期刊
INTERNATIONAL JOURNAL OF BIOLOGICAL SCIENCES
卷 17, 期 11, 页码 2703-2717出版社
IVYSPRING INT PUBL
DOI: 10.7150/ijbs.59404
关键词
ferroptosis; tagitinin C; ROS; ER stress; Nrf2-HO-1 pathway
资金
- National Natural Science Foundation of China [32000548, 82073740, 81703393, U1812403]
- Natural Science Foundation of Yunnan Province [202001AT070053, 202001AT070055]
- State Key Laboratory of Phytochemistry and Plant Resources in West China [P2018-ZZ05, P2019-ZZ06]
- State Key Laboratory of Phytochemistry and Plant Resources in West China
Colorectal cancer (CRC) is a common malignant tumor and traditional treatments have limited efficacy. Ferroptosis, a form of regulated cell death dependent on iron and reactive oxygen species (ROS), has been studied as a promising way to fight against resistant cancers. This study explored the mechanism of action of tagitinin C (TC), a natural product, as a novel ferroptosis inducer in CRC cells, showing that TC induces ferroptosis through ER stress-mediated activation of the PERK-Nrf2-HO-1 signaling pathway.
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. Methods: 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. Results: 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. Conclusion: 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.
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