Research Paper Volume 16, Issue 2 pp 1298—1317
α-Hederin promotes ferroptosis and reverses cisplatin chemoresistance in non-small cell lung cancer
- 1 Department of Radiology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310009, China
- 2 Huzhou Central Hospital, Affiliated Central Hospital Huzhou University, Huzhou 313000, China
- 3 School of Medicine, Huzhou Normal University, Huzhou 313000, China
- 4 Huzhou Hospital of Traditional Chinese Medicine, Zhejiang University of Traditional Chinese Medicine, Huzhou 313000, China
Received: July 11, 2023 Accepted: November 20, 2023 Published: January 18, 2024
https://doi.org/10.18632/aging.205408How to Cite
Copyright: © 2024 Han et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
Background: Cisplatin is a core chemotherapy regimen in non-small cell lung cancer (NSCLC). However, chemoresistance to cisplatin leads to a poor prognosis in NSCLC. α-Hederin is a natural compound extracted from Nigella sativa. The study aims to explore the effects of α-Hederin on cisplatin resistance in NSCLC.
Methods: NSCLC cisplatin-resistant cell lines A549/DPP and PC-9 were cultured to evaluate the efficacy of α-Hederin in the treatment of NSCLC in vitro and in vivo. Metabolomics and RNA-seq analysis were used to determine the potential mechanisms of action of α-Hederin.
Results: The results showed that α-Hederin inhibited cisplatin-resistant NSCLC cells proliferation and metastasis. Mice xenograft, orthotopic, and metastatic A549/DPP cell models also showed the anti-tumor effects of α-Hederin. The metabolomics and RNA-seq analysis results showed that α-Hederin activated DDIT3/ATF3 pathway and ferroptosis via silencing SLC7A11 and GPX4. Furthermore, α-Hederin enhanced the nuclear expression of EGR1. Bioinformatics and luciferase experiments confirmed that EGR1 binds to the miR-96-5p promoter region, inhibiting transcription. In addition, miR-96-5p directly suppressed the levels of DDIT3.
Conclusion: This study revealed that α-Hederin activated EGR1 nuclear translocation and directly repressed miR-96-5p. It also promoted DDIT3/ATF3-mediated ferroptosis and reversed cisplatin resistance in NSCLC.
Abbreviations
NSCLC: non-small cell lung cancer; Cis/DDP: cisplatin; MMC: mitomycin C; PTX: paclitaxel; DOX: doxorubicin; ROS: reactive oxygen species; FT: ferritin; TFR: transferrin receptor; GPX4: glutathione peroxidase 4; GSH: glutathione; DMSO: dimethyl sulfoxide; MRI: magnetic resonance imaging; PI: propidium iodide; NADPH: nicotinamide adenine dinucleotide phosphate; qRT-PCR: quantitative reverse transcription PCR; Fer-1: Ferrostatin-1; DDIT3: DNA Damage Inducible Transcript 3; ATF3: Activating Transcription Factor 3; LUSC: lung squamous cell carcinoma; LUAD: lung adenocarcinoma; WT: wild type; MU: mutant type; miR-mimic: miR-96-5p; miR-inhibitor: miR-96-5p; EGR1: Early Growth Response 1; miRNAs: MicroRNAs.