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P53: A Regulator of Ferroptosis Induced by Galectin-1 Derived Peptide 3 in MH7A Cells.

ABSTRACT: Backgrounds: Rheumatoid arthritis synovial fibroblasts (RASFs) are the primary cells responsible for destruction of marginal cartilage in rheumatoid arthritis (RA). G1dP3, a bioactive peptide derived from galectin-1 domain, possesses potent anti-inflammatory and anti-proliferation properties in RASFs. This study aimed to determine the effects of G1dP3 ferroptosis induction in RASFs and to further clarify the possible mechanisms. Methods: TNF-α was used to establish a RA model in MH7A cells. Cell Counting Kit-8 assays were employed to detect MH7A cell viability with different treatments. The occurrence of ferroptosis was examined by Lipid ROS assay, cellular labile iron pool measurement, reduced glutathione/oxidized glutathione activity, Gpx4 expression and transmission electron microscopy (TEM) morphology observation. Lentiviral-mediated siRNA interference was used to determine the downstream pathway. Results: G1dP3 markedly suppressed MH7A cell viability induced by TNF-α. G1dP3-treated MH7A cells presented the morphological features of ferroptosis. Moreover, G1dP3 triggered ferroptosis in MH7A cells by promoting the accumulation of lipid peroxides as well as iron deposition. Inhibition of ferroptosis alleviated G1dP3-mediated suppression of MH7A cell viability. Furthermore, G1dP3 increased p53 expression, which in turn transcriptionally suppressed SLC7A11, a key component of system X_c ^- essential for ferroptosis. Knockdown of p53 abrogated the ferroptotic effects of G1dP3 on MH7A cells. Conclusion: Our findings reveal that the bioactive peptide G1dP3 promotes RASFs ferroptosis cell death via a p53/SLC7A11 axis-dependent mechanism, suggesting its potential role in the treatment of RA.

SUBMITTER: Hu J

PROVIDER: S-EPMC9289366 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundExtranodal natural killer/T cell lymphoma (NKTCL) is a highly aggressive type of non-Hodgkin lymphoma that facing the treatment challenges. Natural compounds are important sources for drug development because of their diverse biological and chemical properties, among which terpenoids have strong anticancer activities.MethodsThe human NK/T cell lymphoma cell line YT and peripheral blood lymphocytes isolated from NKTCL patients were treated with different concentrations of kayadiol. Then, the following experiments were performed: CCK-8 assay for cell viability, reactive oxygen species (ROS) and glutathione (GSH) assay and co-treatment with NAC, reduced GSH, or ferrostatin-1 for ferroptosis, the proteome profiling for elucidating signaling pathways, and western blot for the expression of p53, SCL7A11, and GPX4. siRNA and CRISPR/Cas9 plasmid for p53 knockout was designed and transfected into YT cells to evaluate the causal role of p53 in kayadiol-induced ferroptosis. The synergistic effect was evaluated by CCK8 assay after co-treatment of kayadiol with L-asparaginase or cisplatin.ResultsIn this study, we found that kayadiol, a diterpenoid extracted from Torreya nucifera, exerted significant killing effect on NKTCL cells without killing the healthy lymphocytes. Subsequently, we observed that kayadiol treatment triggered significant ferroptosis events, including ROS accumulation and GSH depletion. ROS scavenger NAC, GSH, and ferroptosis inhibitor ferrostatin-1 (Fer-1) reversed kayadiol-induced cell death in NKTCL cells. Furthermore, kayadiol decreased the expression of SLC7A11 and GPX4, the negative regulatory proteins for ferroptosis. We then demonstrated that p53 was the key mediator of kayadiol-induced ferroptosis by SLC7A11/GPX4 axis through p53 knockout experiments. In addition, kayadiol exerted a synergistic effect with L-asparaginase and cisplatin in NKTCL cells.ConclusionTaken together, our results suggested that the natural product kayadiol exerted anticancer effects through p53-mediated ferroptosis in NK/T cell lymphoma cells. Hence, it can serve as an effective alternative in the treatment of NK/T cell lymphoma, especially for patients exhibiting chemoresistance.

Project description:Ferroptosis is a recently discovered form of programmed cell death, but its regulatory mechanisms are not fully understood. In the current study, we reported that the BRD7-P53-SLC25A28 axis played a crucial role in regulating ferroptosis in hepatic stellate cells (HSCs). Upon exposure to ferroptosis inducers, bromodomain-containing protein 7 (BRD7) protein expression was remarkably increased through the inhibition of the ubiquitin-proteasome pathway. CRISPR/Cas9-mediated BRD7 knockout conferred resistance to HSC ferroptosis, whereas specific BRD7 plasmid-mediated BRD7 overexpression facilitated HSC ferroptosis. Interestingly, the elevated BRD7 expression exhibited to promote p53 mitochondrial translocation via direct binding with p53 N-terminal transactivation domain (TAD), which may be the underlying mechanisms for BRD7-enhanced HSC ferroptosis. Site-directed mutations of serine 392 completely blocked the binding of BRD7 to p53, and, in turn, prevented p53 mitochondrial translocation and HSC ferroptosis. Importantly, mitochondrial p53 interacted with solute carrier family 25 member 28 (SLC25A28) to form complex and enhanced the activity of SLC25A28, which could lead to the abnormal accumulation of redox-active iron and hyperfunction of electron transfer chain (ETC). SLC25A28 knockdown impaired BRD7-or p53-mediated ferroptotic events. In mice, erastin treatment ameliorated pathological damage of liver fibrosis through inducing HSC ferroptosis. HSC-specific blockade of BRD7-P53-SLC25A28 axis could abrogate erastin-induced HSC ferroptosis. Of note, we analyzed the effect of sorafenib on HSC ferroptosis in advanced fibrotic patients with hepatocellular carcinoma receiving sorafenib monotherapy. Attractively, BRD7 upregulation, p53 mitochondrial translocation, combination of SLC25A28 and p53, and ferroptosis induction occurred in primary human HSCs. Overall, these findings reveal novel signal transduction and regulatory mechanism of ferroptosis, and also suggest BRD7-P53-SLC25A28 axis as potential targets for liver fibrosis.

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P53: A Regulator of Ferroptosis Induced by Galectin-1 Derived Peptide 3 in MH7A Cells.

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