim of this study is to investigate the mechanism of action of tagitinin C (TC), a natural product, as a novel ferroptosis inducer in tumor suppression./nMethods: The response of CRC cells to tagitinin C was assessed by cell viability assay, clonogenic assay, transwell migration assay, cell cycle assay and apoptosis assay. Molecular approaches including Western blot, RNA sequencing, quantitative real-time PCR and immunofluorescence were employed as well./nResults: Tagitinin C, a sesquiterpene lactone isolated from Tithonia diversifolia, inhibits the growth of colorectal cancer cells including HCT116 cells, and induced an oxidative cellular microenvironment resulting in ferroptosis of HCT116 cells. Tagitinin C-induced ferroptosis was accompanied with the attenuation of glutathione (GSH) levels and increased in lipid peroxidation. Mechanistically, tagitinin C induced endoplasmic reticulum (ER) stress and oxidative stress, thus activating nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2). As a downstream gene (effector) of Nrf2, heme oxygenase-1 (HO-1) expression increased significantly with the treatment of tagitinin C. Upregulated HO-1 led to the increase in the labile iron pool, which promoted lipid peroxidation, meanwhile tagitinin C showed synergistic anti-tumor effect together with erastin./nConclusion: In summary, we provided the evidence that tagitinin C induces ferroptosis in colorectal cancer cells and has synergistic effect together with erastin. Mechanistically, tagitinin C induces ferroptosis through ER stress-mediated activation of PERK-Nrf2-HO-1 signaling pathway. Tagitinin C, identified as a novel ferroptosis inducer, may be effective chemosensitizer that can expand the efficacy and range of chemotherapeutic agents.

中文翻译：

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Tagitinin C 通过 PERK-Nrf2-HO-1 信号通路诱导结直肠癌细胞铁死亡

理由：结直肠癌（CRC）是消化系统常见的恶性肿瘤。然而，手术和化疗的疗效是有限的。铁死亡是一种依赖铁和活性氧 (ROS) 的调节性细胞死亡 (RCD) 形式，在肿瘤抑制中起着至关重要的作用。铁死亡诱导剂已被广泛研究，作为对抗治疗耐药性癌症的一种新的有前途的方法。本研究旨在探讨天然产物tagitinin C (TC) 作为新型铁死亡诱导剂在肿瘤抑制中的作用机制。/n方法：通过细胞活力测定、克隆形成测定、transwell迁移测定、细胞周期测定和细胞凋亡测定评估CRC细胞对tagitinin C的反应。还采用了包括蛋白质印迹、RNA 测序、定量实时 PCR 和免疫荧光在内的分子方法。/n结果： Tatiginin C，一种从Tithonia diversifolia中分离的倍半萜内酯，抑制包括 HCT116 细胞在内的结直肠癌细胞的生长，并诱导氧化细胞微环境，导致 HCT116 细胞铁死亡。Tagitinin C 诱导的铁死亡伴随着谷胱甘肽（GSH）水平的降低和脂质过氧化的增加。机制上，tagitinin C 诱导内质网 (ER) 应激和氧化应激，从而激活核因子红细胞 2 相关因子 2 (Nrf2) 的核转位。作为Nrf2的下游基因（效应子），血红素加氧酶1（HO-1）的表达随着tagitinin C的处理而显着增加。上调HO-1导致不稳定铁池的增加，促进脂质过氧化，同时tagitinin C与erastin一起显示出协同抗肿瘤作用。/n结论：总之，我们提供的证据表明，tagitinin C 在结直肠癌细胞中诱导铁死亡，并与erastin 具有协同作用。从机制上讲，tagitinin C 通过 ER 应激介导的 PERK-Nrf2-HO-1 信号通路激活诱导铁死亡。Tagitinin C 被确定为一种新型的铁死亡诱导剂，可能是有效的化学增敏剂，可以扩大化学治疗剂的功效和范围。